The Peter Attia Drive - #171 - Steve Austad, Ph.D.: The landscape of longevity science: making sense of caloric restriction, biomarkers of aging, and possible geroprotective molecules

Episode Date: August 9, 2021

Steve Austad is a distinguished professor of biology at the University of Alabama and director of one of the Nathan Shock Centers of Excellence in aging biology. Steve's current research seeks to understand the underlying causes of aging, specifically with a long-term goal of developing medical interventions that slow the age-related decay of human health. In this episode, Steve tells Peter about his unusual childhood and stints as a cab driver and lion tamer. He goes on to describe what led to his focus on studying aging and some of the major challenges and limitations of working with laboratory animals. Steve and Peter talk about the relationship between caloric restriction and lifespan, including some of the most important studies exploring this question. Additionally, they hypothesize what might explain the sex-related differences in longevity between men and women, explain the importance of finding longevity biomarkers, and discuss the most promising molecules as potential longevity agents. We discuss: Steve’s background and unusual childhood [2:30]; Steve’s adventures driving a cab in New York City [9:00]; How Steve drove to LA and accidentally became a lion tamer [13:30]; How Steve’s early graduate school experiences led him to study longevity [23:00]; The challenges and limitations of working with lab mice [30:45]; The connection between caloric restriction and lifespan [43:00]; Mice vs. rats and rodent aging experiments [51:15]; The impact of dietary composition and the harm of sucrose: Comparing two caloric-restriction studies in monkeys [56:00]; Challenges of studying animals due to major differences in the lab animal vs. wild animals [1:10:00]; Human studies of calorie restriction [1:24:45]; Better dietary protocols for humans: Alternatives to long-term caloric restriction [1:33:45]; The protective effect of fasting [1:38:00]; Reflecting on the sex differences in human lifespan, and why women have more neurodegenerative diseases [1:45:45]; The importance of identifying longevity biomarkers and which ones show the potential to change the landscape of longevity research [2:03:30]; Molecules showing the most promise as longevity agents [2:14:00]; and More. Learn more: https://peterattiamd.com/ Show notes page for this episode: https://peterattiamd.com/SteveAustad Subscribe to receive exclusive subscriber-only content: https://peterattiamd.com/subscribe/ Sign up to receive Peter's email newsletter: https://peterattiamd.com/newsletter/ Connect with Peter on Facebook | Twitter | Instagram.  

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

now, head over to peteratiaMD.com forward slash subscribe. Now, without further delay, here's today's episode. I guess this week is Steve Ostead. Steve is a distinguished professor and chair of the Department of Biology at the University of Alabama, and he's the scientific director of the American Federation for Aging Research. He also directs the University of Alabama's Nathan Shock Center for Excellence in the Basic Biology of Aging, which is only one of six such centers in the United States. Steve's current research seeks to understand the underlying causes of aging, specifically, with a long-term goal of developing medical interventions that slow the age-related decay

in human health. Now, I've known Steve for probably about six or seven years, and in that period of time, I really do consider him to be one of my mentors in this space. Always generous and gracious with his insights and his time, his wisdom, and I was just really excited to have him on the show today. And we talk about his background, which is, as you'll see, very interesting and very unconventional. And we talk about kind of a history of one of the most important discoveries in aging, which is the relationship of caloric restriction and length of life, but also some of the limitations of this research. And we do a very good case study on what is unquestionably the most important experiment ever done on

caloric restriction and dietary restriction. We talk about the possible hypotheses for the sex-related differences that exist between men and women, and we talk about some of the most exciting and interesting, zero protective molecules out there, including rapamycin, metformin, and others. So without further delay, please enjoy my conversation with Steve Austin. Oh. Hey Steve, as we were just talking about a minute ago, this has been a long time coming. I am so excited about this discussion today.

Good, I'm looking forward to it myself. You're one of those people, and they're a handful of people like you where anytime we sit down, if it's over a coffee, a meal, or a short phone call, I feel like my learning increases at a geometric rate. So to now be able to do a very long discussion and then share it with so many people is going to be awesome. But frankly, any discussion about longevity, I think, needs to begin with your background. I think people need to understand the curious character that you are.

And your journey to where you are today is, you know, it's not common. But yet, I think it sort of speaks to the unique lens that you've brought to this space. So give folks a sense of what you did growing up. Like when you were in high school, what were you interested in? You know, it was interesting. And in high school, I was a math nerd. And everybody assumed that I was gonna be a mathematician

including myself. In fact, I was a math major when I first went to college. But what I really did in my spare time in high school when I wasn't playing sports is I like to kick around in the woods. And this was in Southern California, and I would actually go out into the desert. I actually had a high school biology teacher who would take students out in the desert to catch rattlesnakes. And I still am not sure why he was doing that. I think he was milking them and getting money for the venom or something. But anyway, I had a great time doing that. I think he was milking them and getting money for the venom or something.

But anyway, I had a great time doing that. And at that time, I think I was in 10th grade, he said, you're going to be a biologist. And I thought, that's the most ridiculous thing I've ever heard of. I know I'm going to be a mathematician. And then after I got to college, I suddenly discovered after the first year, I year and really like math all that much. And I wasn't about to spend four years doing something I didn't like. So what I really like to do was read. And so I switched to an English major.

And I actually ended up with an English degree. And my goal at that point was to write the great American novel and become, you know, the earnest Hemingway of the latter 20th century. And you went to UCLA for undergrad? Yes, I did. So that was really my job. But the one thing I did is I thought, well, to write novels, I've had a pretty traditional upbringing, middle class upbringing, except for the fact that my family traveled all over.

I went to 20 different grade schools, at least. I'm not sure how many really. We would live two months. My dad sold our house and bought a house trailer that we put behind the car and so for about six years, we would spend three months in this town, four months in that town. So, this wasn't because one of your parents was in the military? No, no. My dad was a newspaper pressman.

And his union had something called a traveling card, which meant that if you were a union member, you could go to any big city newspaper and be hired for some short amount of time. And so he must have just had a travel bug. I really regret that I never asked him, what were you thinking, Dad, when you did this? So that's where we went. We went, you know, El Paso, Dallas, Atlanta, Miami, Virginia, New York, Detroit.

That was my schooling, except doing all this traveling every year, I missed probably two months of school. But when we were traveling, my parents just threw these books at me in the back seat of the car and said, there, it's your study time. And so I learned a lot on my own. And that probably influenced somewhat who I am. Because that's a pretty unusual upbringing probably.

I can't imagine most kids could thrive in that setting because it's so disruptive. Like I actually had a patient once who went to 11 different schools between first and 12th grade. So averaged about a year per school. So at least they didn't have to move during the school year. But I always thought that that was just the social aspect of that, not to mention just the continuity. I mean, when you move from one state to a next, they may have different standards for what you're going to learn in English math or science. But what you

described takes that to a whole new level. Were you ever behind in school? Did you ever show up at the school that you were in and feel like you're out to lunch or was it the opposite? Did you generally feel like you were more than making up for it in the back seat? I felt like I was more than making up for it, but I also think the school systems in Southern California were particularly good at that time. So I usually had had in school a lot of the stuff that I would come across, particularly in the south, which is the first part of this journey where we travel through.

In fact, you know, I was probably made easier for me because I was an only child and I was used to being thrown on my own resources. But one of the things that I quickly figured out because I was always the smallest kid in class, even when I graduated from high school, I was, I was still 105 pounds and about five feet four. And I quickly learned though that I could avoid being beaten up by the bearer kids if I helped them with their homework. So I quickly fell into that and every school I went to, I was the guy that would help you figure out what was going on in math or history or whatever. And you're a normal size person. It's not like you're five foot seven today.

So what do you attribute such a late growth spurt to? Well, it's kind of interesting given the topic we're going to be talking about. But but I when I was in a sophomore in high school, I was still way behind. I was I was wrestler. I was wrestling in the 98 pound division, which is the lowest weight class, but I only weighed 79 pounds. And at some point, my parents took me to the doctor because they were concerned about delayed puberty and me being so small. And I got some sort of injections then. And I don't know if it was growth hormone. I don't know if it was testosterone, but almost immediately after that,

I started going through puberty, and then my real growth was after I got into college. It was very unusual, and I still think of myself as being little. Even though I know I'm normal size, I still think of myself as being small. That's interesting. I probably speak to the psychology

of our sort of formative years, right? Right. Exactly. I really would be curious to know if I got growth hormone when I got those injections or not. So like all good aspiring authors, you somehow lined up in New York. Right. Yeah, I figured that was a place to be if you were going to be a great novelist because

that's where all the publishing was. But the other thing that I figured was that if I'm going to rate a great novel, I don't have anything but a sort of typical middle-class experience because at the time I didn't realize how unusual my background was. So I went there but I decided I needed to start accumulating experiences. So I started having adventures, you know, I would hop a train from Southern California, the San Francisco and back. I got to New York by hitchhiking to New York, and later on,

I hitchhiked back to California again. And when I was in New York, I thought, well, where am I going to get experiences here? So I ended up driving a taxi New York, I thought, well, where am I going to get experiences here? So I ended up driving a taxi there because I thought, wow, this looks like you could really accumulate a lot of experiences in a hurry here. Which was true. How long did it take you to learn the city? I mean, New York is in some ways a pretty straightforward city to learn because it's on a beautiful grid.

But there's some nuance to it, given the one-way streets, and you've got Broadway as diagonal. It's not a trivial city to learn, especially given its size. How long did it take you to be a competent cabbie? Well, I was pretty competent right off because of the logical structure of it. But there are these parts of the city below 14th Street, for instance, that were amazing. Usually, what I would do to hide my ignorance is I would just ask the passenger, which way would you like me to take? And so then they would direct me. So I never really felt like I was lost there. And of course, if you got

to the outer burrows, it was a whole different ballgame. But I didn't go to the outer burrows very much. And when I did, I had to have help getting back because it was challenging. But it was a really unique experience. I drove at night, so I would go to work about four in the afternoon and come home about somewhere between midnight and 2am, depending on what the fairs were like.

And I mean, the experiences I had, I had people who, one person I remember well, wanted me to stop in every bar along the street. And we did this for a while, and he said, and he'd go in the bar, and he'd say, wait for me, and he'd come out, and we go to the next one. And I finally said, if you don't mind my asking, because I was afraid he was going to go into the bar and never come back, and I would be in debt for the taxi fare. He said, I'm looking for my wife, and when I find her, I'm going to shoot her. That's the point at which I said, okay, well, you can pay your fare now. That's a type of thing that happened to me more than a few times.

What years were this? These were in the mid 1970s. In New York, a totally different city from what it is today. Yes. Yes. Oh, in those days, you could get robbed in the daylight in Central Park. And now Central Park is just a wonderful place to go. What was the dodgyest part of the city south of 96th?

Probably the extreme west side, 9th and 10th, because there was a lot of abandoned buildings over there. The lighting wasn't good. And then of course, Harlem was not a great place. That's why I said south of 96. That was like, I took that as a given, yeah. I figured it was, but the interesting thing is a lot of cab drivers would not take Ferris to Harlem and I would. I would take somebody any place they wanted to go, but

I did have some dicey experiences there. I have to say, I never was robbed, but I, when the only taxi driver in this garage that I knew that was never robbed during that time, do you attribute that to pure luck or something else? Yeah, I do. The one time I was certain I was going to be robbed a police car turned to corner and pulled up behind me and couldn't get by because it was a narrow street. So the guys that I could just tell from the vibe, this is not going to be good. They just paid and got out and left.

So that was the closest that I had. Although I did pick up two taxi drivers who had been robbed and their cab had been hijacked and they were on the street and they waved me down. So yeah, I was pretty adventurous time. So where was it in here, Steve, that you also began a little side hustle training animals? Well, that was after my taxi driving years. I what

happened is that I moved back to Portland, Oregon. After all of the travel that my family did, we ended up in Portland, Oregon, where we kind of settled down. So I'd spent my first year six through 10th grades there. I really liked it. And after I got out of college, I went to Portland for a short time before I went to New York. So I went back to Portland and there I was taking karate. And my karate teacher had some African lions that is ranch out in the country. And I used to go out and visit him.

And if he was cleaning the cages, you know, he'd say, come on in. Let's talk while I'm working. And so I do that. And I guess I wasn't too obviously terrified because he got an offer to use the lions in a movie in a Hollywood. And he needed someone to help him drive the lions to Hollywood. So he asked me if I'd do that. And I had a job as a newspaper reporter at the time.

So I thought, well, this is going to be a long weekend. So I said, yeah, I'll help you do it. And I went out to his house and I assumed there was going to be like something like a horse trailer that was modified for Alliance. And what he said was, help me get the backseat out of the car here, Steve. And we're going to put Chirza, which is one of his lions in the back. So we did, we took out the car seat, we put the lion in the back seat, and we took off for LA. And there was nothing between, no screen, no window, nothing between the front

and the back seat. This is when you're wishing for the New York taxi with the Plexigas. Yeah, no kidding. Well, actually I wasn't worried at first because I thought it's his pet, he must know what he's doing. But you weren't worried about the fact that the pet's more familiar with him than you.

And if... No, I should have been. I should have been. But here's the weird thing is that he was driving initially. And the way he controlled this lion was with a cattle electric prod. And so he handed me this prod and it was... If you push the button, it buzzes. And he said the

lion's afraid of that. So if he gets restless, just stick that in his face. Don't touch him with it. Just stick it in his face and buzz it. That worked once and then the battery ran out. Then I said, what am I going to do now? He goes, well, just hold it in his face and go, bzzz with your mouth like that. And I thought, again, I thought, it's his lion.

He must know that his lion's that stupid. And it turned out, his lion wasn't that stupid. That worked once. And then the lion started to get really quite active. And then I realized my friend was scared. And that's when I got scared, because I thought he knows what. So we ended up pulling off on a side road in the middle of the night now,

getting his lion out on a long leash and walking it down this rural country road for several miles to try to get it tired out. I was driving the car so that he could be in the headlights and see where he was leading the lion and Every time we go around a corner in the lion would lose sight of the car We come around the corner of the lion would attack the car would jump up on the hood So I was expecting a catastrophe. I thought there's gonna be a farm and there's gonna be a dog and the dog's gonna run out and

But none of that happened so we put the lion in the back of the car, it was tired, it slept all the way until we got to the Bay Area when we had switched drivers, and suddenly the police lights came on behind me. And so the police went and pull us over, and I jumped out quickly to try to pretend this was just normal. But, you know, in the middle of the night, they'll shine their lights into the car ahead of

them so they can see what's going on. The lion is now getting up and it's pacing back and forth and I'm saying, oh, just bringing the lion down from Disney Studios in Washington. Very routine was I, sorry about that. And in the meantime, my friend who owns the lion is in the front seat, and he's trying to keep it from coming in the front seat. So you can see him, you know, trying to hit it with his elbow,

and then the lion goes over and steps on the car horn. And so the car horn just starts shrieking. So at this point the police went said, um, just get out of my jurisdiction. He didn't know how to deal with it. So we had a rather uneventful trip down to LA. At some point did you at least get a new battery for the taser? Once we got to LA we did. But by the time it was light we were close enough that the line was the sleep still. So we never did.

It was really pretty interesting. And my intention was, as soon as we delivered the lion to fly back to Portland and continue on with my life, but it turned out the movie producer offered me a job on the spot. And he said, we're doing this movie. We're going to have 25 lions in it. We need lots of lion trainers. I said, you don't understand. I have a job as a reporter.

This is the first time I've ever been in close contact with a lion. And frankly, it scared me to death. And he said, that, that's a worry about that. He says, I've got lots of professional training. Translation, you're the only one dumb enough to do this job. I can't find anybody in my union willing to do this, but yes, carry on.

Exactly, exactly. So I was still pretty dubious, I have to sell you, but here was the key. He said, well, the way you're gonna start is I'm raising some lions at my house. And so I'd like you to live at my house for the next few months and take care of the lions. And the only people that you'll have to deal with is my wife and my daughter, my wife

Tippy. And I had this crush on this actress named Tippy Hadron since I had seen her in the birds when I was a kid. And as soon as he said Tippy, I thought, gee, that's an unusual name. And it turns out he was married to Tippy Headron. So suddenly, I'm thinking of going and living in a house with an actress that I had a crush on since I was 11 years old. So that changed my attitude entirely. So I said, okay, you know, when do I start? I mean, at this point, Steve, you have more than enough substrate to write a fantastic novel, right?

Yeah. But by that time, I realized that that's not where my talent lay. So I really wasn't thinking anymore of writing a novel. I was trying to think, I loved animals so much. I thought, gosh, this is great. I get to spend my entire day around these animals. And actually, for the first year, I worked there. I never took a day off on Saturday and Sunday because I just enjoyed it so much. So I'd almost feel like I've been given this gift

of something that I was always meant to do, but by luck it had just stumbled into it. So what finally got you to go back to graduate school? Probably a bad encounter with a lion. I was fairly significantly injured by a lion and I spent a couple of weeks in the hospital and a couple of more months laid up with a lot of time. I jumped me, a lion attacked me under a very bizarre set of circumstances and there was no one around when

this happened so I was completely helpless, you know, pen to the ground by this lion expecting to it would start eating me at any point. And again, it's one of these lucky things. The only thing that saved me is it grabbed me and it sunk its teeth into my leg, but it was getting possessive over my leg because they get that way over food. They get, if you've ever seen a group of lions eating, they'll just get their food in front of them and grab onto it very tightly. And that's what it was doing.

And so I was just trying to stay conscious and not pass out because I thought then he's going to let go of my leg and start to eat me. And the only reason I'm here today is there were some people that were driving by on the road above the compound. And this was kind of a well-known place that people could pull off the road and they could look down and they might see lions running around or tigers. Where was this, Steve? This is in Acton, California, which is just north of Los Angeles, out in the desert, near Palmdale. And so they saw me with this lion on top of me, so they drove up to the front office and said there's a guy in the back with a lion on top of me, so they drove up to the front office and said, there's a guy in the back with a lion on top of him. We don't know if that's supposed to be that way

or not. And so they came and rescued me, you know, the other trainers that were in the office. So that gave me a lot of time to think about my future. And I really, by that time, was kind of disinterested in the Hollywood part of it. I still love the animals. But I really got bored with the movie aspect of it because there's a stereotype that movie people only talk about movies and make them movies and movie deals and movie sequels and movie reruns. And I didn't find that very interesting. And so I'd really gotten bored with that

part of it. So I thought, I've accumulated all this knowledge about animals that's applied. Maybe I should go to graduate school and study it in a formal sort of sense. So I actually went to graduate school with the intention of studying lions in East Africa. And I went to East Africa at that point. There was a long-running Serengeti Lion project that had just ended the people that were doing it. It just quit.

I went to graduate school, my advisor did research in East Africa on monkeys. And he told me, if you get over there, you might be able to take over this project. But I didn't. By the time I got there, someone else had come and taken it over, so it didn't work out. So I ended up doing a PhD that was a very combining my math and my interest in animal behavior. And I did a PhD on sort of theoretical models of animal combat and why animals very seldom fight to the death. And under what circumstances they might do that. So I have nothing really to do with lions.

At that point, I didn't really know. I thought, well, I've got a PhD. I guess I should be a professor somewhere, but I had no interest in aging and never even occurred to me. But I did a postdoc in South America at a biological station. Again, unrelated to aging, I was studying these social birds, but a friend of mine there was studying another group of animals, but he kept catching apostles and his traps. And at one point I said, you know, you're not able to catch the foxes

that you want to, you're catching the apostles, you're studying the wrong thing, you should be studying the apostles. So he said, well, what eventress could we do to the apostles? And we put our ants together and came up with something. It still had nothing to do with aging. But in the course of that project, I would capture apostles once a month and I would weigh them and measure them and look in the pouch, These were all females that were radiocolored. And one of the things I discovered was a age incredibly quickly. You know, so this is an animal that South American ones that we were studying look very much like the North American apostles. Most people would not be able to tell the difference.

So they're about the size of a small cat. And I expected they would live 10 or 20 years like cats do. And here at 18 months, they would get cataracts, they would lose muscle, they would be able to parasitize, they would just look terrible. Even the same animal that I caught three months earlier. And I just became incredibly intrigued with why they would age so much more quickly than a cat. And that really started my interest in aging. In fact, the project that he and I were working on eventually was published in one of the most prestigious scientific journals.

And by the time it came out, I completely lost interest. I was interested in aging. And I've been interested in it ever since. So that's kind of the long story about how I got into this. After you finish your post doc, where did you come back to? When I finished my first faculty position was at Harvard, and it was great because that was the point where I was switching over from what I had done before, which was behavioral evolution to aging.

And at Harvard, junior professors, they don't care what you do, really. So I had some time to really gear up and switch fields. It wasn't like I had to get six grants the first year or something. So it was great. So I basically spent some time developing my first aging study, which was a field study of opossums. And these were North American opossums, but I was comparing the way they aged on an island compared to the mainland. And I was interested in that because there were some theories of aging that suggested that

animals that had evolved in environments that were low risk, and this island had no predators on it, will evolve slow aging at the same time. So I ended up doing this project where I had a population of apostles on the mainland and another population on the island, and I would track them from birth to death, because one of the nice things about apostles is that because the babies are born in a pouch, if you catch the mother that's got babies in the pouch,

pouch young, you can mark them at that point, and then if you later catch them, you can put a radio collar on them. So you know the exact birth date, basically, of every animal in a population fairly quickly, which is pretty unusual for wild animals. That was really how my aging career got started at Harvard

and it was a great experience. It was a wonderful place to be. Unfortunately, my wife hated Boston. It was a wonderful place to be. Unfortunately, my wife hated Boston. And so she was really wanting us to go somewhere else. What did you find out about the apostles and what explained the difference? How much of a difference was there

between the groups that grew up in a low stress environment versus the high stress predatory environment? There was about a 20% difference, okay? So pretty substantial difference. And the next phase to figure this out was to try to work on the mechanism. What is it? And this was...

It was cortisol-related and... Right, exactly. This was in, this by now was in about 1990. And we did have genomics really at that point. If we did, the first thing I would have done is sequence the genome of the oposms on the island of the mainland. But the only thing I could think of to do next was to two things. One, I was interested, is this some genetic thing? Did you do a swap? In other words, did you take the island version and just let them breed, In other words, did you take the island version and just let them breed or, you know, because in one generation, you'd pretty much get your answer, right?

That's exactly right. And I submitted a proposal to do that and it didn't get funded. There was a problem. I could only really do it in one direction. I could take the island of possums and release them on the mainland and see how they did. I didn't want to do the reverse because I thought, if this is really a unique genetic population. Right, you don't want to contaminate it. Yeah.

So I never did that. It was the obvious thing to do. And I thought about it, but I never ended up doing it. And I sort of disappointed. What I did though is I got a population of apostles that I brought into the laboratory. And my plan was to start off with just some regular apostles, and then once I knew how to manipulate

apostles in the laboratory to co-get some from the island. But apostles are really not easy to keep in the laboratory environment, and my colony ended up getting some flesh-eating infection. And so I basically had to abandon that project. You know, I thought about going back to it subsequently. And in fact, I went back to the island, which is called Sappelo Island, which is off the coast of Georgia, about 10 years later with a film crew to do a film about them. And in the interim, a new species had been introduced

to the island. Armadillos had never been there before, and now they were there before. So I suddenly got worried that my population of apostles had also been contaminated. So that discouraged me from going back and working on the genomics of those apostles. So at what point did you start to get interested in the

difference between animals in the wild and animals in the lab as far as longevity differences? And of course where I'm going to go with this Steve is two directions just to give you a heads up. Obviously I want to have a really deep discussion on the largest longevity experiment ever done in animals, which is the Wisconsin NIA experiment, obviously, animals in captivity. And I also want to talk about the distinction

between mice in the wild and mice in the lab when it comes to all of the literature on CR and DR. Right. So it's really, I mean, and these are discussions you and I have had and every time we have it, it gets richer and richer. So I guess what I'm really asking at the outset is when did this subject matter become of great interest to you? Okay, so my background is entirely in field biology at the point when I start doing laboratory biology.

So I'm coming from it from a way different perspective than most people. And when I started to learn about the not just the mice but the other laboratory animals and how much different they were than the same species in the wild. I started to get very interested in what I call laboratory evolution. How have these things changed in the hundred years or so since they were brought into the laboratory? Because when I was in the field, I'm always thinking about, well, how is evolution shaping these animals to do whatever? was in the field, I'm always thinking about, well, how is evolution shaping these animals to do whatever? And in the laboratory, I'm thinking, well, the way that we breed them and the way that

we inadvertently select them, there's very strong evolutionary pressure on laboratory animals. It's just that most people aren't aware of that. So I started thinking, well, what can we learn? Is there anything to learn? And one of the things right off the bat was this dietary restriction experiment. Now, before we even get to it, Steve,

maybe we should explain to people what a laboratory mouse looks like. You know, when you think about the B6 mouse, which is sort of the workhorse of so much of the research that goes into cancer biology, I've had guests on this show before who have made a very compelling case that we simply should never use that mouse model for anything that comes down to cancer therapeutics because whatever you learn in it almost assuredly is not going to apply later on. But notwithstanding that, help folks understand what a mouse in captivity has been through. What does it mean, for example, to be homozygous at each low-sci? What is it that we're

trying to accomplish? And what's the price we potentially pay for that? Yeah, so let me describe the history of the laboratory mouse. So the laboratory mice came from of the laboratory mouse. So the laboratory mice came from what we're called fancy mice. And these were mice that were bred for bizarre coat colors and coat textures, kinky coats, straight coats, silver coats. And people used to have mouse beauty contests, just like the Westminster dog show. There used to be mouse equivalents. And for all that, there used to be mouse equivalents. For all that, there probably

still are mouse equivalents. So at some point, this is early in the 20th century when they just discovered the rediscovered the laws of genetics from Mendel, some geneticists got looking at all these bizarre coat colors and said, this could be a nice model for to see if mammal rules of inheritance are the same as plant rules of inheritance. So they started working with the mice for genetics and then for the for reasons of trying to understand the genetics He started in breeding them and when I say in breeding, I'm gonna talk about cousin breeding I'm talking about brother sister mating and they did that for now hundreds and hundreds of generations. So the mouse that we currently have in the lab, the typical mice, come from mice that were selected for bizarre coke colors and sizes, mice that were then imbred for hundreds of generations so that they're absolutely genetically

identical to one another. And then over the generations, of course, as we're raising these mice, every, you know, once they started being commercially valuable, the companies that produced them would always, the ones that left the most young were the ones that formed the next generation. So you're always getting this selection for bigger and bigger litters and faster growth and more rapid reproduction. So by now you have what a friend of mine calls a mouse-like object. Something that looks like a mouse, but it is, it's not only genetically identical to the other ones. It's now called a strain. So B6 is a strain.

It's not only genetically identical, but again, because of the inbreeding, it's homozygos at every locus that is, it has exactly the same two genetic variants at every single place in the genome. So that makes it very, very different from any kind, from humans, certainly, but from any animal in the wild. And I got very interested in how does that affect all of the experiments, not just in aging, but in cancer, in Alzheimer's disease.

I mean, we used that one mouse, and I used to say to people, this is like if we only test the drugs in the same set of twins time after time after time after time, rather than ever going out. So, I agree with the people you've had on your show that said we need to really avoid this kind of reliance on such a bizarre creature. I mean, it's about as bizarre a creature from a zoological perspective as you can imagine. They're twice as big as a wildmoss, at least twice

as big. They reach sexual maturity about twice as fast. They have much larger litters. They have a bunch of bizarre mutations. And some strains become blind in a few months of age. Some become death. Some of the here allowed noise start having convulsions. And this is the fundamental basis of our biomechanical research enterprise as it applies to mammals. So there's 4,500 species of mammals.

The fact that we've had one species and a very bizarre species at that, be the substitute for all of the others, including ourselves, is just a very weird approach. And to me, it just shows that the culture of evolutionary biology has never really soaked in to the laboratory biology. And I've kind of made it my goal to try to help with that over my career. Now, some people, of course, have gone to great lengths to avoid this. So I recently had Rich Miller on the podcast and we talked about the intervention testing program, the ITP. What is it that they do that raises the bar on on rigor? Right. So Rich Miller is a good friend of mine. We've done a bunch of projects together on on mice, on different kinds of mice. And what that ITP does is that they create

what are called genetically heterogeneous mice. that is every single mouse is genetically unique, but they're all brothers and sisters, so that you can recreate that population at any time, not the specific individual, but the population. Now, the interesting thing about those mice is that their ancestors are all these inbred mice. So, they've been selected for strange genetic alleles that only work seemingly when they're together with themselves. So, I'm a very big fan of that mouse model. I have to say, because I think it's a huge step in the right direction.

It's the least bad option, basically. Exactly. And there's one kind of weakness that I'd like to see them work on, and maybe they will. And that's this. Because of the breeding scheme that they use, all of them might have the same mitochondria.

No matter how genetically diverse they are, they all have the same mitochondria. No matter how genetically diverse they are, they all have the same mitochondria. And we now know that the mitochondrial genotype, because it interacts so closely with the nuclear genotype, can have a huge impact. And in fact, someone here at my university Scott Ballinger has created these mice that have different mitochondria in the same nuclear background.

And they have very different characteristics. The other thing is that because all of the current laboratory mouse came from a relatively small number of these fancy mouse ancestors, they all have pretty much the same mitochondria. The only differences are differences that have evolved slowly by drift over the last hundred years. So for instance, my friend that's got the nuclear mitochondrial exchange mice, his two mitochondria, which are very different by mouth standards, only different five individual nucleotides in the whole 16 and a half thousand nucleotide mitochondria.

How many genes is that again? Is that about 20 genes? Yeah, it's about 17 typical genes, but we're finding new genes. It's interesting, we're finding new genes in the mitochondria. So it's around 20 or 25 genes. So we may be missing out on a huge amount of variability that's due to mitochondria. And humans, of course, have incredibly variable mitochondrial genomes. Now, is it too late, Steve, to sort of say, look, we're going to go into the wild, get

a whole bunch of completely wild mice that are so genetically heterogeneous, and we're going to start letting them breed, and we're're not gonna force them to be in bread. We're just gonna let them breed naturally. Is that just too expensive? Or like why has no one gone about trying to address this? Cause it's such an obvious limitation. Right, well I think one of the reasons is the lack of genetic control that you would have

in that situation. There has been some attempt to do that. That is, people have been working on a genetically diverse population of mice where they took a whole number of the laboratory mouse strains and mixed in a couple of recent introductions from the wild and mixed them all together to create something. The problem isn't talking to those people. The wild backgrounds don't seem to breed as well in captivity. So gradually those genes are lost. But I think there are some reasonable alternatives that are out there that are being developed and have been recently developed. It's just that it's going to take a big change in the culture of the way we do laboratory medicine, I think, before

people will accept that. It probably comes back to a point you made earlier, which is for many people who work in the lab using laboratory mice, that's all they've known. And it might not be as apparent to them how genetically far removed they are from their predecessors, whereas because you came at this from being a field biologist, and also with a much greater lens for comparative gerontology, right? You're looking at this a possum and that a possum and these are both wild and yet they have some differences, but they're not totally different.

It may simply be a blind spot, right? Yeah, I think it is. And I think that even the best mouse is still a mouse. It's still one species. And it's a very different species than we are. And so even the best mouse model is not going to be enough. We need to know more about general mammalian biology if we're going to understand our own biology better. Well, before we leave the mouse, let's let's talk a little bit about Clive McKay and

kind of the the history of caloric restriction. I think most people today are generally well aware of the reported efficacy of caloric restriction in life extension. There are no shortage of people that are now looking at ways to mimic caloric restriction, be it pharmacologically with molecules, or be it using dietary interventions that sort of act like transient periods

of caloric restriction, all in search of what we believe CR does. But let's maybe have you explain to people what this history looks like. Sure. Well, the first person to really do this in a formal way was, as you mentioned, Clive McKay, who was a nutritionist at Cornell at the time. He was an interested in aging either.

He was interested in growth and how to make animals grow faster, because that has all kinds of agricultural implications. When studying growth, he was looking at the effect of restricting the diet on growth rate. When he did that, he noticed that his animals seemed to be staying healthy longer and living longer when he fed them less. And he did this in fish, he did some stuff in dogs, although he didn't look all the way through their lifespan. And then he finally did this experiment in rats.

And that one, he'd let them live their entire lives and documented very convincingly how dietary restriction made. In this case, only females, not males, live longer. And the interesting thing about McKay is that about a decade ago, I was a visiting scholar in Ithaca, New York for a week and I went to the Cornell libraries and I looked through all of his old papers and I don't think he ever really appreciated the significance of what he'd done because he didn't really follow up on that. This was in the 1930s if I recall.

Yeah, this was in the 1930s and he was active until the 1960s, but he got into producing a high protein bread and making nutritional food for the military during World War II. He really kind of dropped this whole thing. Even though he made what in retrospect was really, I think, a landmark discovery. I don't think he really appreciated that because he was never focused really on longevity. So what are the ways in which this got validated and repeated throughout time? Who was the next person to pick up that baton?

You know, I'm not exactly sure who the next person was. There were a whole bunch of people starting really after World War II that started looking at it more closely in rats and more closely in mice. And there were actually a whole bunch of people working on invertebrates that did this experiment by accident. And I'm one of them actually. The first paper I published on this topic was some stuff that I did during my PhD.

So my PhD was testing all these mathematical models about combat, but I was testing it in a small spider. And as part of that experiment, I had groups of spiders that I was feeding various amounts, and I would keep them until they died, but I wasn't paying any attention to that. Once I discovered all of this work, I went back to my data and I said, well, wonder what happened when I fed him less. And it turned out the less I fed him,

the longer they lived. And so after World War II, people really started getting interested in this. And there were a number of people, there were mouse studies now, rat studies. There was really, I think the next big advance was when Roy Wallford got into it, who was very interested, not just in how my sage, but how that might tell him something about human aging and Ed Maserot, another researcher who followed up on rats.

And those two, I think, really jumped it to the next level, which is, can we understand why this is happening? There was really very little investigation of that previously, but Walford, who was an immunologist, was very convinced that was doing something to the immune system, and that was at the base of it. And Maserot was, didn't really have his own hypotheses, but he thought that it was a great way to test hypotheses

about how aging worked. The other big difference between these really fascinating characters, I mean, Walford, what probably one most interesting colorful person at all. You must have known him because he only died, died what maybe 20 years ago, 25 years ago? Oh, yeah. In fact, my first paper, he published the figure out of my spider paper before it was published in a real journal because he had heard about my work. And he asked that I'm writing a book. Can I put this figure in my book?

Oh, yeah. I knew Roy quite well. He was. Of course, he's famous for the bio-dom, right? Yeah, the biosphere, too. A biosphere, yeah, yeah. Yeah. And it's pretty interesting when I was writing my book on, you know, so the biosphere

too was this inadvertent experiment on dietary restriction because these people were sealed in this dome and they couldn't grow as much food as they thought. And Roy was the doctor in there. And so this is a great opportunity. You know, he wanted to know how dietary restrictions worked in people. And here he had all these people that couldn't make enough, anyway. How long were they in the biosphere?

Two years. And when you look at pictures of him when he came out I mean he looked pretty emaciated. Oh, he looked horrible. He looked absolutely horrible in fact They have this famous picture of them all standing on the rafters in the biosphere when they went in naked and they had the same picture that Roy showed at a meeting when they came out and you've seen pictures of him. He looks like he just emerged from a concentration camp, right? Well I wanted to use, and they all look like that.

I wanted to use that picture before and after in my book on aging. And so I asked Roy about that and he said, I'd love to give you that picture, but everything's tied up in litigation. It turned out that the people in that experiment had become enemies, and everybody was suing everybody else over everything having to do with the biosphere. So psychologically, that wasn't such a great success. People would disagree about whether it was a success

scientifically or not. Roy thought it, he looked at it in one way, that it proved everything that he had seen in mice was true in people. Other people were looking at it and say, oh my gosh, I don't know how you felt, but you just looked terrible. And then he died.

Yeah, he died, yeah. Right, I mean. Yeah, well, he was at that, I think he was 79 or something, but he was always, he was always one of these people that if you knew his age, you'd say, man, that guy looks 20 years younger than he is. But after he came out of the biosphere, he didn't look like that anymore. Now, the other thing to be fair that happened in the biosphere

is that the atmosphere got really out of whack. When they ended up without realizing it, they had so little oxygen, they were living at the equivalent of about 17,000 feet. Yeah, and they'd been doing that for they didn't know how long. Eventually, so they had to refresh the air and the environment. And he attributed his later health problems to that, not to the dietary restriction. Which is certainly plausible, I mean, we'll never know, but yeah, to spend some portion of two years at Everest Base Camp, if you haven't grown up there,

it's one thing if you're a Sherpa, right? But it's another thing, if you've spent your whole life at sea level. So going back to the sort of CR insights, sorry, before I do that, what can you tell us about rats versus mice in terms of the genetic diversity and the ability to glean insights that are perhaps more or less interesting? Rats are a lot different to the extent that, as I say, almost all of the traditional laboratory mice strains came from this small handful of weird ancestors.

Rats have a different history. They were used earlier in biomedical research, actually, but they've been domesticated multiple times in multiple parts of the world. So if you look at all the genetic diversity and the mitochondrial diversity that you have in rats is far greater than you have in mice. And so I'm actually working with some other people now trying to bring the rat back more into aging research because we discovered how to manipulate the genes of mice a lot earlier

than we discovered anything else. So they kind of took over. That's really why almost all the focus is now on that one species. We now can do these genetic manipulations in other species just as easily. And I'd like to see something like the rats, for instance, we're working on a rat, which at the two mitochondria were interested in instead of different only at five of these nucleotides or DNA letters, differ at a hundred of them. So that's much more similar to the kind of

genetic diversity that you find in people's mitochondrial genomes rather than rats. So I'm hoping in the next few years I would like to see something like like Rich Miller's intervention testing program in rats as well because I think I'd have a lot more confidence that something we found in mice might have relevance to people if we found the same thing in rats. You know it's not the ideal comparison, but considering because rats and mice are reasonably closely related, they're kind of like we are to a recessed macaque about that degree of divergence. But still, they're very different. We also can do a lot more sophisticated cognitive studies with rats than we can with mice. They're trainable.

cognitive studies with rats that we can with mice. They're trainable, you know. And so I'm hoping that over the next few years we can make an impact and bring the rats back because we might learn something differently. You know, right now one of the most robust findings in mice is that if you somehow disable growth hormone activity, the mice stay healthy and live a lot longer, there's only been one experiment doing that in rats and it came to a very different conclusion. It's kind of like the two primate, calorie restriction studies, but again, it's one study against the gazillion studies

over here, but I'd like to really look at, are we getting a bias picture of something like growth hormone because we only really know a lot about its mechanism in mice. What is your best explanation for why the rats, given growth hormone, fared better? They fared worse. They didn't live any longer. I don't know. No, but they fared better than the fared worse. They didn't live any longer. I don't know. No, but they fared better than the mice, didn't they?

Oh, so we're talking about two different things here. So if you compare dozens and dozens of mouse studies and you look at how much life extension there was with dietary restriction, you look at a whole bunch of rats studies, you're right. The effect is bigger in rats. And growth hormone is suppressed by dietary restriction. The experiment I was talking about was one where they had taken a natural genetic mutation that disabled growth hormone in the rats.

And that didn't live longer, like the same natural mutations occurred in mice. Now why does the effect bigger in rats than mice? That's a good question. I don't think we know why and I also don't know how far to push that comparison because there's been a lot fewer rat studies done. We've done mouse studies with a much greater diversity of mice. And so if you look at the biggest effect that we've ever seen in a mouse and the biggest effect we've ever seen in a rat, those are not that different.

So I think it's a little bit premature to conclude that dietary restriction works better in rats generally than it does in mice. That may be true, but I just don't think we know enough yet. Speaking of course about big experiments with DR and CR, we have to look no further than, I mean, they have to be the largest experiments done the Wisconsin NIA experiment, correct? Yes, I mean, certainly the most expensive aging experiments

that have been done, that haven't been done in people. Yeah, so gosh, this experiment was probably kicked off in the late 80s? Yeah, exactly. Yeah. Tell folks about the experimental design. Yeah, so it was almost serendipitous that they they'd started at the so two groups, one at the National Institute of Aging, one at the University of Wisconsin, and one person, Rick Windrick, had actually was involved in both. He was at the NIA when that project got started, then he moved to the University of Wisconsin.

And the idea was to see whether the results that we saw in these laboratory rodents could be replicated in something that was a lot closer related to humans. And also something that hadn't gone through these bizarre laboratory imbreeding selection and all that stuff, closer to a real animal, in other words. And of course, these things live up to 40 years. Actually many people don't know, but there was another study started at the same time on squirrel monkeys because they were only supposed to live 25 years, and they thought they could do that quicker. But it turned out squirrel monkeys were unusual.

You could restrict their diet, but they didn't lose weight. So they ended up abandoning that study. So anyway, because monkeys live so long and it takes so long to see results, these things went on for years and years, and they would publish, you know, occasional studies about their blood glucose, how it affected blood glucose, their body fat and all these. Eventually when enough died over the next few years, they came to very different conclusions. Now, I've got a lot of friends and been involved in both of these studies. And so at the risk of irritating my friends, I'll have to say that I think we learned something,

but we learned something very different from each of the studies. So let's explain some of these differences. Because I do think there was some interesting differences. And by the way, it's an interesting footnote to just by total coincidence, that when the first of these papers was published in 2011, I believe it was the same day. So I should say not published as in the scientific publication,

but on the day that the New York Times ran the story of the results of the first of them, which I think was Wisconsin. On that same day, they ran the rapa-mice and itp result, the first rapa-mighty p result. 2009. Yeah, 2009, new two in 11, you're right. What's interesting is, of course, the monkey study was front page news. The RAPA study was buried in the back. Barely, barely got it. Yeah. Yeah.

Yeah. Yeah. Yeah. So what was different? Let's talk about what was different between these experiments. Yeah. Well, first of all, let's talk about wild monkeys

versus laboratory monkeys. So they haven't been in the laboratory long enough to really have had the kind of genetic alterations that mice have. But again, this is this comes from I you know, I had a long history with studying you know lions and tigers and other big cats and bears and elephants and captivity and Then seeing them also in the wild and one of the things that we know is that virtually all captive animals are obese, relative to their wild cousins. And community us.

Kind of like those captive humans. Yeah, exactly. Which is what to say. Exactly. And one of the things that I did in the late 80s, early 90s that I did some research in Pop-Win-O-Ginney, where we're basically studying people who are still hunting with spears and arrows.

And it's very similar to wild primates versus captive primates. So all captive animals are obese to a degree. Now there are some that are just frankly obese and there are some that are just frankly obese and there are some that look okay to us because we've only seen animals like that, but they still have a lot more body fat. So with the Wisconsin study did, as they took animals, the control animals that were eating at Liberty, so they had food available pretty much all the time and they were restricted each individual animal

By 30% so they tracked individual animals. How much does it eat over a certain amount of time? And they said okay, it's diet for the rest of its life is gonna be 30% less than that and They did that for the next 35 years and And this was one to one randomization, Steve. Yes. So just to be clear, they follow all the animals, get a baseline intake for them, then they divide them in half randomly. One group gets to continue consuming that amount or gets to continue consuming ad libido. Yeah, it gets what it wants to eat ad libido.

Okay, so that's an important distinction. The CR group gets pegged to 70% of what they were eating during the run-in. Right, and so, you know, 35 years later, they report that the animals that are eating less are living longer, substantially longer. And by all kinds of disease metrics are healthier.

So pretty much replicating the laboratory experiments. Now I have to say that up to this time, I really hadn't thought too much about how you would translate the laboratory rodent experiments into human experiments, but suddenly because I was asked to write something up on these two experiments, I started thinking about, yeah, what are we? I mean, you think about a rat or a mouse spends its life in a cage that's no bigger than a jail cell. Usually has very little, except other animals in the cage. So has zero opportunity for much physical activity.

And needless to say, because they have food available all the time because they've been selected to reproduce as much as possible, they're gonna get really quite big. And I think that that was a perfect replication reproduce as much as possible, they're going to get really quite big. And I think that that was a perfect replication, the Wisconsin study, of what goes on in most laboratory rodent experiments, which I think is what they'd intended. I think the philosophy of the National Institute of Aging Study was different.

I think they were trying to say, what is the relevance for people? And not for people who are sedentary and obese, but for people generally. So what they did differently, well, let's just talk about the way they did the experiment. What they did is they said, we want our control animals to be at what we consider to be a healthy body weight. So we're not going to feed them ad-lib at them. We're going to feed them a couple of times a day, and we're not going to feed them adlib at them. We're going to feed them a couple of times a day and we're only going to feed them enough to keep them at what we think is a healthy body weight. And we're going to restrict our other animals

and our restricted animals 30% from that. So now we're talking the restricted ones are going to be much leaner than the Wisconsin restricted ones. And the controls are also going to be much leaner. So it's a form of pair feeding, but it's a CR pair feed basically. Yeah, exactly. And what they really were saying is, look, if you take a healthy human and you restrict a healthy human, what kind of effect are you likely to see? So almost inadvertently,

because I don't really think they had this philosophical difference worked out at the time, but that's really the way I think it ended up happening. And in this case, the animals didn't live any longer. It was very clear. It wasn't like, well, it's a little bit longer, but not quite enough to be statistically significant. So there's no difference whatsoever. But their controls were also living longer than the Wisconsin controls, which again, not surprising, because they're kept at a healthy body weight. And these others are gotten to be frankly obese. And then we get to the difference in the diets, right,

obese. And then we get to the difference in the diets, right? Which is really stark. I mean, that's, that's not a subtle distinction. No. So the difference in the diets is critical. So if you look at the gross macronutrients, the carbohydrates, the fats, the protein, they're not that different. But here's the critical difference is that they use natural ingredients in the NIA study. In the Wisconsin study, they wanted to use what they call purified ingredients because you're a complete control of this. You might get a different source of corn meal and it might differ slightly in nutrients. But if you're just doing specific, if you're just doing albumin, you know, you're always getting the same protein, the trouble is that that wasn't a very palatable diet and

to make it more palatable to do the carbohydrates, they were adding sucrose. And by the end of it, well, I think by the time they figured out the diet, it was a, they were 28%, 28.5% sucrose diet. It was constant. And, you know, very low sucrose, you know, all these natural ingredients. I think it was about 3% sucrose in the Bethesda mice versus, as you said, 28, 29% sucrose there. Bob Kaplan did an analysis for me.

We've written about this, I think, in a weekly newsletter or something, but the Wisconsin monkeys were effectively eating the equivalent. If they were humans, they were effectively eating three big Macs, two large fries, and two jumbo coaks a day. That was the equivalent of their diet. So you're basically getting a control animal that's eating like three big Macs, two monster fries, and two jumbo coaks a day. And then the CR group was getting 70% of that. In Bethesda, it was basically like a whole foods pescatarian diet with 3% sugar in it.

And, you know, it's a bit of a shame because it doesn't allow us, in my opinion, to appreciate the effect of the weight difference. Because as you said, the controls in each group, there's no comparison, right? The CR group in Bethesda and the control group where the longest lived animals, and they actually lived longer than the CR groups in Wisconsin.

Yeah, yeah. I mean, this isn't a surprise when I said they started off with these squirrel monkeys as well. One of the reasons they abandoned that was they soon realized that the squirrel monkeys were living longer than any squirrel monkeys that have ever been reported to live before as well. And now their recessed Macax have been reported to live longer than any Macax had been before. It's interesting because as often happens in science of two groups,

do what seems to be the same experiment, although I agree with you, this wasn't really the same experiment. But if they seem to do what's superficially the same experiment, although I agree with you, this wasn't really the same experiment. But if they seem to do what's superficially the same experiment, they come to different conclusions, they're not happy about it. And so in one of the attempts to reconcile the data, they looked at the weights of the control animals in Wisconsin versus Bethesda, but compared to all of the Reese's monkeys in the country and all of the research facilities in the country. And the Wisconsin ones were about 10% heavier, the controls now, and the Bethesda ones were

about 10% lighter. So like I say, I think they're telling us something differently. Someone might want to know if instead of eating two big Macs and two helping some fries and two giant cogs a day, what if I only ate 70% of that would I be healthier? Then you, as a physician, would probably say, yeah, yeah, eating less of really toxic food is good for you. That's exactly my conclusion from that study is in a still somewhat contrived way. I think what we learned is the worse the diet, the more beneficial the caloric restriction, the better the diet the less of an impact caloric restriction has.

And what that says to me is dietary restriction might be as important if not more important than caloric restriction by dietary restriction. be as important if not more important than chloroquistriction. By dietary restriction, I mean manipulating or reducing components of the macro or micronutrient. And in this case, the sucrose was head and shoulders. I mean, to me, this was basically an experiment demonstrating the harm of sucrose. Yeah, yeah, because if you looked at what they called

gluteal regulatory problems and the controls that were massive and there were zero of those in the restricted animals. And I'm glad you brought that up because it reminds me the control animals in Bethesda, i.e. the fully fed animals in Bethesda, had less diabetes than the calorie restricted animals in Wisconsin. I don't know that that's correct. I don't I don't remember Wisconsin reporting any. No, I think this was an after publication. I'm pretty sure, yeah. We'll confirm that for the show notes, but I think this is something that came out much later,

but I actually think that the that the group eating 70% of the high sugar diet had had a higher incidence of diabetes than the control in Bethesda. Which again, just speaks to the dramatic differences in what you're feeding. Yeah, and I have to say, I don't think we've ever really gone back and worked out the best diets for mice or rats. I think there's a lot still to be done in those. Most of those standards were really just developed for keeping them healthy so they could breed. And I think that if we really wanted

to understand more about nutrition in those animals, we'd have to go back and do that with modern techniques. If we really wanted to understand nutrition or rats and mice, I don't think we understand it very well. And there's no way to really study monkeys and captivity without limiting their exercise, right? I mean, is it possible? Well, I think it is.

I mean, it's possible. I think there are two problems. One is that because you need to control the diet, the animals were kept individually housed. And this is a very social species, just like we are, right? And so, cognitively, psychologically, these had to be extremely unusual animals. On top of that, because of the size of the cages that they had, yeah, there was virtually no opportunity for physical activity. That's very similar to the rat and mouth studies, right?

But I think for primates, it's probably worse. I think it's, yeah, I think it's much worse. Cognitively, I'd have to think it's terrible. I mean, there were in a room where they could see each other, they could hear each other, they could smell each other, but they couldn't touch each other. So they didn't even get to mingle outside of feeding times? No. No.

Probably had to do with cap to setup that they had in those two places. It's not easy to get strange monkeys to interact with one another. You might end up with a lot of fighting. And at least one of the other differences between the two studies was the Wisconsin animals were all monkeys from India that were born in captivity. And so they knew the precise age. In the Bethesda study, they sort of added animals of different ages as they got them.

Some of them came from the wild, and some of them they kind of guessed the age at the start, and some of them came from China. So there's some genetic differences as well. So yeah, your basic conclusion that nutrients seem to count, I think, is very valid. And I think that, I think it's also something, you know, I always say that humans are the worst animal

of study that you could imagine because they don't do what you tell them to do, you know, and they'll lie about what they do. But on the other hand, there's certain kinds of studies that I think you have to do in humans. And I think that the idea that the nutrition that works best for a mouse, even if we knew what it was, might have tell us anything. My seat seeds an insect larvae in the wild and we're very different.

I think for these kinds of nutritional studies, I think you really do have to study humans because humans have their own unique characteristics. Which is a point I'm gonna absolutely wanna bring us back to as we look to one of the great challenges of studying humans is not only the timescale and the difficulty with interventions, but frankly the lack of biomarkers that could really help us assess zero protection.

But I want to go back to kind of what you think would happen to animals, colorically restricted in the wild. Imagine this as a thought experiment, although I believe this experiment has also been done in some form and other where you calorie restrict wild mice. What do we know about that? Yeah, so I actually did an experiment like this.

So I didn't calorie restrict wild mice in the wild. I calorie restricted wild mice in the lab. Yeah. So I brought them into the lab because one of the ideas that I had, which turned out not to be correct, was that we have selected, well partially correct. We have selected these animals to grow as fast and reproduce as fast as possible. So we may have created gluttonous mice just by laboratory selection over dozens and dozens of generations. Mice after my own heart basically.

So wild mice of course don't have that. So I went out and I caught a bunch of wild mice and I brought them into the lab and I let them have babies for a couple of generations to get rid of all of the contaminants of being in the wild. And then I restricted their diet. And what I found was that there was no difference whatsoever in how long they lived. Now I have to say I'm watching the animals die and they're right on top of one another almost. And I'm just ready to say there's no way that dietary restriction

works in wild mice. But then the last few, the last 20% lived longer. The restricted ones were living longer and longer and longer. So all of the longest-lived ones were in the restricted group. So what I concluded from that is that these are wild animals that are genetically diverse. So I thought, well, maybe because the other part of this I didn't imagine is very early on when I restricted them, a number of the restricted ones died early in the experiment. So maybe, depending on your genes, dietary restriction will be good for you. You can have very little impact on your health or it can be bad for you. The ones that died early, Steve, when you examined them after death, what were you seeing? You know, I don't think that we did enough knee cropsies on the early ones that died to

know that. It's not very easy to get good knee cropsy material on mice because their bodies cool off so quickly and their tissues start to degenerate so quickly. So almost all of what we know about mice pathology is from mice that were euthanized. And I don't think we euthanized any because we didn't expect them to die when they were young like that. So maybe they had some nutritional requirement

that we weren't meeting. Like I say, we were using standard laboratory chow and that's, you know, we don't really know how good that was. Which, I mean, standard mouse chow is total garbage. That's probably a good a good reason to be concerned at the upper end Steve did you see a I mean, I guess if you didn't euthanize them you wouldn't know but you'd expect to see cancer being the biggest difference Although do wild mice suffer cancer to a fraction of the extent that in bread mice to they do to a fraction But they don't yeah, we did for the ones that live longer

red mice too. They do too a fraction, but they don't, yeah, we did for the ones that lived longer, most of those we were watching much more carefully because they were getting to the point where we were expecting them to die. So we have quite a bit, we probably have knee cropsies on about at least 20 mice in each group. And yeah, they still get mice, they still get a lot of cancer because let's face it, mice in the laboratory live on average about two and a half years.

The longest live ones live about three years. In the wild, they live on average about three or four months and the longest live ones live maybe a year or a little longer. So we're talking about incredibly long live mice. So yes, about half of them had cancer when they died. I don't know if that's what killed them, but they had cancer when they died. But that's a lot lower than live mice. If you bring wild mice into the lab, how long do they live when you take away their predators and you ensure them food? They live a little bit longer than your laboratory mice, maybe 20% longer.

Okay, so they are a healthier mouse. They're pretty healthy mouse. Yeah. Despite not being bred for a being in a lot of... Well, I mean, if I gave a handful of these mice to people that were only familiar with laboratory mice, they wouldn't have any idea they're looking at the same species. First of all, they bite. Secondly, they can jump. You know, when we change mice from cage to cage, we set the cage down. We take the top off. We picked the mice up. We put them in the new cage. You take my wild mice, you take the top off and you got popcorn, you know, they're all over the place. And there's a common test that we do in laboratory mice for sort of coordination and balance, which is called a rotor rod,

which is kind of like log rolling for mice, right? The idea is that this is probably 18 inches off the ground, so they're afraid to fall, so they'll sit there and try to stay on the circulating rod. Try that on a wild moss, and it's immediately leap off the thing and leap off to your desk and leap onto the floor and they're gone. There's another one that we call the wire hang, which is just what it sounds. Take mice and you hang them from a wire like they're dangling a push up and you say how long can they stay before they fall off?

It's like kind of a grip strength test. Yeah, yeah. You do this to a wild moss and it does a pull up, it pulls itself up onto the wire and it runs off the wire and that's the end of your test. So when I say there's no comparison between them, I'm really meaning that you could take the most sedentary overweight person you could imagine and say, okay, I'm going to compare you to this trained athlete, you know, and that's the kind of comparison you get.

Cognitively, it would be really interesting to see as well. The trouble is wild mice are not used to being around people. So, you know, they're freaked out when you touch them. And so you can't do the same kinds of cognitive tests, which is unfortunate. But on the other hand, this is what you have with the other thing is, if a domestic mouse wants to get away from you, it jumps back in his cage and sits there. You know, if wild mice wants to get away from you, bites you and then it jumps off the table and onto the floor and is gone. So if you if you had to do the thought experiment, which is you're

going to take a group of wild mice in their environment, remove the predators. So assume that they can live a little bit longer. One group gets a hundred percent of their necessary nutrition. The other group gets 70% of that. Do you believe that the CR group would live longer? No, no, I don't. Do you think they would live shorter? Quite possible. I think probably yes, and I'll tell you why. So this experiment has not been done, because it's hard to do, but the reverse has been done. So there have been a lot of studies where people have supplemented the food of animals in the wild. So they don't have to go out and forage as much because I'm going to give them as much as they need to eat every day. So you would expect, okay,

now I'm going to get obese mice that are going to be short-lived, but that's not what you get. You get mice that live longer. And they live longer because they're foraging less, they're exposing themselves to less predation. The reason I think that if you restricted animals in the wild, they would live shorter is that the first thing is they would have to forage longer. They would have to take chances to go after food, they don't normally go after, they would possibly eat things that they normally

don't eat that might be toxic. So my thought experiment is that the animals, if you did this in the wild, if you could somehow control the available food for them, that they would be shorter-lived. The other thing is that there's a couple of things that calorie restriction does that don't seem compatible with the long life in the wild. One of these is that it slows wound healing. The other thing is that it makes animals more susceptible to certain kinds of pathogens. And those two things in the laboratory are not a big deal because they don't get wounded,

and we spend a great deal of time and effort to keep pathogens out of the colonies. But in the wild, those are very important causes of pathology and things that you need to work well. So that would be my guess is that they would probably be shorter-lived. Are there any other studies in the animal literature that you think can shed light on this very important question as it pertains to an extrapolation into humans? Well, I mean, there's the human studies. Yeah, right. Before we get the calorie and cronies and stuff like that.

No, I don't think so. I mean, you know, when I first came into this and people told me about this phenomenon, the first question I asked, well, if this is so healthy, why don't we animals in the wild not eat less? And of course, the answer is that the animals have the genes that have survived for millions of generations out there are the animals are the best at reproducing. Right, they're not optimizing, they're not optimizing for the longest life, they're optimizing

for the most reproduction. That's right. And so I said, well, of course. So they probably eat more than is perfectly healthy because that helps them reproduce faster It made perfect sense and so I don't find it particularly surprising that You get this kind of health because that's you know, that's that's not what nature has designed any of us to live as long as possible You know, that's kind of up to us to figure out how to stay healthy long.

Nature was fine with us when we were living, you know, 35 years. Yeah. Yeah. There's one experiment that was done where they took mice that had been genetically altered so that they lived longer in the laboratory. And they put those in a field, exposure with some normal mice and just came back 18 months later. And the ones that live longer in the lab were shorter live, they were almost all gone in the real world. So there's a slight complication to that experiment, which is a follow-up experiment showed

that, well, that same mutation they don't necessarily live longer in the lab. It was one of these unfortunate faults for results that couldn't be replicated, but, you know, that's the way science works sometimes. So let's turn to the human studies, then, which obviously don't have the luxury of the same duration relative to the lifespan of the animal, but what have we learned there? Right. relative to the lifespan of the animal, but what have we learned there? Right, so there's, I think, a few of four human studies that are five, maybe. So the first one, I think, was the biosphere two study. But we don't know much about what happened.

Most of the people in that study were pretty young. Roy was a real outlier. Roy Walford was, I think think 66 at the start of that experiment, 68 when he came out. But certainly from their blood analysis, they had very good cardiovascular risk factors. Their blood pressure was extremely low. Their blood glucose was extremely, of course those were all exceptionally healthy people when they went in. So this was not a random group. The calorie studies are the two best controlled studies in humans.

And there was two of them. There was one that was a very short term, six months. And then there was another was slightly longer term, which was two years. How many institutions were a part of these two studies? Three institutions were a part of these two studies. Three institutions were a part of this. Pennington was one, right? Pennington, Washington University, and then Tufts. Okay. And Tufts didn't publish anything out of the first phase of the study.

I don't believe, but in the second one, they did. So, to me, I'll just give you my bottom line on those studies is that people can't do calorie restriction in that traditional sense. I mean, in all cases, the goal was to reduce calorie intake or energy imbalance by about 25%. And then, it never came anywhere close to actually getting that. In the longer study, I think ultimately the amount of restriction was about 11 to 12 percent that people were able to achieve over two years. Because these people were in charge of their own nutrition, it's not like

the study could afford to actually give everybody all of their food every single day, which would at least give you some hope of doing that if participants could limit themselves to eating the provided food. Yeah, as I recall, I think that they provided meals initially for a short term, but they didn't monitor whether the people went and ate anything else as well. And then they were on their own. So it's quite clear that people can't, normal people, there are people that can,

but certainly your average person cannot. So in none of those that they achieve anywhere close to the dietary restriction they had hoped to do. So what did they find with what they did achieve? Cardiovascular risk factors all improved. Certainly blood pressure was better, lower insulin, lower glucose, but there were some things lower bone mineral density as well. So it's a mixed bag and the main thing is if you

look at a dietary restricted mouse, it's got almost no body fat. These both of these experiments, the thing we struggle with is that most people are overweight or obese in the US, where these were both done, right? So your control group is not going to be like the Bethesda monkeys. So what that means is if you can only achieve 10% dietary restriction, you're going to be like the Bethesda monkeys. So what that means is if you can only achieve 10% dietary restriction, you're going to get people that are on the verge of being overweight or obese

and getting them down to a healthy body weight. And I don't think it's a prize anybody that that's good for your health and that's pretty much what they found. They never got people to that extreme leanness that Roy Walford and the people in the biosphere had or that the subsequent the cronies have. So I think you could generally say

from the calorie restuties that, yes, reducing your food intake had lots of benefits, had some possible negative effects in terms of bone mineral density, had some negative effects in strength loss, although not if corrected for body weight, but, yeah, generally beneficial. But again, if you take somebody that's on borderline overweight, reduce them to a healthy body weight. I don't think any physician, it wouldn't have to be a specialist like yourself. Any physician, I think, would say, yeah, okay, what's the news? So that's what I take away from that. Now, the other study is the study of the cronies. And these are people that belong to a society called the Calorie Restriction Society that

have taken the rodent work and assumed that is going to make us healthy longer. And they really have restricted themselves like we really do to mice and they also have good very good cardiovascular risk factors, less inflammation, they're probably going to get less cancer, but they have low bone mineral density, negligible sex hormones, whole suite of things, no muscle mass to speak of, I've spoken at a couple of their conferences,

and they're always exhorting one another to exercise more, because I have trouble with this degree of restriction keeping any muscle mass at all, but it's a struggle because they don't really have the energy. They don't have the energy, yeah. And these people typically have what, how much of a BMI is Steve? These are people that are 17, 18 BMI at this point. Yes I say 17 to 20 yeah. The interesting thing is in that society if you look around the room I would say probably 30% of the people are actually doing it like that. The others are maybe aspiring

to do it but not quite making it they look more like an average person would look. But yeah, that's the problem. And I'm not sure now that all these other diets are starting to come out. How many people are still sticking with that? Because I haven't, I've kind of lost track over the last few years of what's going on with those people. The other thing, they have very low thyroid hormone. So they're, they're cold all the time.

So one of the things I noticed at a comfortable room, everybody would be wearing a jacket that was really BMI of 18. So. And we don't actually know the impact of this on long-term cognition, do we? I think the cardiovascular and cancer, it's pretty clear that they will have a benefit, not clear with respect to dementia, not clear with respect to immune function, and certainly not clear with respect to the diseases of frailty. In fact, I should say it is clear with respect to the diseases of frailty.

They're much, much more susceptible. Yeah, I think that's true. The cognitive part, I mean, in the calorie study, they did a little bit of cognitive research, but again, I, you know, these were people that weren't being restricted to the same extent. And the people in that society are very eager to be studied. The problem is, this is an uncontrolled experiment.

My guess is, before they started the calorie restriction, they were not your average person, with your average person's health habits. Yeah, yeah, this is the poster child example for healthy user bias and epidemiology. We can learn virtually nothing from that without randomization. In terms of the immune system though,

I will have to say that I did ask a lot of people at the conference to get, and often to get coldals or the flu, and they say they don't. And I tend to believe them because I've never met a group of people that are finatically attentive to their own health. Like if I said, what's your BMI?

They could tell me to three decimal points. And then say, well, do you mean in the morning or in the afternoon, you know, so when they tell me they haven't gotten a cold in five years, I believe them. Fair enough. So this highlights an important point, right, which is one, it's a very, very, very rare subset of the population that is going to be able to adhere to 30% caloric restriction every minute of every day. And I would argue that even if you could, the quality of life might be not justified to trade off. Isn't there a joke that says caloric restriction will lengthen your life and it will feel like it or something

to that? Yeah. Yeah. What is it? But I think, you know, for these people, I don't think they perceive it. I don't think they miss it. No, no, no, my point is you couldn't extend, they are the subset who can do that. Yeah. To try to make that the solution for the rest of us who are interested in some form of zero protection.

It's an on starter, yeah. Right. Constant caloric restriction isn't the answer. So we now look to other things. And you maybe heard me talk about this, but I kind of have this framework that says, on the one hand, we have this thing called the standard American diet, which is sort of the cesspool of nutrition we all live in.

So that's the environment where food is infinitely abundant, infinitely cheap, infinitely palatable, and infinitely transportable. So meaning it's so processed that you can actually take it with you anywhere. And it's hard to escape the gravitational pull of that. So we're all sort of in this orbit around the standard American diet. And there's basically a handful of ways out. So I think one, one avenue out of that is time restricted feeding where you start to say, well, look, I'm not going to restrict what I'm eating. I'm not going to engage in any form of dietary restriction.

I'm just going to limit the window in which I expose myself to this toxicity. So I'll not eat for 16 hours, but I will eat for 8 hours. And you can obviously make that window narrow and narrow. Then there's what I call dietary restriction. You and I use these terms a little differently, although I know what you're meaning when you say it. When I refer to dietary restriction, I mean no attempt at reducing the content, but rather changing the mixture of quality.

So dietary restriction, which is probably what most people think of when they think of a diet, like a paleo diet, a vegan diet, a keto diet, a low carb diet, they're not explicitly telling you to eat less, they're just telling you to not eat in certain things. So those two become, I think the main stay of how most people are trying to escape

the gravitational pull of the standard American diet. And then you can actually talk about intermittent forms of fasting. And that can be complete, such as, hey, I'm not going to eat anything. I'm just going to have water for three days every month or every quarter. And they can be partial, sort of like the fast mimicking diet where for five days you consume, you know, 750 calories. When you think about that entire landscape, where do you think we have the best insight about the health benefits? Well, first of all, these are all pretty new ideas, and I don't think they've had a lot of empirical testing at this point. And the empirical

and testing that they have had has mostly been in people that already had some health issues that were diabetic or prediabetic or something like that. However, the logic of it is pretty compelling. And this is something we have learned from the mice. You know, Because something we have learned from the mice, you know, from the mice, we've, in the rapamycin studies, we've learned how suppressing this gene called mTOR can have multiple health benefits. And now we know that it doesn't take that much fasting to also suppress mTOR. So we now kind of have an idea. So, you know, one of the things we should probably mention

is that the people that were studying mice and rats, years later started noticing, well, wait a second, and I noticed this when we go to feed these animals, they're right there, they're doing pull-ups on the cage, waiting for you to get the food, and, you know, literally within half an hour, all their food is gone. And what we never really thought about until recently is wait a second, maybe it's the

timing, that's the important thing. The fact that they're fasting for 23 hours a day or 23 and a half hours a day, maybe that more than the total consumption or as much as the total consumption, is doing it. And now we kind of have a molecular mechanism for understanding how a period of fasting might have benefits. It might have short-term benefits. I mean, I think that's one of the really interesting things is that these short-term fasts, whether they're mice or humans seem to have multiple benefits. I mean, one of the, I think one of the most groundbreaking studies was by Jay Mitchell,

unfortunately, who resettled away a year ago. Yeah, yeah, terrible, terrible. Bicycle, but he showed that if you fasted a mouse for two or three days, they recovered from surgery so much faster. Well, actually, Steve, I mean, we should double click on that a little bit because it's not just that they recovered from surgery. They recovered from a lethal injury. Right. There's one experiment I think, where I think if I'm thinking of the right experiment,

it was, they took a group of mice that were constitutively, calorically restricted their entire lives. They took another group that were fed were constitutively colorically restricted their entire lives. They took another group that were fed, ad lib their whole lives, and then they took another group that were ad lib fed, but I think three days prior to the surgery were severely colorically restricted. So each of them then had the same procedure,

which was a laparotomy with a ligation of the femoral arteries for a period of time and then a reprefusion. So what, you know, for the folks listening, what that means is you clamp off all the blood supply to the lower part of the leg. And then, you know, basically just before the animals about to die, you let it, you let the blood flow again. But because of all of the ischemic damage to the tissue, all the tissue damage due to no oxygen, you create such an injury to the animal that I believe all of the ad-live animals died from that. But yet the two groups that were calorically restricted, one its entire life and one just for three days, survived, suggesting that just that period of caloric restriction could produce a similar benefit.

Now I could be a little wrong on the numbers, but that was sort of the gist of my memory, is that correct? Yeah, well, what he did, it actually cut off, let's apply the kidneys. And then he also had the... Yeah, another one that they did the liver. Same result, though. And you're exactly right. They did these ones that have been caloricly restricted their whole lives, the ones that have been color color restricted their whole lives, the ones that were ad-lib, and then the ones that have been fasted for, they did some that have been fast, restricted for a few weeks,

and then some that have been just fasted, water only fast for two or three days. That's a big fast for a mouse. It is a big fast, that's absolutely right. And they did much better, you're right. I don't remember if all of the controls died, but if not, almost all of them did. And the ones that were restricted lifetime,

or for two or three days, I think none of them died. So you're right. Yeah, when I said a surgery, I guess I was thinking about it from a mausologist standpoint where a lot of our surgeries don't turn out so well. But yeah, this wasn't a minor surgery that you expected everybody to recover from it. This was my little gold blood. They really were expecting most of the mice were going to die and they did.

So yeah, I mean, that kind of, I think, it changed my thinking entirely about dietary restriction. And you're right, we used these in different terms. Initially, it was called dietary restriction because they just restricted the amount of diet. But then after they decided it was calories that counted, then they started being called calorie restriction. And now, probably not exactly calorie.

So I don't know, food restriction, maybe, we should call what they do to the mice at this point. Well, what's your take on the role of the macronutrients here? And I'll pass it to candidates to consider. The first being a subset of amino acids, whether it be methionine, triptophan, loose scene, would be candidates to consider, and then other things such as sugar. Again, the Wisconsin half of the monkey experiment certainly suggested that a reduction in sucrose, perhaps independent of calories, could have played a role, but it's difficult because we can't disentangle it from the weight loss

and other things. But what do we know about amino acids in the role? We certainly know that M-tore, which you brought up a moment ago, is an amino acid sensor. So how do you think that fits in independent of calories, perhaps? Well, I think we need to work that out, you know, because there are these diets around and there are diets that say, oh, what you want to do is you want to eat as many carbs as you can and as little protein and fat as you can. And there are others that say the opposite. I don't think the animal

work is going to tell us a lot about that. I think we have to try to figure out how to do the experiments in people. We have to do it in healthy people because I think if we want to make sick people less sick, that's great. We should be doing that. But a lot of people that are healthy want to know how to stay healthy. And I think that we can't do these things long-term because what if you're in one that's turning out to be really bad for your health? What we need is we need some biomarkers,

which you mentioned before. We need something so we can do an experiment of a few weeks or a few months and have the answer long-term. And we need to do it in people of different ages as well. You know, the thing that we didn't talk about the calorie study, so those were done on people who are basically in their late 30s. And what's good for them is not necessarily good for what people in their 60s might want

to do. You know, one of the things I think that the intervention testing program has demonstrated that shocking is how late in life you can start some kind of intervention and still have a dramatic improvement in health. And that, to me, has really major implications for people, right? Just because you're 50 years old and you've never done any exercise

and you've eaten a terrible diet, doesn't mean you can't improve your health a lot. Because I think a lot of people feel that. I've done this my whole life, so what's the point in doing it now? I'm curious for you, I get to ask you a question occasionally here. What is average age of people

that come to your clinic? Are they people in their 30s or 40s or 70s or 80s? The median age in our practice is high 30s, yeah, would be median and mean is probably a little bit higher, but range is 29 to 79, 29 to 82 maybe is the range. Right. So that makes sense. So that's about the time and life where people start realizing they may not live forever and start making some changes potentially in the way they live their life. You know, I have a dramatic memory of when I first detected aging in myself.

What was that? That was, I probably was 32 maybe, but it was during a basketball game. And I was always the quickest person on the floor. And I was used to blowing by people. And suddenly this person blew by me who was much bigger than me. And I was used to if anybody was going to be as quick as me, it was going to be somebody as small as me. And I thought, gosh, that had to be an accident. And then he did it again, you know, and then he did it again. And I thought, gosh, that had to be an accident. And then he did it again. You know, and then he did it again. And I realized, I lost a step.

This is what they mean by aging. I have lost a step. There's, you know, and if you're a professional athlete, of course, you're tested much more often and you probably noticed this much earlier than I did in a casual neighborhood basketball game. But it was a shocking moment to me, because before then, never entered my mind that my body was going to change in a way that would make it less good at things that used to do. Well, speaking of human longevity, Steve, what do you think is the best explanation for the sex difference between men and women? In the United States

today and much of the developed world It probably accounts for about two years of difference, doesn't it? More like five. Is it that much? Wow. Yeah What's our best attribution? Well, it's a really interesting problem and let's talk about it I think some myths about that difference. It's not that women survive better in an old age. They do, but they also survive better when they're infants, and they also survive better when they're in their 20s and their 30s and their 40s. So they survive better at every age, and they survive better when times are good, and

during epidemics and during famines, and so there's something about their biology that allows them to survive better, and it doesn't seem to depend on conditions. That's very different from a lot of animals, where it depends on the diet, it depends on the circumstances. We don't know any circumstances in which men survive better than women, even prematurely born infants. Being a male infant is a risk factor for dying if you're a preemie. So there's some robust feature of human biology at play here. And unfortunately we don't really know what it is. We don't know, is it sex hormones? Is it something that happens before birth is that something that happens before birth that we can't do anything about later, there's a little bit of weak,

but I think maybe provocative evidence. There's at least two studies showing a major increase in longevity for men who are castrated for one reason or another. Is that relevant? These were unique populations, and maybe there's no relevance whatsoever. But that was kind of put the onus on sex hormone, right?

On the other hand, there's the hormone replacement work in human females, which suggests that, well, maybe replacing those hormones isn't such a great idea. Although, I think we now don't find that to be the case, right? I mean, I think basically every conclusion of the original Women's Health Initiative has been turned over, right? No, I would say that's not the case, but the key factor for the Women's Health Initiative

is the women didn't start doing it until 10 years after menopause on average. And so there have been shorter term for women that start replacement therapy earlier and then stop it, that there may be this window in which it's benefit. But of course, it depends on your family history, all kinds of things. Right. Yeah, but my point is there was no increase in mortality. I think if you really scrutinize the WHOI data correctly, even the most headline grabbing finding, which was that the women in the progesterone and conjugate at equine estrogen group

had a greater 25% greater risk of breast cancer. I mean, I think we now understand that that was a very misleading finding. Yeah, I mean, there were several things that they they were much more likely to have a stroke, but you're right, the overall mortality rate at the time that they stopped the study because of the blood clots and the strokes and there was no difference. You're absolutely right about that. There was no difference in mortality and you could have made the case that they shouldn't have stopped it at that point.

And it's interesting on the castrated literature, the obvious one, you know, the first or Occam's razor view of that would be, well, there's something about testosterone. It's not so much that the men who are castrated are getting estrogen and progesterone. If you castrate them, they're actually gonna have no estradiol versus the estradiol they would have if they could keep their testosterone. But of course, that kind of flies in the face of the testosterone replacement data,

which say, well, actually it doesn't seem to impact mortality either way, at least outside of two or three years. But then that comes to a point you made earlier, maybe it's something that happens early in life with high exposure and Yeah, I mean to me the telling Data points are that the women survive better from ages 0 to 5

You know that suggested me that there's something already in place and It probably may not have anything to do. I mean, let me point out the two testosterone studies are very weak. They were not done with this in mind. They were done post-hoc and there's a lot of complications. So I don't put a great deal of stock in those. It's just provocative. And also the difference in longevity

was something like 20 years in both of them. So it wasn't a trivial difference. I can certainly understand why men would have a lower, or higher all-cause mortality when you factor in a couple of things. One is behaviors. I mean, you know, if I compare my sons to my daughter, it's literally like, they wake up every day,

trying to figure out how to hurt each other and hurt themselves It's and that I mean I'm actually very fascinated by that Steve because I don't understand where that is in their genes Like you would think well that has to be sex linked right but you know when you look at men who are Double wise so you know there are some men who don't get an X chromosome, they get two Ys. They turn out to be no more aggressive than a standard XY. So, it's not something as just as simple as like, well, that Y chromosome has, maybe it's going to be a little bit more nuance than that. But, and I think about the dumb things I did growing up, like, there were literally times I was engaging in such stupid behavior, like into my late teens that it's a miracle I'm sitting here, at least when you almost died,

well, I guess we could argue that was kind of maybe not the wisest behavior, but... Oh, you don't have any clue as to what the really dumbest stuff that I did. We used to, I used to be in a group of friends that hunted with bows and arrows, rabbits, when I lived in Florida. And we would take our bows and arrows and go into a vacant lot in the middle of the night when it was dark and shoot them straight up in the air and then stand around to see where they would come down. So they could have come down straight through the top of our heads. And you look back and you go, yeah, what was going on? You know, I call this, yeah, I say that I call this testosterone dementia.

And I think probably most men go through it at some point, you know, in there, probably in their adolescent years, right? That's what I did. When I was in high school, one of the things we used to do, there's this huge train in Toronto called the Go train. And it was the above ground transit train. And we used to play this game. As soon as you got off it, you would dive underneath it

and see who could lay the most coins on the track and then get out such that when it started rolling, you'd get whoever had the most flattened coins would win. Yeah, can you believe that for a moment? Like it's just hard to believe that a subset of our species could be so stupid to do something like that. Yeah. We would also shoot arrows at one another on purpose and dodge them.

And that ended because I was the first one that didn't dodge well enough when I got an arrow stuck in my leg, at which point our parents investigated what we'd been up to, and that was the end of that. Yeah, and like, do you think, in the history of the, how many billion people have lived, like eight billion? Well, there's almost eight billion alive now. Okay, so probably one hundred billion, yeah.

So, when you think of all the people that have lived, half of them being women, do you think there is one example of a woman doing something so stupid? I can't imagine. I can't imagine. I can't imagine. I can't imagine.

Yeah, yeah. But that's not all of it, right? That doesn't explain the infant mortality in the NICU, right? Right, and it doesn't explain the lower influenza deaths. It doesn't explain the lower. I mean, COVID was, you know, if you look at the COVID, so women are dying at about 45%, men are about 55%. That's pretty much what it looks like for the flu.

And I mean, if you look at all the major causes of death, women die at a lower rate, even if you adjust for age, so you take age out of the equation, then men for all of them with the exception of Alzheimer's disease, which is really interesting to me. And it makes me actually, my private hypothesis that I don't think I've ever said publicly before, is I think Alzheimer's disease is going to turn out to have an autoimmune component because that's the kind of thing that women

seem to be more prone to than men is some of the autoimmune diseases. So there's a few possibilities here. There's one idea that it has to do with the fact that women have a redundant set of genes on their second X chromosome. So if they have a defective gene or genes on one of the X chromosomes, the other one can compensate for it to a certain extent.

If that's true, I don't know if we have enough men with client filters out there, but that would be an interesting comparative analysis, right? Just for folks listening, men with client filters, instead of having xy have xxy. So they would also have that same redundancy of genes. Right. But some of those redundancies might be back, as client-fellars, those people don't live long for certain. I don't know how short-lived they might be, but they're not longer. I didn't realize their lifespan, I mean, they certainly have a unique phenotype, but I didn't realize they lived shorter. Yeah. But that's interesting because women with turners, right, which is X, which is an aneuploidy of X only, one X, they definitely live shorter,

don't they? Right. So that's one idea. And a little bit of support for it is if you look at, so one of the ex-chromosomes typically gets inactivated in each cell and it tends to be random. As people get older, as women get older, there tends to be a bias in one or the other ex-chromosome. So one is inactivated more than the other. Early in life seems to be random. Half of the cells, your paternal X is inactivated. Half of it is your maternal X. But over time, you get a kind of a selection for one or the other. Maybe that might be it. The other thing is that there might be an issue of compatibility of the mitochondrial genome and the nuclear genome because mitochondrial genomes only get passed from female to female. For female to female is the only way they get passed through generations, right? So you'd expect there would

be a lot of selection for excellent compatibility. Now the mitochondria that end up in males are at a dead end. So it may be that the male nuclear genome is just not as compatible with the mitochondrial genome as the female genome. So that's the other possibility. I find both of those really interesting and what we really need to know about is we need to know a lot more about this in X inactivation because it's not total, not every gene on the second X is inactivated, only some of them. But the other thing is the Y chromosome is, it's got to be the first time in the history of medicine that men get less attention for anything than women. But we've always assumed the Y chromosome is about sexual characteristics.

But we now know there are at least nine genes on the Y chromosome that are expressed in every tissue. We have no idea what they're doing in all those tissues, but maybe they're doing something that's not so good for us in some of those tissues. I find both of those ideas, Steve, incredibly fascinating. I'd never thought of either the mitochondrial incompatibility as a brilliant one. I'll have to think for a moment about how what experiments one could do to test that. But on the other one, on the dominant X, it would be interesting to follow women and identify ones who partition more into a dominant

maternal X and then a dominant paternal X in the women who have a dominant paternal X, presumably that X is better than the other X. And then I would like to see if there's a difference in the longevity of that father versus, and it's not a random experiment, so it sort of sucks. But is that a better surviving male than another male that's otherwise comparable? That's one way I would try to get at that. This is a really intriguing area of research and something that we could do now, that we couldn't do a long time ago.

The limitation, of course, because it's humans, is that we're kind of stuck with doing that in blood. And we don't know if the same thing might be going on in the brain or the liver. Although again, I guess from autopsy studies, we could probably figure that out now. But we do have the tools now to do a lot of this. We could do muscle biopsies. Is it the same in the blood in the muscle? That's a possibility. So, you know, my feeling is that we have yet to really explore these sex differences in any depth and that we may end up having somewhat different therapeutics in women and men,

once we start looking into exactly how these things work out between the sexes. Now, the ITP very consistently, whether you talk about its home run drugs like rapamycin and other drugs like recently, 17 alpha estradial, they disproportionately favor the male mice over the female mice. Do you believe that that is simply the result of the fact that they have a higher bar to clear with the females? Possibly, because in the ITP, the female mice live longer. So it's a longer life sex is having no effect and shorter life sex is having the bigger effect. A really interesting one is rapamycin

because you know in rapamycin, the sex bias is very in longevity at least, is very dose dependent. At the lowest dose they'd done, the effect of substantially bigger in females than in males. And that difference gradually goes away as you get it to a higher and higher dose.

And in the highest dose that anybody has used, which is not in the ITP, but in another study, males had a big effect and females had no effect. So the idea is maybe you've overdosed the females at that stage. Now do you recall that in the ITP, the females had a much higher plasma level than the males, despite consuming the same amount? And I don't remember if Rich had an explanation for why that was the case.

Do you? No, I don't think they have an explanation explanation for why that was the case. Do you? No, I don't think they have an explanation. That could explain the difference, right? It could be that it wasn't that at a lower dose, females are living longer because it's a lower dose. It's because they have a higher plasma concentration, and maybe that's the gap that vanishes at a high enough dose. I don't know, because I don't know what the kinetics were in the other study. And what they've published, it wasn't related to blood levels of rapamycin or

metabolites. Something else is going on. But those things get metabolized very quickly, and there's lots of downstream things that could be. But again, I think that mice are particularly bad place to look for these sex differences. And that's because, as I said, in the ITP, the females live longer. But if you look at all the mice studies together, there's mice studies in which males live longer, mouse studies in which there's no difference, mouth studies which females live longer. And they're all over the place, and it's not a genotype thing, because I once looked at 30 black six mouth studies

and you found the same range from males living 25% longer to females living 25% longer. And we don't know what that's a result of, is it something in a diet? Is it something in the bedding or who knows? But the other thing is that mouse sex chromosomes are quite a bit different than human sex chromosomes. Just to give you an example, some genes on the X chromosome do not get inactivated on the inactiv X, about 15 percent, you know, you get expression in both sexes.

In mice, that's about 3 to 4 percent of the genes on the X chromosome get inactivated. They're also genes on the Y chromosome in humans that are not on the Y chromosome. In mice, in vice versa. This again is one of these things where I think of this as looking at the world through one eye. We have one comparison with humans. Now, it's mice. And just like you don't have much perspective when you close one eye, I don't think you have much perspective when you have one comparison. And that's kind of what we have now. Why do you think it's been, I don't want to say so difficult, because I don't know that

we've tried, frankly, but why do you think there hasn't been a greater effort in identifying better biomarkers of aging? Or do you think that there has been an enormous effort, and it's just been too difficult? But for example, we don't know how long one as a human needs too fast to achieve a significant inhibition of rapamycin to extract the benefits that we think are there. Why is that? I would say that of your two alternatives that we haven't tried hard enough, or maybe we've tried hard enough and haven't found anything.

I would say it's the latter because in the 1990s, the NIA put I think $100 million into developing biomarkers of aging and it came out with nothing, but that may have been that we just didn't have the right tools at that point. I think we're really on the verge of something big here so that we can have biomarkers that will tell us exactly this kind of thing. And do you think these biomarkers will be in the metabolism, in the proteome, in the epigenome, all of the above? Yeah, I think they're likely to be all of the above. And right now the hottest one is in the epigenome because that's looking better and better and it seems to work. Or you ought to.

You're optimistic. I mean, I've seen how easy it is to manipulate those and I find it completely uninteresting. And that's going to alienate a lot of people that are listening to this because I'm the naysayer on that. But Steve, when I look at those data, I'm not remotely impressed. And by the way, I've done the experiments on some of my patients, right? You, you know, you measure their epigenetic age on day zero. They do a three day fast. You measure their epigenetic age. It goes down by 10% or more, frankly, have you really learned anything?

And then a week later, it's back to normal. I don't know what that's telling me. Well, it may be, so I'm actually fairly impressed by the epigenetic data, but maybe it's not gonna work in this short term like that. It may be, this is maybe something that tells you something over the course of years, but not over the course of weeks or months.

My only point there is that it's very sensitive to what's happening in the moment, right? And so when I look at a lot of these aging clocks and I look at the inputs, I think to myself, these are very easy to manipulate. What was your vitamin D level on this day? What was your glucose level at the moment of that blood test? I mean, these things are so easy to manipulate and they have so much volatility over time that I don't find them to be clinically quite useful.

Well, they may never turn out to be clinically useful because it may be that they're integrating things over a time scale that's not clinically meaningful. I think the likelihood that we're going to find something in the proteome in the metabolism is higher. I mean, something that's therapeutically useful, just because those things really change rapidly. And if we want to know, if you fast six hours, you fast 12 hours, I think what you're going to look for there is changes in gene activity. And that's going to be in the proteome or in the metabolism. The thing is it's going to be computationally complex.

Now we have all these tools for doing computationally complex things, but they're not cheap tools. And so I don't know how long before they'll be in the clinic where we can afford to do this in people a mass. If I were ZAR for a day and could marshal the resources for the Manhattan Project on longevity, this would be one of the departments, right? Like this would be, you know, if you had a billion dollars to put towards a Manhattan project of longevity, I feel like a quarter of it would go into this problem. Because it, again, if we're interested in longevity, presumably we're interested in human longevity,

and if we're interested in human longevity, we don't have a hundred years to come up with the answer, so we have to come up with markers that are better. Well, and now we have the tools to do that. Every year, the tools, the computational tools, the analytic tools, if you can detect 3,000 different proteins in your blood, then you're much more likely to affect something that's really, really meaningful. Those things are all happening.

Of course, they could happen more if There were more money invested in them. I think that's the big issue, Steve. Personally, I think this is not commercially interesting enough. And I think that that's why it hasn't gotten the attention. I mean, I think the diagnostics space is a lousy space, right? Like, if you're a venture capitalist and someone comes up to and says, I've got a new diagnostic test. I mean, that's nowhere near as interesting as I have a new therapeutic model. That's why I feel like this could only really occur in kind of a Manhattan project or a heavily funded government project. But I just don't— and I use the term Manhattan Project, meaning an entity that is so large

commercially, that they understand that this is an important tool that needs to be developed in research to foster the development of molecules down the line. Yeah, it's an interest. You know, I mean, Craig Ventor tried to do that, and that corporation company wouldn't know where. Yeah, I have thoughts on that. I can't share publicly, but yeah.

But you're right. I mean, I think the key, the key's got to be there. This is not magic. There's stuff going on in the body. I think the blood because it courses through everything in the body is going to have clues to what's going on everywhere once we learn how to read those clues.

And I think part of the problem is that we're not, there's a very small group of people that are interested in making other people live longer. Most of the time it's trying to prevent them from getting a specific disease. There's a lot more money that goes into obesity, I think, than that goes into longevity. And it's hard to say that it's not well spent money because obesity is the huge problem. You made a very famous bet with J. Ashonsky 20 years ago, right? 21 years ago.

Yeah. What was that bet? The bet was about when we would have the first 150 year old human. Which side of that bet did you fall on? So my part of the bet was I think that person was born already, was born by the year 2000, the person who's already alive, who would ultimately become the first hundred and fifty-year-old person. And Jay bet the opposite. And the critical thing was the person had to be mentally competent enough to carry on a sensible conversation about something. Yeah, so that was 20 years ago and nobody's lived as long as the longest life person had

lived at that point since then. Which was about 122? Yeah, 122 and a half roughly. Nobody's even reached 120 since then and so Yeah, I'm asked quite often if I still think I'm right and I do Because I never thought this was gonna happen Because we got better at treating cancer or we got better at preventing heart disease I always thought it was going

to happen because we would develop something, or some things that would fundamentally change the rate of aging. And we haven't developed that yet. We've got a lot of clues, and I think we're getting closer and closer and closer. But the other reason that I'm still confident that I'm going to win that bet is that one of the things that's come out of the interventions testing program is that things can have this big effect, started late in life. So it may be that this doesn't happen until a person that was born in 2001 is 50 years old. But if it happens then, that doesn't mean that they still couldn't live 150 years. Now it's important to note, because this wager gets mischaracterized something.

I'm not saying that I think the life expectancy is going to be 150 years. I'm talking about a single person, probably a Japanese woman. It would be my guess if I had a guess right now. I don't think that 150-year life expectancy is in our future. What do you think is the limit of human life expectancy as we currently exist? Maybe 100 years. I think that's reasonable. Now, if that happens, some people will live 150 years, right? It's like the average is around 80 now, and this one person lived 122 years. I think if we get to 100,

that seems conceivable to me. And also something that could be reached by getting better at what we do now. The key thing is getting people to do what we know is better for them. Now, do you understand the math behind Jay's models that say if we completely eradicated cancer, we would increase life expectancy by X years if we completely eradicated disease Y, we would increase.

And the numbers are very small in his estimates, but I've never actually taken the time to look at the models to see where those numbers come from. Those models rely on a number of assumptions. One of the assumptions that each of these is independent of the other. And I think it's pretty clear. Which is completely untrue. Right.

Metabolic syndrome tells us that's untrue. Right. And eliminating a single cause of death is not the same as delaying 20 causes of death. Right. So I think they're kind of artificial in that respect. So those give me no pause for possibly winning my bet. So when you think about existing molecules, I.e. molecules that are either FDA approved or, you know, like 17 alpha estral dial is not an FDA approved molecule, but it's been tested and it's had unbelievable success in male mice in the ITP. When you think about Kanagaflose and a carboas, of course,

Rapamyson met foreman. What molecule do you think of the molecules we know about today as the most potential for zero protection? Certainly, if we go by the mouse data, it would have to be Rapamyson. If we go by the human data, it would have to be metformin. Both of those are weak statements. In my qualifications for each of those, as a pretty major qualifications, I actually think

that what might turn out to be the most helpful is combinations of these things. So rapamycin plus metformin. What I like about metformin is that the most compelling data come from human studies, not from mouse studies, the mouse data on Metformin are weak. Yeah, it didn't succeed in the ITP, which is were you surprised by that? No, I was surprised by that at all. And I wouldn't be surprised if it didn't work out in humans, just because most clinical trials don't.

I mean, the existing data, which is voluminous and all pretty much points in one direction, which is that it's going to be beneficial. Again, it all comes from people that are taking metformin because they're diabetic. So, this could be a lot like the Wisconsin experiment again, where it's not going to work if you do it on people who are healthy. Right. Now, near would argue against that, right? Near would say that there are many benefits that we see in metformin that go far beyond its glucose regulatory benefits.

There are the obvious benefit that the diabetic patients get. Yeah, no, no, no. Near would be quite emphatic about disagreeing with me on this. I'd love to be wrong about that, but I just if I had to put my money, it's just because most clinical trials fail and most clinical trials fail because they were based on mouse data to start off with at least.

So maybe this is something, it's certainly worth figuring out just because the effects are so manifold. It's dimension, cancer, and heart disease, and we don't know what else. We don't know, for instance, what it might do to muscle function. The best data on that, it's not good for muscle function. But again, that comes from early work,

and I think we have a long ways to go. Because it's so safe, that's the big thing about metformin' is that we know it's so safe, you know, that's the big thing about Metformin is that we know it's extremely safe. Been taken by millions of people. We don't know that about rapamycin yet. But I think it ought to be a high priority to find out what low dose rapamycin does. The trouble is giving drugs of any sort to completely healthy people is something that the FDA is not going to go for.

So we're almost going to have to work these things out on people that have some sort of illnesses to start off with. How would you dose rapamycin in a lung-jevety trial, just as a thought experiment, given two pieces of evidence that seem to be at dialectical odds with each other. So they are as follows. In the mice studies, in all of the ITP studies, the animals were fed rapamycin in their chow, meant, meaning they received rapamycin every day. They were always eating rapamycin.

But based on our mechanistic understanding of rapamycin, we believe that the benefits come not from global inhibition of m-tore, but from the inhibition of m-tore complex one, and not the inhibition of m-tore complex two, and in fact, the inhibition of m-tore complex two might actually have some negative consequences. And if you were to take constitutively rapamycin as patients do with organ transplants, you were suppressing both. How do you reconcile those two, and how would

you design a clinical trial to address this if your stated purpose was increasing longevity? The first thing I would do is I would start off with a dose that's been already been tested in human for its effects and enhancing vaccine response to influenza because they did multiple doses. Now that was a wrap up. That's right. A compromise. No, that was a wrap up wrap up wrap up wrap up wrap 20 milligrams of Evalolamus given once a week did just that Right, and the lower dose had was just effective at boosting immune response as the higher dose and had fewer side effects So I would start off with that Episodically like they did because I think there's some evidence that you're getting just as big a boost from

that without the side effects. Without the side effects. And also, I think, you can imagine how much the drug companies are working to find a wrap-up blog that doesn't inhibit complex two. I mean, that's going to be huge if they can come up with something that works really differentially on complex one. That's really where be huge if they can come up with something that works really differentially on complex one. That's really where I would start.

I think those vaccine studies were a great start because they were, those were healthy people. They just were older people. They were people, I think 65 and older. I would like to see those things continued. Now, it's interesting, a number of years ago, we tried to get funding for what I thought was a really good rapamycin study, but we were unsuccessful, which is that there was an NIH clinical trial to look at rapamycin as preventative for the reoccurrence of kidney cancer.

So, this is people that already had a kidney removed, but were seemingly cured, but they have a higher than average rate of relapse. They were giving one year of rapamycin to see if it reduced that. And I said, wait a second, why don't we jump in and measure inflammation, muscle strength, you name it, all these things in this experiment that was already ongoing, but unfortunately that didn't get funded. But on the other hand, it may have been too high a dose because this is therapeutic dose for immunosuppressive purposes, right? So it may not have been the right dose anyway.

So we might have come to a conclusion that was misleading. I thought that that vaccination study was a great avenue for starting a longer term study. And I know they're doing some of that in a private company, you know, spin off from... Yeah. Are you excited about the SGLT2 inhibitors? I think it's a little early to tell.

You know, that in the NAD, various NAD precursors, I think it's a little too early. I typically, you know, this is so scientists are often by temperament and training extremely skeptical. And I think that's why we make boring interviews so often. We don't ever come down on and make a clean statement. But I really need to see the data before I start to get excited. And I never get excited by a single mouse study. I get intrigued, but I don't get excited. Although the human data on the SGLT2 inhibitors is also remarkable. I think that's the sort of, that's the theme

here, right, is you have a great ITP outcome. And of course, the human data are not for longevity, but they're, again, they suffer the limitations of all human studies, namely that they're being used in a subset of the population that might not be the subset of interest, but the impact on kidney failure, all-cause mortality, heart failure is pretty impressive. And I think what's interesting about what the ITPs show us with both Kanagaflose and Acarbose is that the benefits might not have to do anything with reducing caloric intake, which was the proposed reason for Acarbose, but rather has to do with glucose kinetics. And I find that very fascinating actually. I do too. And I have to say I'm disappointed in the ITP that they dropped their paraphed arm of that. When they started off, there was going to be a paraphed arm. And they dropped

that. And I'm a bit disappointed because we don't know now. We only have body weight. We don't have food consumption. So we don't know how much of these effects might be due to food consumption and how many might not be. Or changes in the temporal pattern of food consumption. You know, maybe if it makes your stomach feel a little bit queasy, you don't want to eat the temporal pattern of food consumption. Maybe if it makes your stomach feel a little bit

queasy, you don't wanna eat again for 20 hours. So the human data, I mean, we're gonna make real progress when we have human biomarkers. And we can do a five year study, and we can say, we know this is gonna decrease dementia, heart disease, cancer, preserved muscle strength, boost immune response, not just immune system because we have to be careful

of that. I think people think, oh yeah, we want to boost the immune system. Well, we don't want autoimmune diseases. We don't want our immune system to go haywire because it mischaracterized something as an invasion. But we want to boost immune responsiveness, certainly. I mean, I think the limiting factor right now is biomarkers. Yeah, you know my feelings on that. So I think we end on the same page there, Steve. This has been a lot of fun. And we're long overdue to share a dinner and continue these discussions. So hopefully the next time it'll be in person.

That's a great mix of New York, Austin, wherever. Perfect. Alright, well thanks so much, Steve. I'm sure everybody enjoyed this as much as I did. Well great talking to you, Peter. Thank you for listening to this week's episode of The Drive. If you're interested in diving deeper into any topics we discuss, we've created a membership program that allows us to bring you more in-depth, exclusive content without relying on paid ads.

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