Peter Attia MD171- Longevity science: caloric restriction studies, aging biomarkers & possible longevity molecules
EVERY SPOKEN WORD
135 min read · 26,670 words- 0:00 – 0:10
Intro
- PAPeter Attia
[upbeat music] Hey, everyone. Welcome to the Drive podcast. I'm your host, Peter Attia. Hey, Steve.
- 0:10 – 7:19
Steve’s background and unusual childhood
- PAPeter Attia
As we were, uh, just talking about a minute ago, this has been a long time coming. I am so excited about this discussion today.
- SASteve Austad
Good. I'm looking forward to it myself.
- PAPeter Attia
You're, you're one of those people, and there are a handful of people like you, where any time we sit down, if it's over a coffee, a meal, or a short phone call, it... 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, um, is, is gonna be awesome. But, you know, frankly, any discussion about, uh, longevity, I think needs to begin with your background. I think people need to understand the curious character that you are.
- SASteve Austad
[laughs]
- PAPeter Attia
And, and your, your journey to, to where you are today is, um... You know, it's not, it's not common, right? And I... But yet I think it, it sort of speaks to, uh, the unique lens that you've, you've brought to this space. So, um, give folks a sense of, of, you know, what you did growing up. Like, when you were in high school, what were you interested in?
- SASteve Austad
You know, it was interesting. In high school, I was a math nerd, and everybody assumed that I was gonna be a mathematician, including myself. In fact, I, 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 liked 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. Um-
- PAPeter Attia
[laughs]
- SASteve Austad
But anyway, I had a great time doing that. And at that time, I think I was in 10th grade, he said, "You're gonna be a biologist." And I thought, "That's the most ridiculous thing I've ever heard of. I'm... No, I'm gonna be a mathematician." And then after I got to college, I suddenly discovered after the first year, I didn't really like math all that much. [laughs] And, um, I wasn't about to spend four years doing something I didn't like. So what I really liked 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, the, the Ernest Hemingway of the latter 20th century.
- PAPeter Attia
And you went, you went to UCLA for undergrad? You were in SoCal.
- SASteve Austad
I, yes, I did.
- PAPeter Attia
Yeah.
- SASteve Austad
Yeah. Um, so that was really my job. But I... 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. Um, we would live two months... You know, 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.
- PAPeter Attia
Oh, so this wasn't because one of your parents was in the military?
- SASteve Austad
No. No. My dad was a, 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, I really regret that I never asked him, "What, what did you... What were you thinking, Dad, when you did this?" Um, so that's where we went. We went, you know, El Paso, Dallas, Atlanta, Miami, Virginia, New York, Detroit. I... That's, that was my schooling, except in doing all this traveling every year, I missed probably two months of school. Um, 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, um, you know, I, I, I learned a lot on my own, and that probably influenced, uh, somewhat who I am, because that's a pretty unusual, uh, upbringing probably.
- PAPeter Attia
Well, I, I mean, [clears throat] I can't imagine most kids could thrive in that setting because it's so disruptive. Like I, I, I hear... I, I, I, I actually had a patient once who went to 11 different schools between first and 12th grade, um, so averaged about a year per school. So at least they didn't have to move during the school year. Um, but I always thought that that was, you know, just the social aspect of that, not to mention just the continuity. I mean, when you move from one state to the next, they may have different standards for what you're gonna learn in English, math, or science. But what you describe takes that to a whole new level. Um, were you ever behind in school? Did you ever show up at the, 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?
- SASteve Austad
Uh, 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, where, where we traveled through. In fact, you know, it 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. E- even when I graduated from high school, I was, I was still 105 pounds and about five feet four. And I, I quickly learned, though, that, uh, I could avoid being beaten up by the bigger kids if I helped them with their homework. Um, so I quickly fell into that in 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
- PAPeter Attia
And you're a normal-sized person. It's not like you're five-foot-seven today. So what, what do you attribute such a late growth spurt to?
- SASteve Austad
Well, it's kind of interesting given the topic we're gonna be-
- PAPeter Attia
Yeah
- SASteve Austad
... talking about. But, but I, when I was in, a sophomore in high school, I was still way behind. I was, I was a wrestler. I was wrestling in the 98-pound division, which is the lowest, uh, weight class, but I only weighed 79 pounds. And at some point, my parents took me to the doctor 'cause 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 w- I started going through puberty, and then, uh, my real growth spurt was after I got into college, you know? So, um, it, it, it was very un- unusual, and I still think of myself as being little. You know, even though I know I'm normal size, I still think of myself as being small.
- PAPeter Attia
[laughs] Well, that's interesting. That probably speaks to the psychology of our, uh, sort of formative years, right?
- SASteve Austad
Right. Exactly. But I really would be curious to know if I got growth hormone when I got those injections or not.
- 7:19 – 12:11
Steve’s adventures driving a cab in New York City
- PAPeter Attia
So like all good aspiring authors, you somehow wind up in New York.
- SASteve Austad
Right. Yeah, I figured that was the place to be if you were going to be a great novelist, 'cause that's where all the publishing was. But the o- other thing that I figured was that if I'm gonna write a great novel, like, 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. Um, so I went there, but I decided I needed to start accumulating experiences, so I started having adventures. You know, I would, you know, I would hop a train from Southern California to San Francisco and back. Uh, I got to New York by hitchhiking, uh, to New York. And, uh, later on, I hitchhiked back to California again. And w- and when I was in New York, I thought, "Well, where am I gonna get experiences here?" Uh, so I ended up driving a taxi there, 'cause I thought, "Wow, this looks like you could really accumulate a lot of experiences in a hurry here," which was true. [laughs]
- PAPeter Attia
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 you know, there's some nuance to it given the one-way streets, and you've got, you know, Broadway is diagonal, and s- so it's, you know, it's not a trivial city to learn, especially given its size. H- How long did it take you to be a competent cabbie?
- SASteve Austad
Um, 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, that were a maze. And usually what I would do to hide my ignorance is I would just ask the passenger, um, "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. Now, then, then of course, if you got to the outer boroughs, it was a whole different, uh, ballgame. But I didn't go to the outer boroughs very much, and when I did, uh, [laughs] I had to have help getting back because it was challenging. Um, but it was a, it was a really unique experience. I drove at night, so I would go to work about 4:00 in the afternoon and come home about, you know, somewhere between midnight and 2:00 AM, depending on what the fares were like. And I mean, I, you know, uh, the experiences I had, I had people who... One person I remember well wanted me to stop at every bar along the street. And w- and we did this for a while, and I... He'd say, and he'd go in the bar, and he'd say, "Wait for me," and he'd come out, and we'd go to the next one. And I finally said, um, "If you don't mind my asking," 'cause I was afraid he was gonna c- go into the bar and never come back, and I would be, you know, in debt for the taxi fare. Uh, he says, "Oh, I'm looking for my wife, and when I find her, I'm gonna shoot her." And so that's the point at which I said, "Okay, well, you can pay your fare now, um, [laughs] but..." So th- that's a type of thing that happened to me more than a few times.
- PAPeter Attia
This was... W- W- What years were this?
- SASteve Austad
These were in the mid-1970s.
- PAPeter Attia
And New York's a, a totally different city from what it is today.
- SASteve Austad
Yes. Yes. No, in those days, um, you could get robbed in the, in s- daylight in Central Park, and now Central Park is just a wonderful place to go. Uh, i- it wa- it was, in retrospect, um, really quite the interesting time. And, and, in fact-
- PAPeter Attia
What was the, what was the dodgiest part of the city south of 96th?
- SASteve Austad
About... It was probably the extreme West Side, Ninth and 10th, 'cause there was a lot of abandoned buildings-
- PAPeter Attia
Mm-hmm
- SASteve Austad
... over there. The str- lighting wasn't good. Um, and then, uh, and then of course, Harlem was, was not a great place then, and I was, a lot of the-
- PAPeter Attia
That's why I said south of 96th.
- SASteve Austad
Yeah.
- PAPeter Attia
That was like, I took that as a given.
- SASteve Austad
I figured I've-
- PAPeter Attia
Yeah.
- SASteve Austad
I figured it was. But the interesting thing is a lot of cab drivers would not d- take fares to Harlem, and I would.
- PAPeter Attia
Mm-hmm.
- SASteve Austad
I would take somebody any place they wanted to go. Um, but I did have some dicey experiences there, I have to say. And I never was robbed, but I was the only taxi driver in this garage that I knew that was never robbed during that time, so...
- PAPeter Attia
Do you attribute that to pure luck or something else?
- SASteve Austad
Yeah, I do. The one time I was certain I was gonna be robbed, a police car turned a corner and pulled up behind me and couldn't get by because it was a narrow street. And, uh, so the guys that I, I could just tell from the vibe this is not gonna be good. They just paid and got out and left. So that was the closest, uh, that I had. Although I did pick up two taxi drivers who had been robbed and their cab had been hijacked. Um, and they were on the street, and they waved me down. And, uh- So yeah, [laughs] it was a pretty adventurous
- 12:11 – 22:18
How Steve drove to LA and accidentally became a lion tamer
- SASteve Austad
time.
- PAPeter Attia
So where was it in here, Steve, that you also began a little side hustle training animals?
- SASteve Austad
Well, that was after my taxi driving years. I, uh, what happened is that I moved back to Portland, Oregon. I'd, uh... And 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 years, uh, sort of sixth through 10th grades there. I really liked it, and after I got out of, uh, college, I, I went to Portland for a short time before I went to New York. So I went back to Portland, and there, uh, I was taking karate, and my karate, uh, teacher had some African lions at his ranch out in the country. And I used to go out and, and, and visit him and w- if he was cleaning the cages, I would, uh... You know, he'd say, "Come on in. Let's talk while I'm working." And so I'd do that, and I, I guess I wasn't too obviously terrified, because he got a offer to use the lions in a, in a movie in Hollywood, and he needed someone to help him, uh, drive the lions to Hollywood. So he asked me if I'd do that. Um, and I was... I had a job as a newspaper reporter at the time, so I thought, "Well, this is gonna be a long weekend." So I said, "Yeah, I'll, I'll, I'll help you do it." And I went out to his house, and I assumed there was gonna be, like, something like a horse trailer that was modified for lions.
- PAPeter Attia
[laughs]
- SASteve Austad
A- and what he said was, um, "Help me get the backseat out of the c- car here, Steve, and we're gonna put Cherza," which is one of his lions, "in the back." So we did. We took out the car seat, we put the lion in the backseat, and we took off for LA. And there was nothing between, noth- no screen, no window, nothing between the front and the backseat. Uh, but in my naïveté-
- PAPeter Attia
This is when you're, this is when you're wishing for the New York taxi with the plexiglass
- SASteve Austad
... Yeah, no kidding. Uh, uh, well, actually, I wasn't worried at first, because I thought, "It's his pet. He must know what he's doing." Later on, after I knew more-
- PAPeter Attia
But you weren't worried about the fact that the pet's more familiar with him than you, and if... [laughs]
- SASteve Austad
No, I should've been. I should've 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 p- 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." And so, um, that worked once, and then, uh, the battery ran out and, uh... [laughs] So, uh, then he s- I said, "What am I gonna do now?" He goes, "Well, just hold it in his face and go bzz with your mouth like that."
- PAPeter Attia
[laughs]
- SASteve Austad
And I thought again, I thought, "It's his lion. He must know that his lion's that stupid." [laughs] And it turned out it wa- his lion wasn't that stupid. That w- [laughs] that worked once.
- PAPeter Attia
[laughs]
- SASteve Austad
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, 'cause I thought, "He knows what..." So we ended up pulling off on a side road in the middle of the night now, um, getting his lion out on a long leash, and walking it down this, uh, this rural country road for several miles to try to get it, uh, tired out. And, uh, 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 would go around a corner and the lion would lose sight of the car, um, we'd come around the corner and the lion would attack the car. It would jump up on the hood. Um, 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 [laughs] gonna run out, and..." Uh, but none of that happened. Uh, 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, uh, we had switched drivers and it w- a- and suddenly the police lights came on [laughs] behind me. And so, uh, uh, the policeman pulled, pulled us over, and I jumped out quickly to try to pretend this was just normal. But, you know, you know how 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 speeding? 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.
- PAPeter Attia
[laughs]
- SASteve Austad
And so the car horn just starts shrieking. [laughs] So at this point, the policeman said, um, "Just get out of my jurisdiction." [laughs] He, he didn't know how to deal with it. Uh, so we had a rather uneventful trip, uh, down to LA.
- PAPeter Attia
At some point, did you at least get a new battery for the taser?
- SASteve Austad
We didn't. We didn't. Um, once we got to LA we did, but, uh, by the time it was light, we were close enough that, um, the lion was asleep still, so we ne- 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. Um, but, uh, it turned out the movie producer offered me a job [laughs] on the spot. And, uh, he said, "We're doing this movie. We're gonna have 25 lions in it. We need lots of lion trainers." I said, "You don't understand."
- PAPeter Attia
[laughs]
- SASteve Austad
"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." So, um, he says, "Ah, that, don't worry about that."
- PAPeter Attia
[laughs]
- SASteve Austad
Um, uh, he says, "I've, I've got lots of professional trainers."
- PAPeter Attia
Translation, "You're the only one dumb enough to do this job."
- SASteve Austad
Yeah. [laughs]
- PAPeter Attia
"I can't find anybody in my union willing to do this, but yes, carry on."
- SASteve Austad
E- exactly. Exactly. So I was still pretty dubious, I have to tell you, but here was the key. Um, he said, "Well, what, 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 r- months and take care of the lions. And the only, uh, people that you'll have to deal with is my wife and my daughter, uh, my wife Tippi." And I had this crush on this actress named Tippi Hedren since I'd seen her in The Birds when I was a kid. And as soon as he said Tippi, I thought, "Gee, that's a unusual name." And it turns out he was married to Tippi Hedren, 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. [laughs] So I said, "Okay, you know, when do I start?"
- PAPeter Attia
I mean, at this point, Steve, you have more than enough substrate to write a fantastic novel, right?
- SASteve Austad
[laughs] Yeah, I... By, by that time I realized that that's not where my talent l- lay. Um, so I really wasn't thinking any more 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, I worked there, I never took a day off on Saturday and Sunday, 'cause I just enjoyed it so much. Um, so I'd almost feel like I'd been given this gift of, uh, o- of something that I was always meant to do, but just by luck had just stumbled into it.
- PAPeter Attia
So what finally got you to go back to graduate school?
- SASteve Austad
Uh, probably a bad encounter with a lion. [laughs]
- PAPeter Attia
Hmm.
- 22:18 – 30:35
How Steve’s early graduate school experiences led him to study longevity
- SASteve Austad
reruns, and I didn't find that very interesting. And so I'd really gotten bored w- 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. Um, and I went to East Africa at that point. The, there was a long-running Serengeti lion project that had just ended. Uh, the people that were doing it had just quit. Uh, I went to graduate school bec- my advisor, um, did research in East Africa on monkeys, and he told me, "If, like you get over there, you might be able to take over this project." But I didn't. Uh, 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, um, and under what circumstances they might do that. So it had nothing really to do with w- with lions. So, uh, at that point I didn't know, really know. I thought, "Well, I've got a PhD. I guess I should be a professor somewhere." [laughs] Um, but I had no interest in aging. It never even occurred to me. Um, 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, uh, was, uh, studying another group of animals, but he kept catching opossums in 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 opossums. You're studying the wrong thing. You should be studying the opossums." So he said, "Well, what, what of interest could we do to the opossums?" And we put our heads together and came up with something. It still had nothing to do with aging. Uh, but in the course of that project I would capture opossums once a month, and I would weigh them and measure them and look in the pouch. These were all females that were radio collared. And one of the things I discovered was they aged incredibly quickly, you know? So this is an animal, the South American ones that we were studying looked very much like the North American opossums. Most people would not be able to tell the difference. Um, 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 all parasitized. They would just look terrible, even the same animal that I'd caught three months earlier. And I just became incredibly intrigued with why they would age so much more quickly than a, than a cat. Um, 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, you know? So that's kind of the long story about how I got into this.
- PAPeter Attia
So where, where did you ... When you, after you finished your postdoc, where did you come back to?
- SASteve Austad
When I finished my po- uh, my first faculty position was at Harvard. Um, and, 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, 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. Uh, and so it was great. So I, um, I basically spent some time developing my first aging study, which was a field study of, uh, 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, a population of opossums 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 opossums is that because the babies are born in a pouch, if you catch a 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 birthdate basically of every animal in a population fairly quickly, which is pretty unusual for wild animals. So that, that was really, um, how my aging career got started at Harvard, and, uh, it was a great experience. Uh, it w- it was a wonderful place to be. Um, unfortunately, my wife hated Boston [laughs] [clears throat] and so she was really wanting us to go somewhere else.
- PAPeter Attia
What did you find out about the opossums, and, and what explained the difference? H- how much of a difference was there between the, the groups that grew up in a low-stress environment versus the high-stress predatory environment?
- SASteve Austad
There was about a 20% difference, okay? So pretty substantial difference, and the next phase to figure this out was to, to try to work on the mechanism. What, what is it? And this was-
- PAPeter Attia
Yeah, was it cortisol related? I mean, what-
- SASteve Austad
Right, exactly. This was in ... You know, this by now was in about 1990, and we didn't have genomics really at, at that point. If we did, the first thing I would have done is sequence the genome of the opossums on the island and the mainland. But I, the only thing I could think of to do next was to... Two things. One, I was interested, is this some genetic thing-
- PAPeter Attia
Did you do a swap?
- SASteve Austad
Or an environmental... No, I, I, I-
- PAPeter Attia
In other words, did you take the island version and just let them breed, uh, or, you know, 'cause y-
- SASteve Austad
I, I-
- PAPeter Attia
In one generation, you'd pretty much get your answer, right?
- SASteve Austad
That's exactly right, and I, and I submitted a proposal to do that, and it didn't get funded. The, there was a problem. I could only really do it in one direction. I could take the island opossums 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-
- PAPeter Attia
Right, you don't want to contaminate it
- SASteve Austad
... now, yeah.
- PAPeter Attia
Yeah.
- SASteve Austad
So, um, so I never did that. It was the obvious thing to do, and I, uh, I thought about it, but I never ended up doing it, and I'm sort of disappointed. What I did, though, is I, I got, um, a population of opossums that I brought into the laboratory, and I, my plan was to start off with just some regular opossums and then once I knew how to manipulate opossums in the laboratory to go get some from the island. Um, but opossums are really not easy to keep in the laboratory environment, and my colony ended up getting some, uh, flesh-eating, uh, infection. And so I basically had to, uh, abandon that project. I, I thought, um, you know, I thought about going back to it subsequently, you know? And, and in fact, I went back to the island, which is called Sapelo Island, which is off the coast of Georgia, about 10 years later with a f- with a film crew to do a film about them, and in the interim, a new species had been introduced to the island. Um, um, armadillos had never been there before, and now they were there before. So I suddenly got worried that my population of opossums had also been contaminated. So that discouraged me from going back and working on the genomics of those opossums.
- 30:35 – 43:49
The challenges and limitations of working with lab mice
- PAPeter Attia
So at what point did you begin to come, uh, did you start to be get, 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 gonna go with this, Steve, is two directions, just to give you a heads-up. Obviously, I wanna 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 wanna talk about the distinction between [lip smacks] um, mice in the wild and mice in the lab when it comes to all of the literature on CR and DR. Uh-
- SASteve Austad
Right. Certainly
- PAPeter Attia
... so, so, so it's really, I mean, and this, these are discussions you and I have had [clears throat] um, and every time we have it, it gets richer and richer. So, uh, you know, w- I guess I, what I'm really asking at the outset is, when did this subject matter, uh, become of great interest to you?
- SASteve Austad
So w- okay. So my, my background is entirely in field biology at the point when I start doing laboratory biology. So I'm coming from a, 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, in the, in the wild, I started to get very interested in what I call laboratory evolution. How have these things changed s- in the hundred years or so since they were brought into the laboratory? Because, you know, when I 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, um, so I started thinking, "Well, what can we learn? Is there anything to learn?" Um, and one of the things that right off the bat was this, this dietary restriction experiment.
- PAPeter Attia
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, the, 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 gonna apply later on. But notwithstanding that, um, help, help folks understand what a mouse in captivity has been through. What does it mean, for example, to be homozygous at each loci? What, what is it that we're trying to accomplish? And, and in ex- what's the price we potentially pay for that?
- SASteve Austad
Yeah. So, so let me describe the history of the laboratory mouse. So the laboratory mice came from, um, what were 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 probably still are-
- PAPeter Attia
[chuckles]
- SASteve Austad
... mouse equivalents. So at some point, um, research... Uh, 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, they started inbreeding them. And when I say inbreeding, I'm not talking 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, um, come from mice that were selected for bizarre coat colors and sizes, mice that were then inbred, um, for hundreds of generations so that they're absolutely genetically identical, uh, to one another. Uh, 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, uh, calls a mouse-like object. Uh, you know, a [chuckles] [clears throat] um, something that looks like a mouse, but it is, uh, it's not only genetically identical to all of its, uh, uh, the other ones. It's now called a strain, okay? So B6 is a strain. It's now called a s- it's not only genetically identical, but again, because of the inbreeding, it's, it's homozygous 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, uh, not just in aging, but in cancer, in Alzheimer's disease. I mean, we use that one mouse. A- and I used to say to people, "This is like if we only tested 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. You know, I mean, it is about as bizarre of a creature from a zoological perspective as you can imagine. They're twice as big as a wild mouse, at least twice as big. Um, they, they reach sexual maturity about twice as fast. They have much larger litters. They have a baz- bunch of bizarre mutations and some strains, um, become blind in a few months of age. Some become deaf. Some, if they hear a loud noise, start having convulsions. And, and this is the fundamental basis of our biomedical [laughs] research enterprise as it applies to mammals. So, um, 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, 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.
- PAPeter Attia
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 investigation, uh, um, the, the intervention testing program, the ITP. What is it that they do that raises the bar on, on rigor?
- SASteve Austad
Right. So, so Rich Miller is a good friend of mine, and we've done a bunch of projects together on, on mice, on different kinds of mice. And what the, what that ITP does is that they create w- what are called genetically heterogeneous mice. That is, every single mi- mouse is genetically unique. Um, but they're all brothers and sisters. They, um... 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 i- in, when they're together with themselves. So I, I'm, 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.
- PAPeter Attia
It, it's sort of the, it's the least bad option, basically.
- SASteve Austad
Yeah, exactly. And there's, there, there's one kind of weakness that I'd, 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 the mice 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. Uh, and in fact, um, 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. So, um, 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, um, evolved slowly by drift over the last hundred years. So for instance, um, his, uh, my, my friend that's got the nuclear mitochondrial exchange mice, his two mitochondria, which are very different by mouse standards, only differ at five individual nucleotides in the whole 16 and a half thousand nucleotide mitochondria.
- PAPeter Attia
How many genes is that again? Is that about 20 genes?
- SASteve Austad
It's, uh, it, 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-
- PAPeter Attia
Mm-hmm
- SASteve Austad
... uh, 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.
- PAPeter Attia
Now, is, is it too late, Steve, to, to sort of say, "Look, we're gonna go into the wild, get a whole bunch of completely wild mice that are so geneter- g- genetically heterogeneous, and we're gonna start letting them breed, and we're not gonna force them to be inbred. We're just gonna let them breed naturally"? Um, is that just too expensive? Or, like, why has no one gone about, you know, trying to address this? 'Cause it's, it's, it's such an obvious limitation.
- SASteve Austad
Right. Well, I think one of the reasons is, is the lack of genetic control that you would have in that situation. There has been some attempt to do that. That is, the, the, people have been working on a, a, a, a diverse, 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, uh, to create something. The problem is, in talking to those people, the, 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 gonna take a big change in the culture of the way we do laboratory medicine, I think, before people will accept that.
- PAPeter Attia
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- um, how genetically far removed they are from their predecessors. Whereas because you came at this from, you know, being a field biologist a- and also with a much greater lens for comparative gerontology, right? You're looking at this opossum and that opossum, and, you know, these are both wild, and yet they have some differences, but they're not, you know, they're not totally different. Um, th- there... It, it may simply be a blind spot, right?
- SASteve Austad
Yeah. I, I, 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, uh, even the bo- best mouse model is not gonna be enough. We need to know more about general mammalian biology if we're gonna understand our own biology
- 43:49 – 52:30
The connection between caloric restriction and lifespan
- SASteve Austad
better.
- PAPeter Attia
Well, before we leave the mouse, let's, let's talk a little bit about Clive McCay and kind of the, the, the history of caloric restriction. Um, I think most people today are generally well aware of the, uh, reported efficacy of caloric restriction in life extension. Uh, 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, let's maybe have you explain to people what this history looks like.
- SASteve Austad
Sure. Well, well, the first person to really do this in a, in a, in a formal way was, as you mentioned, uh, Clive McCay, who was a nutritionist at, at Cornell at the time. And he wasn't interested in aging either. He was interested in growth and, uh, how to make animals grow faster, 'cause that has all kinds of agricultural implications. Um, and so in studying growth, he was looking at the effect of restricting the diet on growth rate. And 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, in dogs, although he didn't look all the way through their lifespan. And then he finally did this ex- this, this, um, experiment in rats, and that, in that one, he let them live their entire lives and documented very convincingly how dietary restriction made, in this case, only females, not males, um, live longer. And, um, the, the interesting thing about McCay is that about a decade ago, I was, uh, I was a, a visiting scholar, uh, at, 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, of what he'd done because he didn't really follow up on that.
- PAPeter Attia
This was in the 1930s, if I recall.
- SASteve Austad
Yeah, this was in the 1930s.
- PAPeter Attia
Yeah.
- SASteve Austad
And he was active until the 1960s. But he got, uh, into producing, you know, high-protein bread and, um, um, making nutritional food for the military during World War II.
- PAPeter Attia
Mm-hmm.
- SASteve Austad
And he really kinda dropped this whole thing. So even though he made what, in retrospect, was really, I think, a landmark discovery, I don't think he really appreciated that, 'cause he was never focused really on longevity.
- PAPeter Attia
So what are the ways in which this got, um, validated and repeated throughout time? Who was the next person to pick up that baton?
- SASteve Austad
You know, I'm, I'm, I'm not exactly sure who the next person was. There were a whole bunch of peoples starting really after World War II that started looking at it m- more closely in rats and more closely in mice. And there were actually, um, 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, um, on this topic was some stuff that I did during my PhD. So my PhD, um, 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 w- I was feeding various amounts. And I would keep them until they died, but I wasn't paying any attention to that. Once I s- once I discovered all of this work, I went back to my data, and I said, "Well, I wonder what happened when I fed them less." And it turned out the less I fed them, 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 was mouse studies now, um, rat studies. There was really... Uh, I think the next big advance was when Roy Walford, uh, got into it, who was very interested not just in how mice age, but how that might tell him something about human aging. And Ed Masoro, another researcher who followed up on rats. And those two, I think, really took it to the next, jumped it to the next level, which is, can we understand why this is happening? Um, there was really very little investigation of that previously. Uh, but Walford, who was an immunologist, um, was very convinced that it was doing something to the immune system, and that was at the base of it. And Masoro 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 wa- probably one of the most interesting and colorful personalities.
- PAPeter Attia
You must have known him because he only died t- what? Maybe 20 years ago, 25 years ago?
- SASteve Austad
Oh, yeah. In fact, my first paper... Uh, he published the figure out of my spider paper before it was published in a real journal, um, because he had heard about my work and he asked, said, "I'm wr- I'm writing a book. Can I put this figure in my book?" So yeah, I knew Roy, uh, quite well.
- PAPeter Attia
Of course, he's famous for the Bio Dome, right? That's, that was the-
- SASteve Austad
Yeah. Yeah. Oh, um, the Biosphere 2.
- PAPeter Attia
Oh, Biosphere.
- SASteve Austad
Right.
- PAPeter Attia
Yeah, yeah, yeah. Sorry. Yeah.
- SASteve Austad
Yeah. Um, and it's pretty interesting. When I was writing my book on... You know, so the Biosphere 2 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, was the doctor in there, and so this was a great opportunity. You know, he wanted to know how dietary restriction worked in people, and here he had, uh, all of these people that couldn't make enough... Anyway, um-
- PAPeter Attia
How long were they in the biosphere?
- SASteve Austad
Two years. Two, two years.
- PAPeter Attia
And when you look at pictures of him when he came out, I mean, he looked pretty emaciated.
- SASteve Austad
Oh, he looked horrible. He looked absolutely horrible. In fact, um, 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?
- PAPeter Attia
Yeah.
- SASteve Austad
Well, I wanted to use th- and they all look like that. Uh, 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, I'd love to give you that picture, but, um, everything's tied up in litigation." It turned out that the people in that experiment had become, uh, enemies, and everybody was suing everybody else over everything having to do with the biosphere. So psychologically, that wasn't such a great success. Um, people would disagree about whether it was a success scientifically or not. Roy thought it, you know, he looked at it in one way, thought it proved everything that he s- 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 look terrible." And then he died.
- PAPeter Attia
Yeah, he died young, right? I mean-
- SASteve Austad
Not... Yeah. Well, he wasn't that young. I think he was 79 or something.
- PAPeter Attia
Oh, okay. I thought he was younger.
- SASteve Austad
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-"
- PAPeter Attia
Right
- 52:30 – 57:32
Mice vs. rats and rodent aging experiments
- PAPeter Attia
so [coughs] going back to the sort of CR, um, insights, w- which was the... Oh, by the way, uh, sorry, before I do that, um, what can you tell us about rats versus mice, uh, in terms of the, uh, genetic diversity and the ability to glean insights that are perhaps more or less interesting?
- SASteve Austad
Um, rats are a lot different to the extent that, as I say, almost all the, the, well, 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, um, that you have in rats, it's far greater, uh, 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, and so they kinda took over. That's really why almost all the focus is now on that one species. Um, we now can do these genetic manipulations in other species just as easily, and I'd like to see, uh, something like the rats. For instance, we're working on a rat which it, um, the two mitochondria we're interested in, instead of differing only at five of these nucleotides or DNA letters, differ at 100 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 we can really, um, I, I would like to see something like, like Rich Miller's, uh, interventions testing program in rats as well.
- PAPeter Attia
Mm-hmm.
- SASteve Austad
Because I, 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 rhesus macaque, about that degree of divergence. But still, they're, they're very, they're very different. Uh, we also can do a lot more sophisticated cognitive studies with rats than we can with mice. They're trainable.
- PAPeter Attia
Mm-hmm.
- SASteve Austad
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, you know, calorie restriction studies. Um, but again, it's one study against the gazillion studies over here. But I'd like to, I'd like to really look at are we getting a biased picture of something like growth hormone because we only really know a lot about its mechanism in mice?
- PAPeter Attia
What, what is your best explanation for why the rats given growth hormone, uh, fared better?
- SASteve Austad
Oh, they fared worse. They didn't live any longer. Um, that was, that w- that was... I don't know. I-
- PAPeter Attia
No, no, but they fared better than the mice, didn't they?
- SASteve Austad
You know. Oh, so two... We're talking about two different things here. So if you compare dozens and dozens of mouse studies-
- PAPeter Attia
Yep
- SASteve Austad
... and you look at how much life extension there was with dietary restriction, and you look at a whole bunch of rat studies, you're right, the effect is bigger in rats. Um, 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, is the effect bigger in rats than mice? That's a good question. I don't, I don't think we know why, and I also don't know how far to push that, um, comparison because there's been a lot fewer rat studies done. We've done, uh, 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, in mice. That may be true, but, um, but I just don't think we know enough yet.
- 57:32 – 1:12:22
The impact of dietary composition and the harm of sucrose: Comparing two caloric-restriction studies in monkeys
- PAPeter Attia
So speaking of course about big experiments with DR and CR, we, we have to look no further than... I, I mean, they have to be the largest experiments done, the Wisconsin NIA experiment, correct?
- SASteve Austad
Yes. I mean, certainly the most expensive aging experiments that have been done, that haven't been done in people.
- PAPeter Attia
Yeah. So, um, gosh, this experiment was probably kicked off in the late '80s?
- SASteve Austad
Yeah, exactly. Yeah.
- PAPeter Attia
Tell folks about the experimental design.
- SASteve Austad
Yeah. So it, it was, it w- it was almost serendipitous that they, they'd started at the sa... So two groups, one at the National Institute of Aging, one at the University of Wisconsin, and one person, Rick Weinrich, had actually was involved in both. He was at the NIA when that's 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 inbreeding selection and all that stuff, uh, uh, closer to a real animal, in other words. And of course, these things live up to 40 years. Um, actually, many people don't know, but there was another study started at the same time on, uh, 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 ab- 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 affect their blood glucose, their body fat, and all these. Eventually, when enough died over the next few years, they, um, 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, 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.
- PAPeter Attia
So let's explain some of these differences, 'cause I do think there were some, there were some interesting differences. And, 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, 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, um-
- SASteve Austad
Yeah
- PAPeter Attia
... on that same day, they ran the rapamycin ITP result, the first rapa ITP result.
- SASteve Austad
Oh, the, the 2009.
- PAPeter Attia
Yeah, 2009.
- SASteve Austad
Yeah.
- PAPeter Attia
Not 2011, you're right.
- SASteve Austad
Yeah, yeah.
- PAPeter Attia
Uh, what's interesting is, of course, the, the monkey study was front page news. The rapa study was buried in the back, uh, barely, barely-
- SASteve Austad
Really?
- PAPeter Attia
Yeah, yeah.
- SASteve Austad
See, I didn't remember that at all. That's interesting, yeah.
- PAPeter Attia
So-
- SASteve Austad
So-
- PAPeter Attia
What was different?
- SASteve Austad
Yeah.
- PAPeter Attia
Let's talk about what was different between these experiments.
- SASteve Austad
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. Um, but ani... Again, this is, this comes from my... You know, I had a long history with studying, you know, uh, lions and tigers and other big cats and bears and elephants in 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, including us
- PAPeter Attia
Kind of like us captive humans. [laughs] Exactly.
- SASteve Austad
Yeah, exactly
- PAPeter Attia
I was just about to say
- SASteve Austad
Exactly. And one, you know, one of the things that I did in the, in the late '80s, early '90s, that I did some research in Papua New Guinea, where we're basically studying people who are still hunting, you know, with, uh, spears and arrows, and it's very similar to wild, you know, primates versus captive primates. So, so all of whi- uh, all captive animals are obese to an a- degree. Now, 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 what the Wisconsin study did is they took animals, the control animals that were eating ad libitum, so they, they had food available pretty much all the time, and they 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, its diet for the rest of its life is gonna be 30% less than that." And they did that for the next 35 years. [laughs]
- PAPeter Attia
And this was one-to-one randomization, Steve?
- SASteve Austad
Yes. Yes
- 1:12:22 – 1:28:22
Challenges of studying animals due to major differences in the lab animal vs. wild animals
- SASteve Austad
Yeah. And, 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. You know? We- most of those standards were really just developed for keeping them healthy so they could breed. And, uh, 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 of rats and mice. I don't think we understand it very well.
- PAPeter Attia
And there's no way to really study monkeys in captivity without limiting their exercise, right? I mean, there's, it, there's... Is it, is it, is it possible?
- SASteve Austad
It... Well, I, I think it is. I mean, it's, 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.
- PAPeter Attia
Yeah.
- SASteve Austad
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, uh, opportunity for physical activity. That's very similar to the rat and mouse studies, right? But I think for primates-
- PAPeter Attia
It's probably worse
- SASteve Austad
... I think it's, yeah, I think it's much worse. Cognitively, I'd have to think it's terrible. Um, I mean, they 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. And I, I think if you-
- PAPeter Attia
So they didn't even get to mingle outside of feeding times?
- SASteve Austad
No. No.
- PAPeter Attia
Why?
- SASteve Austad
Probably had to do with the, with the, with captive setup that they had in those two places. Um, it's not easy to get strange monkeys to interact with one another. You might end up with a lot of fighting.
- PAPeter Attia
Mm.
- SASteve Austad
And at least, uh, one, the, one of the other differences between the two studies was the Wisconsin animals, uh, were all, um, monkeys from India that were born in captivity, and so they knew the precise age. In the Bethesda study, they, they sort of added animals of different ages as they got them. Some of them came from the wild, and some of them, they kinda guessed the age at the start, and some of them came from China.
- PAPeter Attia
Mm.
- SASteve Austad
So there's some genetic differences as well. So, um, so yeah, your, your, your basic conclusion that nutrients seem to count, I think, is, is very valid, and I think that ... I think it's also something ... You know, I always say that humans are the worst animal to study that you could imagine because they, they don't do what you tell them to do, you know? Uh, a- and they'll lie about what they do. Um, 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, um, might not tell us anything. I mean, mouse, mice eat seeds and insect larvae in the [laughs] in the wild, and, and, you know, we're very different. So I think for these kinds of nutritional studies, I think you really do have to study humans 'cause humans have their own unique characteristics.
- PAPeter Attia
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, uh, but frankly, the lack of biomarkers that could really help us assess geroprotection. Um-
- SASteve Austad
Right
- PAPeter Attia
... but I wanna go back to kind of what you think would happen to animals calorically, calorically restricted in the wild. Do you think that if we could ... And, and, and imagine this is a thought experiment, although I believe this experiment has also been done in some form or another, where you calorie restrict wild mice. What do we know about-
- SASteve Austad
Oh
- PAPeter Attia
... that?
- SASteve Austad
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.
- PAPeter Attia
Yeah, yeah.
- SASteve Austad
So I brought them into the lab, 'cause one of the ideas that I had, which turned out not to be correct, was that we have select- 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.
- PAPeter Attia
Mice after my own heart, basically.
- SASteve Austad
[laughs] Right. 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 the contaminants of being in the wild, and then I restricted their diet, and what I found was that, um, there was no difference whatsoever in how long they lived. It ... 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 a, 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. They're genetically diverse. So I thought, well, maybe ... 'Cause the other part of this I didn't mention is very early on when I restricted them, a number of the restricted ones died early in the experiment. So I thought maybe depending on your genes, dietary restriction would be good for you, can have very little impact on your health, or it can be bad for you. Um-
- PAPeter Attia
The ones that died early, Steve, what did you, w- when you, um, examined them after death, what were you seeing?
- SASteve Austad
You know, I don't think that we did enough necropsies on the early ones that died to know that. It's not very easy to, um, to get good necropsy material on mice because, um, their bodies cool off so quickly, and their, uh, tissues start to degenerate so quickly. So almost all of what we know about, um, mice, um, pathology is from mice that were euthanized, and I don't think we euthanized any 'cause we didn't expect them to die when they were young like that, right? So, um, maybe they had some nutritional requirement that we weren't meeting. Uh, like I say, we were using standard laboratory chow, and that's ... You know, we don't really know how good that was.
- PAPeter Attia
Which, I mean, standard mouse chow is total garbage. That's probably a good, a good, a good reason to be concerned. Um, at the, at the upper end, Steve, did you see a re- I mean, I guess if you didn't euthanize them, you wouldn't know, but you, you'd expect to see cancer being the biggest difference, although do wild mice-
- SASteve Austad
Oh, yeah
- PAPeter Attia
... suffer cancer to a fraction-
- 1:28:22 – 1:37:18
Human studies of calorie restriction
- PAPeter Attia
So, um, let's turn to the human studies then, which obviously don't have the luxury of the same duration, uh, relative to the lifespan of the animal, but, uh, what, what have we, what have we learned there?
- SASteve Austad
Right. So there's, uh, I think you have four human studies that... Five if- maybe. So the first one, I think, was the, was the Biosphere 2 study, um, 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, 66 at the start of that experiment and 68 when he, when, when he came out. Um, 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. Um, there was one that was very short-term, six months, and then there was another, was slightly longer term, which was two years.
- PAPeter Attia
How many institutions were a part of these two studies?
- SASteve Austad
Three institutions-
- PAPeter Attia
So Pennington was one, right?
- SASteve Austad
... were a part of the study. Pennington, uh, Washington University, and then Tufts.
- PAPeter Attia
Okay.
- SASteve Austad
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, um, people can't do calorie restriction [laughs] in that traditional sense. I mean, in, in all cases, the goal was to reduce calorie intake or energy imbalance by about 25%, and they never came anywhere close to g- actually getting that. Um, in the longer study, I think ultimately the amount of restriction was about 11 to 12% that people were able to achieve over two years. Um-
- PAPeter Attia
Because these people were in charge of their own nutrition. It's not like-
- SASteve Austad
Right
- PAPeter Attia
... 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.
- SASteve Austad
Yeah, as I recall, I think they, the, the, they provided meals initially for a short term, but they didn't monitor whether the people went and ate anything else, uh, as well, and then they were on their own, right? And, uh, so it's quite clear that y- people can't... Nor- normal people. Uh, you know, there are people that can, um, but certainly your average person cannot. So in none of those did they achieve anywhere close to the dietary restriction they had hoped to do. Um, so what did they find with what they did achieve? Um, cardiovascular risk factors all improved, certainly. Um, you know, blood pressure was better. Lower insulin, lower glucose. Um, but there were some things, lower bone mineral density as well. Um, so it's, it, 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 the, uh, both of these experiments, the s- 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 gonna be like the Bethesda m- uh, monkeys that... So what that means is if you can only achieve 10% dietary restriction, you're gonna 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 surprise to anybody that that's good for your health, and, 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, uh, have. So I think you could generally say from the calorie re- studies that, yes, reducing your food intake had lots of benefits, had some possible negative, uh, effects in terms of bone mineral density, had some negative effects in strength loss, although not if corrected for body weight. Um, but yeah, generally beneficial. But again, 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.
- PAPeter Attia
[laughs]
- SASteve Austad
Any physician, I think, would say, "Yeah, okay. What, what [laughs] , where's the news?" Um, so that's what I take away from, fr- 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 w- work and assumed, "That is gonna make us healthy longer." And they really have restricted themselves like the, we really do to mice. And, um, they also have good, very good cardiovascular risk factors, um, less inflammation. They're probably gonna get sle- ca- like, get less cancer. But they have low bone mineral density, negl- negligible sex hormones, you know, whole suite of things, no muscle mass to speak of. I've s- I've spoken at a couple of their conferences, and they're always exhorting one another to exercise more 'cause they have t- trouble with this degree of restriction keeping any muscle mass at all. But it's a struggle 'cause they don't really have the energy to-
- PAPeter Attia
They don't have the energy, yeah
- SASteve Austad
... yeah, yeah. So, um, so that's, that's a-
- PAPeter Attia
And these people typically have what, how much of a BMI, Steve? These are people that are 17, 18 BMI at this point?
- SASteve Austad
Yes, I, I'd say 17 to 20.
- PAPeter Attia
Yeah.
- SASteve Austad
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, th- that, that's, 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 'cause I haven't... I've kind of lost track over the last few years of what's going on, uh, with those people. The other thing is they're all, they, they have very low thyroid s- 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 or so.
- PAPeter Attia
And we don't actually know the impact of this on long-term cognition, do we? I think the, on 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.
- SASteve Austad
Yeah. I, I th- I think that's true. The, uh, the cognitive part, uh, I mean, the, in the calorie re- study, they did a little bit of, uh, cognitive research, but again, I, you know, these were people that weren't being restricted to, to the same extent. And, [clears throat] you know, the people in that society are very eager to be studied. The problem is this is an uncontrolled experiment.
- PAPeter Attia
Yeah.
- SASteve Austad
My guess is before they started the calorie restriction, they were not your average person-
- PAPeter Attia
No, of course
- SASteve Austad
... with your average person's health habits.
- PAPeter Attia
This is, this is... Yeah, yeah. This is the poster child example for healthy user bias in epidemiology. Uh, we can learn virtually nothing-
- SASteve Austad
Yeah
- PAPeter Attia
... uh, from, from that without randomization.
- SASteve Austad
Uh, in terms of the immune system, though, I will have to say that I, I did ask a lot of people at the, at the conference, "Do you get, hey, how often do you get colds or the flu?" And they say they don't.
- 1:37:18 – 1:42:12
Better dietary protocols for humans: Alternatives to long-term caloric restriction
- PAPeter Attia
Um, I mean, 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. Um, and I would argue that even if you could, the quality of life might be, uh, not justify the 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, like the, the, the g-
- SASteve Austad
Yeah.
- PAPeter Attia
Yeah. What is it? It's... [clears throat]
- SASteve Austad
But I, but I think, you know, for these people, I don't think they perceive it as... I don't, I don't think they, they miss it.
- PAPeter Attia
No, no, no.
- SASteve Austad
The feeling-
- PAPeter Attia
My point is it, you couldn't extend... They, they are the subset who can do that.
- SASteve Austad
Yeah. Yeah.
- PAPeter Attia
To try to make that the solution for the rest of us-
- SASteve Austad
Yeah
- PAPeter Attia
... who are interested in some form of gero-protection, uh, it-
- SASteve Austad
Yeah
- PAPeter Attia
... uh, it-
- SASteve Austad
It's a non-starter.
- PAPeter Attia
Right.
- SASteve Austad
Yeah.
- PAPeter Attia
Sort of, sort of con- you know, constant caloric restriction isn't the answer.
- SASteve Austad
Right.
- PAPeter Attia
So we now look to other things, and y- uh, you maybe heard me talk about this, but I kind of have this framework, right? 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. Um, so that's, that's the environment where food is infinitely abundant, infinitely cheap, infinitely palatable, uh, and, and, and infinitely transportable. So meaning it's so processed that, that you can actually take it with you anywhere, right? Um, 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 gonna restrict what I'm eating. I'm not gonna en- 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 eight hours." And you can obviously make that window narrower and narrower. And then there's the, uh, 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. Uh, when I refer to dietary restriction, I mean no attempt at reducing the, uh, content, but rather changing the mixture or quality. So dietary restriction, which is probably what most people think of when they think of a diet, like a, 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 certain things.
- SASteve Austad
Mm-hmm.
- PAPeter Attia
Um, and so those two become, I think, the mainstay 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. Um, and that can be complete, such as, "Hey, I'm not gonna eat anything. I'm just gonna have water for three days every month or every quarter." And it can be partial, sort of like the fast-mimicking diet where for five days you consume, you know, 750 calories. Um, uh, when you think about that entire landscape, where do you think we have the best insight about the health benefits?
- SASteve Austad
Well, first of all, these are all pretty new-
- PAPeter Attia
Mm-hmm
- SASteve Austad
... ideas, and I don't think they've had a lot of empirical testing at this point. And the empirical, uh, testing that they have had has mostly been in people that already had some health issues, that were diabetic or pre-diabetic or something like that. However, the logic of it is pretty compelling. And this is some of... This is something we have learned from the mice. You know, from the mice we've, in the rapamycin studies, we looked-- 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 b- were studying mice and rats, you know, years later started noticing, "Well, wait a second," and I noticed this when we would 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 a 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,
- 1:42:12 – 1:50:53
The protective effect of fasting
- SASteve Austad
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 in mice or, or, or humans, seem to have multiple benefits. I mean, one of the... I think one of the most groundbreaking studies was by Jay Mitchell, um, unfortunately-
- PAPeter Attia
Who just passed away a year a-
- SASteve Austad
Recently
- PAPeter Attia
... I mean-
- SASteve Austad
Yeah
- PAPeter Attia
... yeah.
- SASteve Austad
Yeah. Terrible, terrible. Um, bicycle acc- but i- he showed that if you fasted a mouse for two or three days, they recovered from surgery so much faster than-
- PAPeter Attia
Well, well, well, actually, Steve-
- SASteve Austad
Yeah
- PAPeter Attia
... I mean, we should double-click on that a little bit, 'cause it's not just that they recovered-
- SASteve Austad
Yeah
- PAPeter Attia
... from surgery. They recovered from a lethal injury, right?
- SASteve Austad
Right.
- PAPeter Attia
There's one experiment he did-
- SASteve Austad
Right, right, right. Yeah
- PAPeter Attia
... where I think if I, if I'm thinking of the right experiment, they took a group of mice that were constitutively calorically 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 calorically restricted. So, 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 reperfusion. 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 animal's 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 lib 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?
- SASteve Austad
Yeah. Well, what, what he did, the, the... It actually cut off blood supply to the kidneys.
- PAPeter Attia
Was it the kidneys? Okay.
- SASteve Austad
And they all had another-
- PAPeter Attia
Yeah
- SASteve Austad
... they had another s- one that they did the liver.
- PAPeter Attia
Okay.
- SASteve Austad
Same result, though. And you're exactly right. They did these ones that had been calorically restricted their whole lives, the ones that had been... that were ad lib, and then the ones that had been fasted for... They did some that had been fast, uh, restricted for a few weeks, and then some that had been f- just fasted, water-only fast-
- PAPeter Attia
For a day
- SASteve Austad
... for two or three days.
- PAPeter Attia
Okay.
- SASteve Austad
For two, two or three days.
- PAPeter Attia
That's a big fast-
- SASteve Austad
And they did j-
- PAPeter Attia
... for a mouse. [laughs]
- 1:50:53 – 2:10:17
Reflecting on the sex differences in human lifespan, and why women have more neurodegenerative diseases
- PAPeter Attia
Well, speaking of human longevity, Steve, what do you think is the best explanation for the sex difference between men and women? Um, in the United States today and much of the developed world, it probably accounts for about two years of difference, doesn't it?
- SASteve Austad
More like five.
- PAPeter Attia
Is it that much? Wow.
- SASteve Austad
Yeah.
- PAPeter Attia
Okay. What, what's our best-
- SASteve Austad
Yeah
- PAPeter Attia
... attribution?
- SASteve Austad
Well, it's a really interesting problem and, and, and, and, and let's sort of, uh, talk about, uh, I think some myths about that difference. It's not that women survive better in old- in 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 in their 30s and their 40s. So they survive better at every age, and they survive better, uh, 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, um, it depends on the diet. It depends on the circumstances. We don't know any circumstances in which men survive, uh, better than, than, than women, even prematurely born infants.
- PAPeter Attia
Hmm.
- SASteve Austad
Being a male infant is a risk factor for dying if you're a preemie. Um, 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 that we can't do anything about later? There's, there's a little bit of weak but, um, I think maybe, uh, a provocative evidence. There's at least two studies showing a major increase in longevity for men who were castrated for one reason or, or another. Is that relev-- Now, these were unique populations, and maybe it has no relevance whatsoever, but that would kind of put the onus on sex hormone, right? On the other hand, there's the hormone replacement, you know, work in human females which suggests that, well, maybe replacing those hormones isn't such a great idea. So I don't think we know. So I'll tell you the three-
- PAPeter Attia
Although I think, I think that's-- I, I think we now don't find that to be the case, right? I mean, I think the-- I think basically every conclusion of the ori- or- original women's health initiative has been turned over, right?
- SASteve Austad
No. I don't-- I, I would say that's, that's, that's not the case. But the, but the, the, the key factor from the women's health initiatives is the women didn't start doing it until 10 years after menopause on average. And so th- 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, on all kinds of-
- PAPeter Attia
Well, yeah, but my point is there was no, there was no increase in mortality. I think if you really scrutinize the WHI data correctly, even the, the, the, the most headline-grabbing, um, finding, which was that the women in the, um, progesterone and, um, conjugated equine estrogen group had a greater, 25% greater risk of breast cancer. Um, I mean, I, I think we now understand that that was a very misleading finding. Um-
- SASteve Austad
Yeah, I mean, there were several things that they, they, they were much more, they were more likely to have a stroke. Um, 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.
- PAPeter Attia
Yeah.
- SASteve Austad
There was no difference in mortality, and you could have made the case that they shouldn't have stopped it at, at that point. But, um-
- PAPeter Attia
And it's interesting. On the, on the castrated study, uh, um, on the castrated literature, you know, it-- the obvious con- one, you know, the first or Occam's razor view of that would be, well, there's something about testosterone, right? And 'cause that's-- it's not so much that the men who are castrated are getting estrogen and progesterone. If you castrate them-
- SASteve Austad
Right
- PAPeter Attia
... they're actually gonna have no estradiol versus the estradiol-
- SASteve Austad
Right
- PAPeter Attia
... they would have if they could keep their testosterone. Um, 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, uh, at least outside of two or three years." Um, but then that comes to a point you made earlier. Maybe it's something that happens early in life with high exposure and...
- SASteve Austad
Yeah, I mean, to me, the telling data points are that the women survive better from ages zero to five. You know, that suggests to me that there's something already in place, and it probably ha- may not have anything to do... I mean, let, let me point out, the two testosterone studies are, are, are very weak. They were not done with this in mind. They were done post hoc.
- PAPeter Attia
Yeah, yeah, yeah.
- SASteve Austad
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, I mean, the difference in longevity was something like 20 years in both of them, so it wasn't [laughs] -
- PAPeter Attia
Yeah
- SASteve Austad
... a trivial difference. But I, uh-
- PAPeter Attia
I can certainly understand why men would have a lower all-cause mortality, uh, or a higher all-cause mortality when you factor in a couple of things. One is behaviors.
- SASteve Austad
Mm-hmm.
- PAPeter Attia
I mean, you know, if I compare my sons to my daughter, it's, it's literally like they wake up every day trying to figure out how to hurt each other and hurt themselves. It's, it's-
- SASteve Austad
Yeah
- 2:10:17 – 2:21:35
The importance of identifying longevity biomarkers and which ones show the potential to change the landscape of longevity research
- SASteve Austad
what we have now.
- PAPeter Attia
Why do you think it's been... I don't want to say so difficult, 'cause 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? Um, 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 to fast to achieve a significant inhibition of rapamycin to extract the benefits that we think are there. Why is that?
- SASteve Austad
Well, I, I would, I would say that o- of your two alternatives, that we haven't tried hard enough or, 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. Um, but that may have been that we just didn't have the right tools-
- PAPeter Attia
Mm-hmm
- SASteve Austad
... at that point. I think w- 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.
- PAPeter Attia
And do you think these biomarkers will be in the metabolome, in the proteome, in the g- in the epigenome, um, all of the above?
- SASteve Austad
I think they're... Yeah, I think they're likely to be all of the above. Um, and right now, the hottest one is in the epigenome, 'cause that's looking better and better, and it seems to-
- PAPeter Attia
Are you optimistic?
- SASteve Austad
... work well ac-
- PAPeter Attia
I mean, it is... I, I, I've seen how easily it is to m- how easy it is to manipulate those, and I find it completely uninteresting. And I... That's gonna alienate a lot of people that are listening to this because I'm the, 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. Like, I, I, that... I don't know what that's telling me.
- SASteve Austad
Well, it may be... So I'm actually fairly impressed by the epigenetic data, but maybe it's not gonna work in the short term like that.
- PAPeter Attia
Yeah.
- SASteve Austad
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. I think humans more like-
- PAPeter Attia
M- my only point there is that it's very sensitive to what's happening in the moment, right? And so when you, when I look at a lot of these aging clocks, and I look at the inputs, I, 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? What... 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.
- SASteve Austad
Well, they may never turn out to be clinically useful because it may be that they're integrating things over a, a timescale that's not clinically meaningful. I think the likelihood that we're gonna find something in the proteome and the metabolome is, is, is higher.
- PAPeter Attia
Mm-hmm.
- SASteve Austad
I mean, something that's, that's, that's therapeutically useful.
- PAPeter Attia
Yeah.
- SASteve Austad
Just because those things really change rapidly.
- PAPeter Attia
Yeah.
- SASteve Austad
You know? And, and, um, if, if we want to know if you do X for the... If you, if you fast six hours or you fax, fax, uh, fast 12 hours, I think what you're gonna look for there is changes in gene activity and, and that's gonna be in the proteome-
- PAPeter Attia
Yep
- SASteve Austad
... or, or in the metabolome.
- PAPeter Attia
Yep.
- SASteve Austad
Um, the thing is, it's gonna, it's gonna be computationally, uh, complex. Now we have all these tools for doing computationally complex things, but, 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, uh, uh, in people en masse.
- PAPeter Attia
I- if I were you know, czar for a day and could marshal the resources for the Manhattan Project on longevity, [smacks lips] 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. Um-
- SASteve Austad
Yeah
- PAPeter Attia
... because it, again, if, 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 100 years to come up with the answer, so we have to come up with, with markers that are better.
- SASteve Austad
Well, and now, now we have the tools to do that.
- PAPeter Attia
Yeah.
- 2:21:35 – 2:34:58
Molecules showing the most promise as longevity agents
- PAPeter Attia
So when you think about existing molecules, i.e. molecules that are either FDA approved or, you know, like 17, uh, alpha estradiol is not an FDA-approved molecule, but it's been tested and it's had unbelievable success in male mice in the, um, ITP. When you think about canagliflozin, acarbose, of course rapamycin, metformin, um, what molecule do you think of the molecules we know about today has the most potential for geroprotection?
- SASteve Austad
Certainly if we go by the mouse data, it would have to be rapamycin. Um, if we go by the human data, it would have to be metformin. Both of those are weak statement ... And my qualifications for each of those is 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. Um, the, what I, what I like about metformin is that the most compelling data come from human studies, not from mouse studies.
- PAPeter Attia
Mm-hmm.
- SASteve Austad
The mouse data on metformin are weak.
- PAPeter Attia
Yeah. They, it didn't succeed in the ITP, which is ... Were you surprised by that?
- SASteve Austad
No. No. [laughs] No, I wasn't surprised by that at all. Um, and I wouldn't be surprised if it didn't work out in humans. It's c- 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, is that it's, it's gonna be, uh, beneficial. Again, it all comes f- from people that are d- taking metformin because they're diabetic. And-
- PAPeter Attia
So this could be a lot like the Wisconsin experiment again, where it's not gonna work if you do it on people who are healthy.
- SASteve Austad
Right.
- PAPeter Attia
Now, Nir would argue-
- SASteve Austad
And we don't know
- PAPeter Attia
... against that, right? Nir would say-
- SASteve Austad
I know. I, I-
- PAPeter Attia
... that there were many benefits that, that, you know, we see in metformin that go far beyond its, uh, glucose regulatory benefits that are the obvious benefit that the diabetic patients get.
- SASteve Austad
Yeah. No, no. Nir would be quite emphatic about disagreeing [laughs] with me on this. Um, I, 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, maybe this is something do- It's certainly worth figuring out, just because the effects are so manifold. You know? It's, it's, it's dimension, cancer, and heart disease, and we don't know what else. Uh, we don't know, for instance, what it might do to m- muscle function. The, you know, the best data on that, it's not good for muscle function. But again, that comes from, uh, early work, and I think we have a, a, a long ways to go. Because it's so safe-
- PAPeter Attia
Mm-hmm
- SASteve Austad
... you know? That's the, that's the big thing about metformin, is that we know it's extremely safe. It's been taken by millions of people. We don't know that about rapamycin yet. Um, but I think it ought to be a high priority to find out what low-dose rapamycin does. Um, the trouble is it, you know, giving drugs of any sort to h- completely healthy people is something that the FDA is not gonna go for, so we're almost gonna have to work these things out on people that have some sort of illnesses to start off with.
- PAPeter Attia
How would you dose rapamycin in a longevity trial, just as a thought experiment, given two pieces of evidence that seem, um, 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 mTOR, but from the inhibition of mTOR complex one and not the inhibition of mTOR complex two, and in fact, the inhibition of mpor- mTOR complex two might actually have some negative consequences. And if you were to take constitutively rapamycin as patients do with organ transplants, you are 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?
- SASteve Austad
Well, I, I, the first thing I would do is I would start off with a dose that's been, already been tested in human for its, uh, effects in enhancing, uh, vaccine response to influenza, because they did multiple doses.
- PAPeter Attia
That's right.
- SASteve Austad
Now, that wasn't rapamycin.
- PAPeter Attia
No, that was-
- SASteve Austad
That was a rapa-
- PAPeter Attia
... everolimus
- SASteve Austad
... rapalog.
- PAPeter Attia
Yeah.
- SASteve Austad
Yeah. Right.
- PAPeter Attia
And that was fi- so five milligrams of everolimus and 20 milligrams of everolimus given once a week did just that
- SASteve Austad
Right. And the lower dose had, was just as effective at boosting immune response as the higher dose, and had fewer side effects. So I would start off with that episodically-
- PAPeter Attia
Yeah
- SASteve Austad
... like they did.
Episode duration: 2:34:58
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Transcript of episode WNKRSiSGvGE
