Steven: Sure. I like to explain it in the simplest terms. It has to do with the fact that we eat and we breathe. So if we didn’t do either of those, we would not have a problem with aging.  Aging is a continuous battle against those destructive processes that are going on inside us all the time. And we have imperfect defenses against those processes, and eventually they overwhelm us.  

 Gordon: I think we’re going to get into those defenses later on.  But first I want to talk about a second book that you’re a co-author on, which is Real People Don’t Own Monkeys. Is that the title? 

Steven: Yeah, that . . . So that book I wrote with my wife, which — you know, one of the miracles of that book is that our marriage survived,  us both writing on that together.  It’s a collection of-of just bizarre animal stories and events that have happened, you know, surrounding animals. There’s a story about me trying to get a tiger out of a tree. There’s a story about an indestructible cat — pet cat that we had, and one in which my wife discovered that one of her clients had-had-had been a secret murderer for many years. And,just, just any bizarre story of — surrounding animals that we could come up with.

 Gordon: You mentioned the tiger in the tree. I hadn’t heard that story. I did hear a story about you and your lion-wrangling years. Was that an alternative career earning money outside college, or what was that?

Steven: My ultimate goal was to be a famous novelist, to be Ernest Hemingway. And since you’ve never heard of any of my novels, that shows you how well that went. But to try to keep food on the table, I had a variety of strange professions, the last one of which was training big cats for the movie business.   And,   I have to say I really loved it. I don’t know if there’s anything that I’ve ever loved more than spending the day with these animals. Let me just give you one story I don’t think you’ve heard. I did a commercial for a famous perfume. And, to do the commercial, the model was supposed to be draped over a lying-down lion while she looked into the camera holding this perfume and said one sentence. And we did over 40 takes, and she couldn’t get the one sentence right. And after about 40 takes, the lion had had enough of these lights in his eyes and these microphones swinging back and forth. And so when she leaned on it, it sort of turned around — didn’t really snap, but it gave her a, it gave her a growl. 

Gordon: Yikes. 

Steven: Freaked everybody out — except for me. 

Gordon: Mm-hmm. 

Steven: And people said: “Aah, that’s the trouble with working with these wild animals on a set.” And I said: “No, this is . . . ” Well, I won’t say what I said  but I . . . 

[General laughter]

Gordon: Good story. , the . . . I mean, was working with the animals, was that the big influence in going back into biology? 

Steven: Oh, yes. I had to make a decision about whether I wanted to do that the rest of my life. 

Gordon: Mm-hmm. 

Steven: , and I got pretty seriously injured one time. I had a lot of time in the hospital to think about it, and I thought: “No, I . . . But I’ve gotten really interested in the way they behave. I’d really like to go back, study biology, and study lions in the wild.” And so I went to graduate school. That was my plan, was to study lions in the wild, but it just didn’t-didn’t pan out. 

Gordon: Well, Hollywood has given us an amazing scientist. So thanks for that. 

MUSIC INTERLUDE  

Gordon: What was the major question that pulled you into aging in the first place? 

Steven: Yeah, so I had this idea. So I was a newly fledged assistant professor at Harvard. And I was looking for a way to test this evolutionary theory of aging which I . . . Because of my background in evolutionary biology, I was very much interested in that. And because I was a field biologist at the time, I wanted to do a field study because that’s where evolution is doing its business. So I spent several years looking around for an island on which there were opossums. And the reason was that part of this evolutionary theory is the — was the prediction that animals that live in safe environments, say from all kinds of external danger, should eventually evolve slower aging than the same animals in more dangerous environments. And I knew, because by this time I had studied opossums for four or five years — I knew that about 80 percent of them all died from cars or predators on the mainland. , and I found an . . . I was looking for an island that had opossums but had a lack of predators because islands are well known for lacking a lot of the same predators that you might find on a nearby, mainland. So I finally located an island, and I started a study there where I was comparing aging in those animals with aging on the adjacent mainland — at a large, actually nuclear weapons facility, on the mainland. And the only reason that I was using the nuclear weapons facility was that you could do field experiments, and nobody would mess with them because the place was surrounded by barbed wire and lots of people with machine guns. So, what I did then is I started marking opossums when they were still in their mother’s pouch.  so at that time, when they’re about the size of a honeybee, you can actually mark them. So when I would catch them months later, when they were close to being adults, I would be able to identify them, know exactly when they were born, and then put a radio collar on them. And I could then track them the rest of their life. 

Steven: I had these radio collars that changed the signal when they stopped moving. So if they died, the signal changed. Then I could go out and-and find out when they died . . . So within, three years I had, I had basically followed a group of opossums from birth to death on both the mainland and the island. 

Gordon: That’s incredible. And what did you find? 

Steven: So I found that, indeed, on the island they were aging slower. In fact, they weren’t all entirely dead at the end of three years. And on the mainland, I had never found — you know, with hundreds of animals, I had never found one that lived to 3 years of age.  but as interesting as that, you would expect they would live longer because there were no predators —

Gordon: Yeah

Steven: — on the island. But on top of that, what I looked at is I looked at their reproductive aging. And on the mainland, opossums for their first year, opossum females, produce just fine. But for the few that survive into a second year, they have smaller litters. They’re more likely to be infertile.  They’re more likely to lose a litter. There’s all kinds of signs of reproductive aging. But on the island, the animals in their second year didn’t show any of those signs at all. And the third thing I did was I looked at the aging of their tendons.  Now, tendons age. It’s one of the reasons that athletes get more injuries as they get older. And so I took some tendon samples out of the tails of the opossums. And I did the appropriate chemistry and found out that their tendons were aging more slowly on the island at all. 

Gordon: Wow. So this all makes perfect sense. I want to dig deep– more into this — the evolutionary biology angle here, in thinking about aging and studying aging.  And just before we do that, just give us a notion of the range of longevities across the animal kingdom: the longest, the shortest. 

Steven: Sure. Well, the shortest is probably a matter of . . . It depends on how far you want to go in the animal kingdom. Right? 

Gordon: Yeah. 

Steven: There are animals that we mistakenly think are short-lived. Mayflies are a good example. Mayflies are kind of the, I’d say, the poster child for short life. They live only a day or two as adults. But here’s the interesting thing: They live several years as immature animals in the stream. So we tend to think of them as very short-lived, but they’re only short-lived adults. There are animals — I mean, the animals that you study, Gordon. There are worms that are probably as close to being as short-lived as any multicellular animal. 

Gordon: Yeah. 

Steven: It’s one of the reasons it’s so useful in-in research.  

Gordon: Which is about 15-20 days? 

 Steven: Yeah. And on the other end, we’re still discovering new animals. Now, I have a new book coming out, so I may as well plug my new book. 

Gordon: Excellent.  

Steven: Methuselah’s Zoo: What Nature Can Teach Us About Living Longer, Healthier Lives. It’s going to be — come out next year. But in that book, I go through all of the animals that are exceptionally long-lived that we know about. The longest-lived of all of these is a tube worm that lives on the bottom of the ocean in the Gulf of Mexico that lives at least a few thousand years, maybe as many as six or seven thousand years.  

Gordon: Is that the record holder for lifespan? It used to be clams, I guess. 

Steven: Clams, yeah. Now, these . . . The trouble is that it’s a very indirect measure. What they’ve done is they’ve marked some animals. They’ve come back a couple years later and measured how much they’ve grown, and then made some sort of calculations about how long they would have had to live to be that size. So it’s very indirect.  Of the animals that we can age precisely, yes, the oldest one that we know about is a clam: Arctica islandica, the ocean quahog. And we know that so precisely because they have annual growth rings, like trees. So the longest-lived one was born in 1499 and died in 2006. 

Gordon: Wow. 

Steven: That’s about as precise as you could, as you could be.  

Gordon: I want to just touch on the evolutionary biology thing here because it seems like there’s a bit of a tension in the aging field. I don’t know if it still exists. But you’ve probably been in rooms where you’ve seen scientists, they get quite heated with each other over different ideas of the-the evolutionary origins of aging. And I just want to briefly characterize the-the two ideas. One would be that-that aging is really non-biology. It’s an emergent effect of selection for other important stuff, like growth and development and so on. The genes just happen to also affect aging. And then the other school of thought is that aging has somehow evolved to be good for us as a, as a species or a group or something, and that-that the aging mechanisms that we study in the lab are-are like clocks. They are, they are programs to kill us. So first of all, is that characterization fair? And then what do you think about this? 

Steven: Yeah, I think that’s a fair characterization. And,  . . . Well, I think the argument that it’s programmed… And there are many ways to define a program. Right?  But let’s just say that the length of life, is set by some sort of suicide mechanism: that at a certain point, you just . . . To me, that makes no evolutionary sense because it’s hard to imagine how death could be good for us unless our direct offspring somehow benefited from our death. And the scenario that I like to paint here is, let’s just imagine that’s true, and that we’re living in a population where we all live, let’s say, 70 years, at which point we die. We all have two children. So the population is in stable equilibrium. Now, what comes — what happens if a new gene comes along that doesn’t kill us at 70, that allows us to live a few years longer and also to reproduce a few years longer? Well, now you can see: well, the ones that have that new mutation are going to leave more descendants than the ones that don’t have the mutation. And so we’ve now destroyed our –this simple, ideal community. And that logic seems to play out really quite well with most everything that we know about large patterns of aging. Now, I have to say that the whole idea was put together to explain why we age as opposed to why we don’t age. 

Gordon: Mm-hmm. 

Steven: I mean, that’s the fundamental, I think, mystery. I think we understand it now. But, I mean, a good question: George Williams, a famous evolutionary biologist, put it this way: Why can’t nature, that does such a magnificent job of going — of developing from a single egg to a perfectly healthy adult frog or fish or human, why can’t it do the much simpler task of simply keeping us healthy forever? And I think that was a really brilliant question to ask. And that’s what these evolutionary models were really trying to do was answer that question: Why do we age as to not age? Now, there are lots of wrinkles on that. Well, why do some animals age longer than others? And are there any animals that maybe don’t age? And if so can we predict what they are?

Gordon: Right. 

Steven: But the basic idea is simply that evolution only cares about the amount of offspring that we leave. It doesn’t care about how we go about, leaving those offspring.  and so what we’ve really done is sacrificed the non-aging ability by our ability to reproduce. That’s one metaphor by which to think of it. 

Gordon: Well, that’s great,  although th-there are people, of course, who point to interesting examples of — , in aging, I — and maybe it’s not aging; you can let me know — where it sure looks like a program. So one example would be these mutations in the tiny nematode worms, where, um . . . And I don’t think this was necessarily predicted by any sort of population genetic theory or anything, but combinations of these mutations can increase lifespan by 500 percent — 5X longer. And that seems shocking to people, I think. And, it  looks like a program when you’re looking down a microscope — it’s something that should have been dead 50 days ago, and it’s still alive. You think: “I’ve broken the clock here.” And then the other example maybe you could address is just what salmon do when they-they-they, you know, do this incredible thing of getting up the river, laying a gazillion eggs, and then just blow up. 

Steven: Yeah. So let me, let me talk about the worms first ’cause they’re, I think, the excellent example because we know so much about their aging.  I mean, one thing that worms don’t all do is they don’t all live 15 days and then abruptly die like salmon do. Right? 

Gordon: Yeah. 

Steven: So even the longest-lived ones, some of them will die early, some of them will die late. On average, you can make them live a lot longer with appropriate mutations, and I think that’s exactly what you would expect. Now, from an evolutionary standpoint, you would expect that there might be a cost to doing that. 

Gordon: Yes. 

Steven: A reproductive cost. And in fact, the best experimental work showing that is from your own laboratory — 

Gordon: Thank you very much. That’s very kind of you. 

Steven: — where you competed some of these, some of these long-lived worms against some of the wild type worms, and then — and the wild type won. And I think from an evolutionary standpoint, that was a brilliant series of experiments that confirmed exactly what we might have thought about it. Um . . .

Gordon: Well, thank you. I’ll make sure that my family will hear that little snippet. And then the salmon? 

Steven: Yeah, the salmon are an interesting case. They may be an example where you really do have a program. We don’t know. But one thing we do know is that salmon, when they come back to their natal stream after they’ve been out in the ocean,  they — very abruptly they-they reproduce, and then they die. And we even know pretty much why they die: They reabsorb all of their internal organs, basically, and turn them into eggs. And then they’re exhausted, and they die by just basically, complete immune-system collapse. And we know that that’s mediated by hormones. Now, how could that possibly be adaptive for them? That’s a question. It would be adaptive if, by dying in this little pool and decomposing, they were providing nutrients that would help their own offspring grow and develop. But it would have to be their own offspring. If they were just doing it to all of the offspring, then that would be great, you know? The others could cheat on the system, have their offspring take advantage of these poor, dead, rotting salmon, to live longer and produce more of their own offspring. So, salmon are a really interesting case. And-And,  there’s actually a really interesting case on the East Coast of the U.S., a fish called American Shad. They’re also like salmon: They-They go out to the ocean, and they come back and they reproduce. And it varies, whether they die after they reproduce, by latitude. In the South, they all die when they come back to reproduce. As you go farther north, those rivers have salmon that maybe half of them die. But half of them live. They go back out to sea. They come back a few years later and do it again. And the farther north you go, the more frequently they survive and come back multiple times. I think that’s a fascinating system for understanding more about the evolutionary biology of some of this seemingly programmed aging. 

Gordon: Fantastic. I mean, one of the challenges to this comparative approach, I guess, is mechanism. And we’ll-we’ll maybe talk more about mechanism in a bit. But I’m thinking of a specific example where there’s been some progress, which is the naked mole-rat. Could you introduce the naked mole-rat and-and talk about — the kind of science that people are doing? 

Steven: Yeah. It’s interesting. So I was . . . I’ve been interested in naked mole-rats since my PhD student days, when I was really a behavioral biologist. And that’s because . . . This is a small rodent, about the size of a mouse. It lives underground in vast tunnel systems in colonies. And a curious thing about it is that there — they have the same sort of social system as a honeybee or as ants, where there’s a reproductive queen; there’s one or a few males that keep the queen inseminated; and the rest of the colony, basically, is sterile, non-reproductive workers that help the queen raise her young. , so that’s been known since the ’70s. What I was originally interested in — in my opossum days, even — was in honeybees, we know, and in ants, the queen lives many, many times longer than any of the workers. And so I was curious as to whether that was true in naked mole-rats.  And so I contacted the woman that had started studying these, Jennifer Jarvis in South Africa, and asked her. And at that time, she’d only had naked mole-rats in her lab for a couple of decades. And she said: “Oh, yeah. The queens can live, oh, close to 20 years. But the workers are short-lived at all.” So I thought: “Well, this is just like a honeybee.” Now, if you fast-forward many years, one of her students, Rochelle Buffenstein, brought some of those to the United States and really started them as a model species to try to understand slow aging because it turns out in captivity, it’s not just the queen that’s long-lived. They’re all long-lived, and not . . . And late teens is not as long as they live; they live late thirties now. And so you figure this is an animal that’s the size of a mouse.  it seems to have no special traits except for these social traits. But yet, it’s got this incredibly long lifespan that-that just makes it fascinating. 

Gordon: So that first colony you mentioned, the-the workers were shorter lived. And then as the animals continued to be cultured in laboratories, the worker lifespans then expanded. That’s — 

— kind of amazing, h? 

Steven: Well, I think that at that point, sh– that’s probably what sh-she was expecting. My guess is maybe the workers didn’t get the same amount of care because in the wild . . . So this parallel group of people have been studying these for decades in the wild. And in the wild, it’s true: Workers only live a couple of years, and queens live into their late teens, you know? And so, um . . . In the laboratory, though,  it-it — where the workers are not being exposed to so much danger . . .  the workers are the ones that will excavate the dirt and kick it out on the surface. And when they do that, they also defend the colony. So in Equatorial East Africa, where they live, that’s probably a relatively hazardous job to have. 

Gordon: I see. I see. So I think we-we can maybe talk about mechanism. What-What’s our understanding of the longevity of the naked mole-rat?  Why is it so much longer lived than the mouse? 

Steven: Yeah. I mean, it’s probably multifactorial. Right? I mean, for one thing, they have a lower metabolic rate. And if the . . . If metabolism is the fire of life, and the fire of life is damaging, then you might expect that they would live somewhat longer from that but not nearly the amount of time . . . There’s certain other things. They’re very cancer-resistant. We’re-We’re really, surprisingly, learn– . . . We still [don’t] understand very much about the underlying mechanism. There’s a . . . There is a theory that it may have to do with this special chemical that they secrete in their skin — this high molecular weight, hyaluronic acid, that may contribute to their cancer resistance. I actually think that there’s something about living with the stresses of low oxygen. So deep in these tunnels, where their latrines are, the air has got very low oxygen, very high CO2, very high ammonia. You know, a mouse wouldn’t live, an hour probably in a deep naked mole-rat . . . 

Gordon: Hmm. 

 Steven: They’ve somehow adapted to those stresses, and I suspect that there’s something about that that’s somehow involved in their long life because other animals that live a similar underground life also tend to be quite long-lived. There’s a blind mole-rat that lives in the Middle East that’s not a close relative at all, despite the name. They also live in very low-oxygen, high-CO2 environments. They’re also incredibly cancer-resistant, maybe even more so, and they’re also long lived. They don’t live . . . They don’t seem to live as long as naked mole-rats, but they live into their twenties, which, again, is remarkable.  

Gordon: Okay. So I guess that would be a sort of evolutionary explanation as to why they-they-the-they-they are able to live longer. But they’re not under those conditions in the lab. Right? They’re under pretty normal conditions? 

Steven: Right. Yeah. I mean, like most things, I think the length of life is a side effect of other things. And I think that there’s . . . You know, it’s really hard for me to imagine why a naked mole-rat would be so long-lived just because of what we know about its ecology. 

Gordon: Hmm. 

Steven: I think it’s an epiphenomenon of having to deal with extremely [physiological-s-ly] stressful conditions. You know, there’s another animal that lives in a very, very low–oxygen environment. It’s-It’s a salamander called the Olm that lives in Croatia. And they’re even more resistant to low oxygen than naked mole-rats. , and they seem to live a hundred years or more. And so it’s hard for me to imagine that . . . There’s various things that all have one similarity, which is that they’re extremely resistant to low oxygen. And we know that oxygen can be toxic. Right? 

Gordon: Yeah. 

Steven: So there’s some relationship there. I’m not exactly sure what it is, but, um . . . You know, the naked mole-rats were also instrumental in abusing us of one of the key things that, I think, aging researchers thought for a long time, which is that a key to aging was-was the amount of damage that oxygen did to your tissues over time. Right? 

Gordon: Yes. Oxygen-Oxygen Radical Theory or Free Radical Theory. 

Steven: Yeah, ex-exactly. And in fact, in our laboratory mice, if we make them live longer, they almost always have less oxygen radical damage to their tissues. Well, Buffenstein discovered that the naked mole-rats simply have a toleration for high levels of damage to their tissue. And-And I remember when, when she reported that. I said: “Oh, that can’t be. There’s got to be a mistake.”  and, “It must be that she really doesn’t know how to measure these things correctly.” And it turned out that, at that time, she was doing a sabbatical at the place where I was, which was, you know, the Mecca for oxidative-damage studies. 

Gordon: Mm-hmm. 

Steven: And they tried all their fancy methods, and they kept coming up with exactly what she had found, which is that-that naked mole-rats h– just have a tolerance for these high levels of damage. 

Gordon: So that’s a molecular assay — right — of oxidative damage to proteins and so on?  I’m thinking about the different levels here because y-you were talking about, essentially, metabolism and physiology in reference to oxygen levels and so on. When you go in and you take the cells out of a naked mole-rat and you compare them to a mouse — well, lab-mouse cells or, I don’t know, maybe even a wild-mouse cell —  do you see the differences there? In other words, are the differences system-level differences, whole animal? Are they cell differences? And you’ve mentioned now, one molecular difference. 

Steven: Yeah, I think they’re probably all of the above. Certainly we do know, ’cause people have done the studies, if you take the cells out and you subject them to various kinds of stressors, and you compare them to a mouse cell, then they’re much more resistant to the stressors. They’re still healthy, where a mouse cell would be dead. I’m not sure that that’s the most telling comparison that I would like to see. I would like to see how they do relative to human cells. And I’m sure that’s been done.

Gordon: Hmm. 

Steven: One of the other things is that we know how to make cells turn cancerous in a dish. There are certain chemicals that we can give the . . . And if you give those to naked mole-rat cells, they’re very, very resistant to transforming. Again, I don’t know if they’re more resistant than human cells. I know they’re way more resistant than mouse cells, though. So there are some things that are maintained —

Gordon: Yeah. 

Steven: — at the isolated cellular level. But my guess is there are also systemic things, that there are hormonal things, that there are other things, as well. You know, one of the things we were all hoping is that, at some point, aging would collapse from this incredibly complicated process into the greater simplicity. And I think one of the reasons we were hoping that is from the work in-in-in worms, where a single mutation in a single gene can have these phenomenal effects on longevity. But we haven’t found those in humans. I would think, given that there are almost 8 billion of us now, that if a simple mutation like that had occurred, that every once in a while we’d see “Aah, there’s a 200-year-old human,” you know? 

Gordon: Yeah. 

Steven: And so far, we haven’t seen that. 

Gordon: So you’re not a believer in the immortal Illuminati somewhere?

Steven: No. I’m not, no.  

 Gordon: How important do you think mitochondrial studies are?

Steven: I think mitochondria are . . . If I had to pick one thing that I would say is at the base of aging biology, it would be the mitochondrion.  

Gordon: Aah.  

Steven: And that’s because it provides the energy for virtually everything else, for . . . , you know, you need energy to make the proteins to repair your DNA. You may . . . You know, you need energy to make the proteins to just run your cells. And when that starts — that machinery starts to go bad, not only does it produce oxygen radicals, which are bad. But it also produces a lack of energy, which has all kinds of negative consequences. And so I really think that understanding the biology of the mitochondria . . . Of course, it’s harder to manipulate the mitochondria ’cause we have, you know, hundreds of them to thousands of them in each of our cells. But I think that we’re still going to learn a tremendous amount from them. In fact, we’re learning new things all the time. I mean, just recently, you know, it’s been discovered that they have these genes in the mitochondria that we never suspected before. Goodness sakes. What a shock, you know, that was. Those may turn out to be important in aging. 

Gordon: The, you know, the mitochondria, I guess, are studied in almost every human age-related chronic disease — right? In both diabetes and Alzheimer’s, and everywhere else. I mean, that . . . Do you think that is the critical connection between aging itself and-and chronic disease? 

Steven: I wouldn’t be at all surprised.  And, you know, if you think about the fact that we have thousands of mitochondrial genomes per cell, and that each of those genomes can be damaged in different ways . . . , and mitochondria can be replaced and repaired. 

Gordon: Mm-hmm. 

Steven: And-And-And if you look at the whole m-mitochondrial dynamics, I think that’s probably going to be the most important thing in ultimately understanding the mechanisms of aging. 

MUSIC INTERLUDE 

Gordon: We’ve had enormous progress in aging research the last 30 years, and, you know, we’ll-we’ll talk about interventions in aging and how important all this work is for humans. But it starts with lab animals, for the most part — right? — in contrast to what you’ve been talking about in comparative biology. And I think you’ve made the point that there are limitations there. And we’re talking about mice, worms and flies. And so are these, are these laboratory animals any good at all? 

Steven: So, um . . . And this is a large part of, of-of my book that’s coming out. I think they’ve been very useful at pointing us in the right direction, at telling us what processes and where in the genome to look for things that have a major effect on aging.  I don’t think we’re going to learn how to keep humans healthy longer from work that comes directly from those. I think what we need to do is take advantage of nature producing things that solve all these problems, not just better than a wild worm or a wild fly or a wild mouse but better than humans do, because we’re already — if you think about it, we’re already pretty darned successful at aging. We’re the s– at least — probably the second- or third-longest-lived mammal. That’s pretty good.  and so we’re pretty good already. So,  I think that where the big breakthroughs are going to come is figuring out: “Well, how do birds and naked mole-rats and things that seem to do things better than we do, how do they do that?” Discovering that.  and I think we’re just beginning on that because we’re developing better and better tools for doing this kind of comparative biology. It used to be . . . You know, and the-the great attraction of these laboratory animals is that you can do such fun biology with them. 

Gordon: Mm. Mm-hmm. 

Steven: I mean, it’s-it’s just remarkable. , you know, we can turn any gene on or off in any tissue at any time in any of these things, and that’s taught us a great deal.  It’s just that I remain skeptical that it’s going to teach us, really, how to keep humans healthy longer. I think we need to go to the animals that do it better than we do. 

Gordon: This is such a fascinating point of view, Steven. I think you’re-you’re one of the few people that-that, you know, articulate this, in a, in a really effective way. The vast majority of people working on aging are in labs studying their one small laboratory animal system, and there’s almost an assumption that what they’re doing will translate into humans. , so this-this is a really — , very interesting point of view. And one of, one of those laboratory experiments that are fun is you either let the animals eat as much as they want, or you take some of the-the calories away, and you compare those two groups of animals. And the-the caloric-restricted animals live longer. And this is a classic experiment from the ’50s. It works in many, many species, but not all. So going to to your point about wild animals compared to lab animals, you did an experiment where you decided to calorie-restrict wild mice. Right? What was the result? 

Steven: I did. Yeah, I did as a way to try to get at the fact of: Did-Did this mean anything? And so I decided to test that, and to test it in a couple of ways. One, just to see: Well, how much does a wild mouse eat compared to a laboratory mouse? And we did some work on that. And what we discovered, to my surprise, is that wild mice and laboratory mice that are fed all they want, eat about the same amount. But they do something very different with it because a wild mouse is half the size because they’re trying to stay warm, they’re reproducing, they’re running around, they’re escaping predators. So they eat just as much, but they’re much, much thinner. 

Gordon: Mm-hmm. 

Steven: They have very low levels of body fat. So then when I . . . Then I said: “Well, what would happen if we took one of these wild mice, brought it into the laboratory, raised it for a couple of generations to get rid of whatever pathogens they had, and then restricted those guys?” And when we did that, we found a puzzling result. The-The-The result I was expecting as I watched them die . . . And initially the ones that were restricted were dying, actually, at a higher rate. 

Gordon: Mm-hmm. 

Steven: But that was only at the very beginning. 

Gordon: Aah, okay. 

Steven: And then they started dying, at about the same rate. And so with about 90 percent of them dead, it looked like there was no difference at all. And in fact, when they were all dead, statistically there was no difference at all. But the interesting thing was that the last half dozen animals that were alive were all the ones that were eating less. 

Gordon: Yeah. 

 Steven: And so my nice, simple story suddenly was a lot more complicated than I thought. Now, these were wild mice, so they were all different genetically. And so one of the interpretations of that experiment was that, well, the ones that died early, dietary restriction wasn’t so good for them. And for most of them, it didn’t have much of an effect. But there was this subgroup of them, and it was — had a very health-giving effect. 

Gordon: Right. 

Steven: And that was really where I thought the message probably was. 

Gordon: Mm-hmm. 

Steven: And then a few years later, some people did some work on a whole bunch of different genotypes of mice and found something pretty similar: that it wasn’t good for some of them, and it was very good for some of them. 

Gordon: Yeah. 

Steven: And for a lot of them, it made no difference.

Gordon: And that, you know, this is one intervention, of course, that we’ve been talking about in humans for a long, long time, and finding mimetic, chemical compounds that are, you know, bringing about these caloric-restriction effects. So that’s  super-important to think about: different genetic backgrounds responding differently to different levels of caloric restriction.  Well, let’s get to humans, then, and-and especially your interest in interventions in human aging and-and . . . I mean, I must say . . . And, you know, I wanted to maybe push back a little bit on the model-organism stuff- is that many of the interventions that we’re thinking about have been studied, extensively in model organisms. And there-there are signs . . . And I guess some of the confidence in human interventions come from the model-organism work. Would you agree? 

Steven: I would agree that that’s where the confidence comes from. 

Gordon: [Laughs]

Steven: I’m not sure the confidence is well placed. 

Gordon: Right. 

Steven: But no, you know, I think we’ve done remarkable stuff in understanding the biology of aging from the model organisms. I just . . . If you think about it, though, we’ve now had . . . You know, less than one in 10 cancer therapies that work well in mice works in humans- been hundreds of failures of Alzheimer’s treatments  

Gordon: Yes. Yes. 

Steven: — that worked in mice. And so to me, it’s not that we’re not learning anything. We’re learning a lot about the fundamental processes of aging. But I think it may be very rare where we find something that works in mice that also works in people. You know, one of the things that . . . Let me just see what . . . I’m curious as to what h– see what you have to do with this. It seems to me that as we get to more complicated animals, as we move up from worms to flies to mice . . . And I don’t think . . . They’re just more complicated because they have more cells, more types of tissues…

Gordon: Yes. Yes. 

Steven: These interventions work successfully less well as we go up the complication scale and also the longevity scale. 

Gordon: Mm-hmm. Yeah. 

Steven: And that’s another thing that makes me wonder about the human implications of some of our findings in the model organisms. 

 Gordon: I think that’s an excellent point and very fair. I mean, one-one counter-argument could be that in the simple model organisms we’ve done tens of thousands of experiments to optimize interventions. We-We can’t do anything like that in-in even flies, and certainly not in mice. And so in some ways, we haven’t optimized for the interventions that would really work in those systems. Even though you see traces of-of mechanistic commonality, it kind of falls down because of the lack of number of experiments that we’ve done. But I know you’re an optimist, Steve. and I know this because you-you have a bet with a University of Illinois professor Jay Olshansky. Could you tell us about that? 

Steven: Sure. So, the bet is this: that,  if a human that was alive in the year 2001 is still alive in the year 2150 — so was 150 years old; only has to be one person,  which is good for me ’cause I don’t think we’re going to have everybody living 150 years — then,  I’m going to win our bet. And our bet was — is now a billion-dollar bet. So the bet was that we each put $150 into an investment account, and we let that money sit there for 150 years. The billion dollars is what that $300 would turn into at the current growth rate of the stock market in 150 years. So I’m hoping in the best case that not only do I get the money but that it’s more than a billion dollars at the time. And also that the billion dollars does more than buy dinner, you know, in the year 2150. 

Gordon: [Laughs]

Steven: Now, unfortunately, the oldest person alive — , to ever live at that point, was 122 years and a half. And some 20 years later, no one has lived longer than that. 

Gordon: Right, right. 

Steven: No one ap-approached that age again yet. So that has given me a little pause, I must say. 

Gordon: Yeah. 

Steven: But one of the things that, I think, we have learned from the laboratory animals is that we can get pretty remarkable effects from some of these interventions, even when they’re started relatively late in life. And I don’t think any of us really anticipated . . . I just assumed that for something to have a dramatic effect, it would have to be started pretty early. 

Gordon: Yeah, yeah. 

Steven: But we now know that that’s not seemingly true. And so, I’m pretty optimistic. I mean, it’s not like we’re not getting anywhere with the model animals. We’re developing more and more of these interventions, and I think some of them probably will work in humans. It’s just how many are we going to have to go through to figure out the ones that have the-the major effects in humans?

Gordon: Yeah, and that . . . I mean, that’s . . . That gets to your interest in human clinical trials in general. And you and your colleagues have been very influential on telling the community that this is possible. How does your work in comparative evolutionary biology carry over into this? Is it just simply intellectual interest: “Is this possible?  Can this be done?”  or do, or do you feel that there’s — you’ve seen something in comparative biology, beyond the massive lifespans, I guess, that allows you to think that, “No, this is possible. It’s possible now,” that we could actually have clinical trials and interventions in human aging?

Steven: Yeah. Well, I think the fact that there are animals that age more successfully than we do shows us that there’s — it’s not a biological impossibility, and . . . But there are certain constraints that we have with the human biology that we have. And I think that we’re likely to discover mechanisms . . . Like, let’s just imagine. One of the things that seems to be coming out in studies of whales and rockfish and large tortoises is that the ability to repair DNA —

Gordon: Mm-hmm. 

Steven: — very, very efficiently seems to come up again and again. Now, in almost none of these do we really understand how it works better than that. But my guess is eventually we will discover something like that and develop some way to mimic that. 

Gordon: Mm-hmm. 

Steven: but I don’t think we’re likely to find anything that’s going to allow us to live 200 years. I think

Gordon: Yeah. Yeah. 

Steven: I think if we could live 20 percent — if we could stay healthy 20 percent longer, 

Gordon: Which is the key, right? Yeah. 

Steven: Yeah. That would be a major achievement. That would be enormous. That would change everything. 

Gordon: Yeah, yeah. 

Steven: So instead of life lasting — healthy life lasting, three score and 10, maybe it lasts four score and 10. And that-that changes everything. 

 Gordon: Yeah. And there’s a bit of a debate out there, really still, as to whether lifespan extension in model organisms actually represents a health-span extension. And I think we can point to examples of both of those things — and even-even recently,  examples of compressing the period of sickness at the end of life. So yeah, I share your optimism that there’s-there’s-there’s good signs there that this is possible.  I mean, you must have a good idea of what the landscape is for clinical trials on aging right now. We’ve got two groups of humans, one of which has a whole different chromosome: the Y chromosome. And, it… You know, is there something to be learned from differences in sex and aging? 

Steven: Yeah, I think we’re . . . I think we’ve overlooked a huge opportunity here because . . . I generally frown on any idea that says that humans are unique in any way. I just think of us as a long-lived, hairless chimpanzee, really. But one thing that we really seem to be distinctive, if not unique, in is the fact that females live longer than males under virtually any circumstances. When times are good, they live longer. When times are bad, they live longer. They live longer in hunter-gatherer societies. They live longer in the very most modern societies. And it’s not because males get heart attacks earlier, although they do get heart attacks earlier, on average. It’s because females are more resistant to cancer, to influenza, to Covid-19, as we know —

Gordon: Mm-hmm. 

Steven: — to-to most of the things that cause us . . .  Parkinson’s disease.  so there’s a broad spectrum of things that-that women do better than men at surviving. And the interesting thing, though, is that there’s this paradox, which is that, particularly at later ages, the surviving women tend to be less healthy than the surviving men. 

Gordon: Mm. Mm-hmm. 

Steven: And so I think there’s two potential lessons. First of all, how do women survive better than men? But also, how do men stay healthy longer than women? So if we could figure that out and make men live as long as women, and women stay healthy as long as men, then we’d go a considerable distance towards, really making a dramatic impact on human health and longevity. 

 Gordon: Steve, I am often asked,  “When is it all going to happen? How long are humans going to live in five years?” It seems like every scientist says five years, for, just about any subject: “This will be discovered in the next five years.” But aging seems like a tough nut to crack. If you were to look out 10 and 50 years, where do you think we’ll be?

Steven: I don’t think there’s going to be an abrupt jump in healthy longevity. I think there’s going to be a gradual increase. You know, a friend of mine once said: “The best way to look like a fool in science is to start making predictions.” But, I’ve looked like a fool in the past. There’s no reason for me not to continue to do so.

Gordon: [Laughs]  Brilliant. Fantastic.  Steve, thank you so much. I’ve had a great time talking to you today. I always learn tons when I talk to you. And, hope to see you soon. 

Steven: I hope to see you, Gordon. It’s always a pleasure to chat with you. 

SHOW OUTRO  

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  “We’re not getting any younger, yet!” is made possible by a generous grant from the Navigage Foundation. The Navigage Foundation is enhancing the lives of older people through the support of housing, health, education and human services. Our podcast is produced by Vital Mind Media: Wellington Bowler is here with me using sign language to keep me on course and recording the podcast. Stella, who I love spending time with talking about science, as you know, is our editor with the Creative Direction of Sharif Ezzat and the Buck Institute’s very own Robin Snyder as the executive producer.

  If you’re listening to this podcast, you know that there’s never been a more exciting time in research on aging. Discoveries from our labs or moving into the clinic to help us all live better, longer. 

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