Why We Get Old & How We Can Stop It - Dr Andrew Steele | Modern Wisdom Podcast 265

1. 0:00 – 0:25

   Intro

   1. ASDr Andrew Steele0:00

      Toward the end of the book, I start talking about what our cure for aging is actually gonna look like. And I think it's gonna be much more complicated than anything we've talked about so far. The reason I've got some faith that it's gonna happen is because we're undergoing a computational revolution in biology at the moment. You know, even if we don't get to general intelligence, I think we're gonna get to a point where AI programs are able to interpret this huge sort of torrent of data that biologists are producing in a way that humans just can't understand.

2. 0:25 – 1:35

   What is aging

   1. CWChris Williamson0:25

      What is aging?

   2. ASDr Andrew Steele0:29

      That is an excellent question. There are many, many different ways you could define this, and I think e- every different scientist could give you a different answer. But I've got two ways of thinking about it, one of them statistical, one of them biological. And the statistical way of thinking about it, which I think is the most sort of catchall definition of aging, is it's what happens to your risk of death with time. So the longer you've been alive, how much does your risk of death increase? So let's take the example of humans. Um, if you're in your 30s, your risk of death is about one in 1,000 per year. If you're lucky enough to make it as far as 80, your risk of death goes up to 5% a year. So it's- it's, you know, hundreds of times more. And what... Uh, s- yeah. Yeah, so what that means actually, if you look at the stats, is... Can I start that again? 'Cause I think it's not hundreds of times, is it? The difference between five and 1,000 is on- it's 200. It's 200 times more. I'm right. (laughs)

   3. CWChris Williamson1:13

      That's fine.

   4. ASDr Andrew Steele1:14

      Sorry. Let me do that-

   5. CWChris Williamson1:14

      It's correct.

   6. ASDr Andrew Steele1:14

      Let me-

   7. CWChris Williamson1:15

      It's correct, Andrew. We're- we're- we're-

   8. ASDr Andrew Steele1:16

      (laughs)

   9. CWChris Williamson1:16

      We're, the- the- the internet, you're here because you're a scientist, not because you're a mathematician.

   10. ASDr Andrew Steele1:20

       (laughs) And what you find actually is the- the better people are at maths, in terms of, like, the- the proper theoretical hardcore maths, the worse they are at mental maths. And you find yourself second-guessing yourself all the time.

   11. CWChris Williamson1:31

       (laughs)

   12. ASDr Andrew Steele1:31

       If you get a proper hardcore number theorist, they can't add two and five.

   13. CWChris Williamson1:34

       (laughs)

   14. ASDr Andrew Steele1:34

       (laughs)

3. 1:35 – 3:20

   Mortality rate doubling time

   1. ASDr Andrew Steele1:35

   2. CWChris Williamson1:35

      I remember my-

   3. ASDr Andrew Steele1:36

      So that-

   4. CWChris Williamson1:36

      My old housemate did a PhD in pure mathematics, and he once ordered a four-seater taxi for five of us because apparently in pure math, you count from zero.

   5. ASDr Andrew Steele1:44

      (laughs) Yeah, yeah, it's off by one error. Classic in computer programming as well. (laughs)

   6. CWChris Williamson1:49

      Unbelievable, man.

   7. ASDr Andrew Steele1:49

      So-

   8. CWChris Williamson1:49

      You spend all this time doing maths, you can't count to five?

   9. ASDr Andrew Steele1:52

      I know. Got a PhD, can't even manage it. So what, where was I? Yeah, yeah. So the- so humans, the- the sort of way to sum up all that stuff that I just failed to add up in my head is that our risk of death doubles every eight years. So you can say in some sense, our rate of aging is encapsulated in this number. We're saying that if our... That's, you know, this... It's called the mortality rate doubling time. So how long does it take your mortality rate to double? And if you look around the animal kingdom, this isn't universal at all. For mice, it's a matter of months. Um, but if you look at something like a giant tortoise, um, which you'll find on the cover of my book, and the reason is that they're what's called negligibly senescent. They have a risk of death which is constant with time. So effectively, their mortality rate doubling time is infinite. And that doesn't mean they're immortal. It doesn't mean they're gonna live forever, but what it does mean is it doesn't matter how long ago they were born, um, their risk of death stays the same. So that's the statistical definition of death. The biological definit- sorry, of aging. The biological definition of aging, I'd say, is to look at the individual components of the aging process. And there was a paper published in 2013 called The Hallmarks of Aging, and it lists these nine different changes in your cells, in your molecules. Um, and they- they tend to increase with age, all of these things. Um, they tend to... If you accelerate these changes, then the animals will have their aging accelerated, so they'll die more quickly. And if you slow these changes down, then the animals get less disease and die more slowly. So that's the sort of criteria by which they define these different hallmarks, which are a sort of more nitty-gritty, molecular, what's-actually-going-on definition of aging, as opposed to that high-level statistical one we started with.

4. 3:20 – 4:12

   Cultural blind spot around aging

   1. CWChris Williamson3:20

      Yeah. Is there a cultural blind spot around aging? Like hearing the word cure and aging in the same sentence is not very common.

   2. ASDr Andrew Steele3:30

      Yeah, I think there is. And I've- I've used the word cure slightly to the chagrin of some of the scientists who read the book, actually. Um, because it is a bit of a controversial way of putting it. But the- the reason I want to put it that way isn't necessarily because I think a cure is just around the corner, but it's because I want to normalize the idea that aging is something that should be cured. I think there's an interesting discussion as to whether it's... you know, it should be classified as a disease or not. But nonetheless, whatever it is, whether you think of it as a disease or whether you just think of it as a sort of a disease syndrome, I've heard scientists describe it as, or if you just think of it as a natural process, the fact is, it means that we get much more likely to get diseases, we get much frailer, we lose our mental faculties. None of those things are good things. And I think to try to cure them, to at least aim for that target is where we should be

5. 4:12 – 6:06

   Are there not things we need to fix first

   1. ASDr Andrew Steele4:12

      going with medicine.

   2. CWChris Williamson4:12

      Are there not things we need to sort out first, like cancer and heart disease? Now surely they're easier to fix and quicker to happen than- than aging.

   3. ASDr Andrew Steele4:23

      Yeah, the strange- the strange thing is it might actually be easier to sort aging than to sort all of those diseases individually. So the reason that our risk of death doubles every eight years, as it does, um, you've got to die of something, right? You don't just like drop dead-

   4. CWChris Williamson4:35

      (laughs)

   5. ASDr Andrew Steele4:35

      ... in the street with no underlying cause. And the things that you die of are actually exactly the diseases you just listed. Cancer, heart disease, stroke, dementia, all of these terrible diseases which are primarily suffered from by old people. You know, a few people in their 30s do get diagnosed with cancer, but by and large, it's people in their 60s and their 70s and their 80s. And the risk of all of these diseases rises in exactly the same sort of terrifying exponential way with time. And that's because it's all the same biological processes. They drive wrinkles, they drive gray hairs and the sort of superficial changes. They drive the, you know, loss of muscle mass that makes it harder to do stuff around the house, the frailty, but they also drive the cancer, the heart disease, the dementia, et cetera. And actually, um, if you look at the- the international classification of diseases, there's this massive sort of attempt by scientists and doctors to assign a code to everything that can go wrong with your body.

   6. CWChris Williamson5:21

      (laughs)

   7. ASDr Andrew Steele5:21

      And there are about... I think there are 11,000 of these in the latest edition. I might have got that slightly wrong, but it's, you know, it's thousands and thousands of different ways that you can go wrong. It's a bit depressing, really-

   8. CWChris Williamson5:28

      Yeah.

   9. ASDr Andrew Steele5:28

      ... when you think of it like that. But a significant fraction of these are- are basically aging. You know, they're- they're things that, uh, they're cancer, there's loads, and you know, every single subtype of every cancer in every organ. There's all the different ways that your heart or your circulation can go wrong. There's everything that can happen in your brain, all the different kinds of dementia. So we can either, as scientists and doctors, go after these thousands of individual causes, or we can go after the root cause, the thing that causes almost all of those diseases, and that's aging. And so although, you know, aging is not gonna be an easy thing to crack, it's gonna be, you know, s- there's some research still needed.... it's quite possibly gonna be easier than taking out every single one of those possible ways your body can go wrong all at the same time.

   10. CWChris Williamson6:05

       Yeah.

6. 6:06 – 7:00

   Modern medicine targets symptoms

   1. CWChris Williamson6:06

      You said, "Much of modern medicine targets symptoms a few steps removed from the root cause of the illness." Guess it relates to what you're-

   2. ASDr Andrew Steele6:12

      Mmm.

   3. CWChris Williamson6:12

      ... talking about there.

   4. ASDr Andrew Steele6:14

      Exactly, yeah. And I think that our, our... It's sort of natural because the way we used to treat infectious diseases, you'd get a, you know, you'd get measles, and what you need to do is either vaccinate people, so they don't get the, so they can fight off the virus before it becomes an infection, or you need to treat them in some way. And if it's a bacterial infection, you can give them an, antibiotics. Once you've got rid of the disease from the body, you've cured it. But with something like cancer, you can... Even if we had a cure for cancer, right, we could remove the cancer from the body per- perhaps very successfully, but then it would still, in essence, be an old body that you were left with, a body with a huge risk of developing another cancer, a body with a huge risk of heart disease, perhaps already, already has heart disease, perhaps already has the beginnings of dementia. And so by treating the diseases as these sort of atoms, these individual entities that are separate from the processes going on in the rest of the body, um, it's just an approach that's doomed to failure ultimately-

7. 7:00 – 14:04

   Average life expectancy

   1. CWChris Williamson7:00

      Yeah.

   2. ASDr Andrew Steele7:00

      ... I think.

   3. CWChris Williamson7:00

      I was interested to look at the average life expectancy work that you'd done. Um, and I think it was 35 years old about sort of 20,000, 30,000 years ago, classic hunter-gatherer, uh, and only 200 years ago, the average life expectancy was 40 in the UK, which that blew me away.

   4. ASDr Andrew Steele7:20

      Yeah.

   5. CWChris Williamson7:20

      But you highlight an interesting, uh, quirk, I guess, of statistical science that that is skewed massively by infant mortality, that you've got ridiculous volumes. I think it was like, you only had a 60% chance of making it to 18, 20,000 years ago, something like that?

   6. ASDr Andrew Steele7:36

      Yeah, so it's hard to get the exact numbers but that's the sort of ballpark. Yeah, it's basically like tossing a coin to see if you'll make your 21st birthday-

   7. CWChris Williamson7:42

      (laughs)

   8. ASDr Andrew Steele7:42

      ... or something like that, which is ridiculous to modernize. Like, imagine if we were running that sort of gauntlet in our ki- childhood and teens. It's crazy.

   9. CWChris Williamson7:49

      Yeah. Yeah, that was mad. So, one question that I became fascinated by, and I've had David Sinclair and Andrew Scott talking about longevity on the show before, and I didn't even think to ask them this question. Is there a purpose to dying? I thought that we were supposed to be adaptive fitness maximizers, right? And surely this certain end to life is a bit of an error. Like what, why has evolution not made us immortal?

   10. ASDr Andrew Steele8:15

       Yeah, it's an interesting question and I... There's, there, so there are two aspects to this. Firstly, is there an adaptive advantage to dying? And secondly-

   11. CWChris Williamson8:22

       (laughs)

   12. ASDr Andrew Steele8:22

       ... is there an adaptive advantage to aging? Which is sort of, they, they sound like they're the same question, but they're not. Um, so to a- answer the first one about death, there could be an argument that the reason that creatures die is because evolution, um, it can only happen between generations, right? You and I, we've got our DNA that was, you know, half from my mom, half from my dad, and that DNA is what we're stuck with for life, you know, more or less. We can't, you know, adapt to be better, faster, stronger. We can obviously, we can train, we can eat well, we can do whatever we like to try and improve our fitness, but ultimately we're stuck with the genes that we've got. So, if you want to evolve, you've gotta have kids and those kids will differ from you in a few different ways, you know, differ from the partner you had the children with. And it's through these tiny differences, maybe that'll give your kid a slight evolutionary advantage over the kids of the people next door and over generations and generations, whatever, you know, properties your child had that made them fitter in, for that environment will cause them to evolve. So the problem is, if you have an organism that doesn't die, how does it evolve? Because it can't, unless it can, you know, go in and change its own DNA, which isn't a thing-

   13. CWChris Williamson9:19

       But-

   14. ASDr Andrew Steele9:19

       ... that organisms can do.

   15. CWChris Williamson9:20

       ... uh, the changing in DNA occur due to birth, not death. Dying doesn't seem to be-

   16. ASDr Andrew Steele9:25

       So the-

   17. CWChris Williamson9:25

       ... a part of reproduction.

   18. ASDr Andrew Steele9:27

       No, it's not, but imag- ima- so imagine that we're, you know, cheetahs out on the savanna and we're really well adapted for our particular evolutionary niche, we're really good at running fast, and then we're, and we're also immortal cheetahs so this is a- (laughs)

   19. CWChris Williamson9:40

       I love it already.

   20. ASDr Andrew Steele9:41

       ... this is a, you know, thought experiment, shall we say. Um, so we're immortal cheetahs running around on the savannah, you know, eating gazelles. The problem is, as, you know, say for example, there's a, there's a massive famine of the particular kind of tree that the, the gazelles we most like to eat, eat. And so all the gazelles die and we eat the ones, you know, we eat, we eat the handful that are still left. Suddenly, um, what we need to do is adapt. Our environment's dramatically changed. We haven't got any gazelles to eat anymore. But because we have got our fixed DNA, we can't adapt. We've still got sharp teeth, we're still, you know, a- adapted to run quickly and catch stuff, we're still adapted to digest meat. And the only way that we could adapt would be to do that over evolutionary time. So perhaps our kids are slightly better at eating leaves than we were and so they can slowly move away and they perhaps get on an omnivorous diet so they can eat meat and leaves, then eventually they might become completely vegetarian or, you know, this is a, a slightly ridiculous thought experiment. But the point being, once you're in existence, if you just don't die, you can't adapt to your changing environment. And so it's, it's actually a point of contention how important a fact this is, but it's definitely possible that a literally immortal species just couldn't evolve. And so as soon as the world, you know, the world would change around it and it'd be doomed that way.

   21. CWChris Williamson10:46

       Yeah. I've been fascinated. I went to, uh, Dubai earlier this year and, uh, went to the marina and saw a huge crocodile, sorry, an alligator-

   22. ASDr Andrew Steele10:56

       Mmm.

   23. CWChris Williamson10:56

       ... that they'd taken from God knows where. And, um, I was reading about how alligators and sharks basically lucked out with their, uh, adaptive properties and they've essentially unchanged for millions and millions and millions of years. They just landed perfectly on their evolutionary niche, as you called it. And I guess that that would be the only way that you'd be able to survive, that the roll of the dice-

   24. ASDr Andrew Steele11:18

       Exactly, yeah, you just-

   25. CWChris Williamson11:18

       ... would be like 20 sixes in a row. And you're like, "Yes, I've got the teeth I needed and the, the hide I needed and the legs I needed and everything. And also this environment better not change."

   26. ASDr Andrew Steele11:30

       Yeah, exactly. And as soon as, you know, we, we could imagine something like climate change could certainly push certain sharks out of existence just because they've been adapted for this environment for millions and millions of years. But if we come along and change it too quickly or an, or an external factor comes along and changes it, they might not be adapted anymore. And so, yeah, that could be the end of those living fossils.

   27. CWChris Williamson11:46

       What's the other half of why we die then, in terms of evolution?

   28. ASDr Andrew Steele11:52

       So in terms of evolution, um, aging is an accident. And so you're absolutely right to sort of couch it in terms of evolution is designed to maximize fitness and that isn't always quite in the way that you expect.... a- in that it doesn't always mean that you're gonna be bigger, faster, stronger, 'cause obviously other, you know, otherwise animals would slowly evolve to become huge monsters and they clearly don't do that, right? They optimize themselves to, for their current environment. And so that might mean occasionally it makes a change that doesn't seem like it's making the animal fitter. Like for example, again if we're, we're back to our cheetahs, not immortal anymore, but we're back to our cheetahs on the savanna, there is probably a point at which there's no point in running any faster because what that means is that you're gonna spend energy building bigger muscles and stronger bones in order to be able to run more quickly. But if you can already run faster than all your prey, you're effectively wasting that energy and you could be using that energy for something else evolutionarily. So you could be using it to, you know, make your fur slightly better camouflaged or you could be using it to have more kids. And so all of these things are ways to redirect your energy away from sort of the, the naive conception of what fitness means, 'cause I think as, you know, we often imagine fitness to mean big, hard, strong animals, but that's not always the case, because you know, we've got frogs, we've got insects, we've got all things that are tiny and, you know, strong and weak, and all different kinds of, um, animals adapted very differently for different environments. So aging is exactly the same sort of thing in that it's, it's an evolutionary compromise because if you build an animal that's effectively immortal, um, so it doesn't ha- you know, has a risk of death that doesn't change with time, for example, it's gotta put energy into being immortal. It's gotta put energy into maintaining its body. It's gotta ma- uh, put energy into making sure that no cancers start off, and it's gotta have an immune system that's constantly patrolling, looking out for those cancers. And all of these different, um, sort of ways to spend that energy, it could be spent in other ways. You could spend it having an extra kid or you could spend it, um, having slightly stronger muscles again to catch up with those gazelles. So there's this sort of as, as an organism, you're trying to choose between, uh, you're just, you're trying to optimize across all these different parts of your body, and that could be longevity, that could be how strong your muscles are, that could be how tall you are depending on the environment you're in. And longevity isn't always gonna be the winner. So even though you might expect the big, you know, biggest, fastest, strongest, longest lived animal to always win, sometimes the shorter lived one's gonna win because it puts less energy into maintaining its body and it can put more energy into something that's more evolutionarily important in its niche.

8. 14:04 – 14:54

   Survival of the fittest

   1. ASDr Andrew Steele14:04

   2. CWChris Williamson14:04

      It's like a Malthusian trap a little bit. It's like, um, that you're going to be out-competed by something else that has a more, uh, a, a higher chance of not only surviving but also reproducing. And if your survival is at the, uh, cost of your reproduction, like, it's not happening.

   3. ASDr Andrew Steele14:24

      Yeah. That's exactly right, and I think this, this phrase survival of the fittest, it's really become like a part of popular culture. But actually, what we should say about evolution is it's reproduction of the fittest.

   4. CWChris Williamson14:34

      (laughs)

   5. ASDr Andrew Steele14:34

      And that is the key point.

   6. CWChris Williamson14:35

      Yeah, 'cause it doesn't matter if you survive. You can survive, but if you don't reproduce, any traits you have have been competed out of the gene pool.

   7. ASDr Andrew Steele14:43

      Exactly. And like, at some point, a, a bus or, you know, or a cheetah is gonna come along and get you and you're gone. You might as well not have existed.

   8. CWChris Williamson14:50

      I tell you what I found out this year that I thought was fascinating. It's the,

9. 14:54 – 16:54

   Technological progress

   1. CWChris Williamson14:54

      uh, nonzero existential risk from natural risks that we have that means we have to have technological progress. So this is from, uh, Toby Ord's The Precipice.

   2. ASDr Andrew Steele15:04

      Mm-hmm.

   3. CWChris Williamson15:04

      And there's a lot of concerns at the moment around are we moving too quickly towards artificial general intelligence or bioweapons or nanotechnology and we're all gonna get turned into gray sludge or paper clips or whatever the next thought experiment is. But, what he did say is there is a nonzero chance that we're going to be killed eventually. If you stuck around for long enough, we're gonna be hit by an asteroid or a super volcano's gonna go off or the sun's gonna swallow us or something. So we need technological progress, and it's kind of the same as we're seeing e- in evolution, right? That's just like a macro aggregated version. You need to have this cost payoff between the two.

   4. ASDr Andrew Steele15:40

      Yeah. Definitely. And I think that's, that's exactly right 'cause there are some problems that we can't evolve our way out of. Like if we had just not... not... if we hadn't developed computers and spacecraft and all these different things, like what on earth are we gonna do in a billion years when the sun starts getting a bit bigger and hotter and the earth just gets toasted and all the oceans boil? Like there's no level of, um, natural living (laughs) evolution that's gonna get us out of that situation. So, fingers crossed that we can sort it out ourselves.

   5. CWChris Williamson16:03

      So why do we age?

   6. ASDr Andrew Steele16:06

      Fundamentally, that's exactly why. It's this tra- this evolutionary trade-off. And what that mean- what that means is that our bodies in a variety of ways have decided not to put as much energy into maintaining our, uh, physique as they could as we get older. And so the idea is that, you know, if I were to, uh, you know, put all that energy into maintaining my body, I would have fewer kids. You might have more kids because you put less energy into maintaining your body from an evolutionary perspective. And your two kids are eventually gonna mean that they have four kids and they have eight kids, whereas my one kid's only gonna have two kids. It's constantly gonna be a step behind. And that means that in an environment where, you know, eventually I'm gonna get hit by a bus or I'm gonna get eaten by a saber-toothed cat or, you know, just gonna die of an infection in pre-history, then your weight of numbers is gonna outweigh my slight extra lifespan advantage. And ultimately, evolution makes this trade-off and unfortunately it's, uh, come down with us aging.

10. 16:54 – 17:56

    Aging

    1. ASDr Andrew Steele16:54

    2. CWChris Williamson16:54

       What's the process of us aging? What i- what, what is happening inside? Why does it, why does it do what it does?

    3. ASDr Andrew Steele17:01

       It's a variety of different things. It's, it is basically a load of things falling out of balance, a load of things getting broken, and, um, it, it's, it's a, it's quite a complicated thing, right? So I think there's, um, there's, there's... there have been a lot of theories of aging that have tried to ascribe it to a single cause. But I think what the hallmarks show us, and I talk about the hallmarks in my book in a slightly modified form. They've got nine, I've got 10. I sort of, I combined a couple and added an extra couple. But it's, it's basically the same kind of thing 'cause obviously the, the process is, um, is very similar. But it's everything from the, you know, the DNA inside our cells getting damaged, um, to the populations of cells falling out of kilter, to certain molecules being damaged and never being repaired, to signals that change that cause cells' behavior to change. So it's a complicated sort of processes upon processes upon processes, which ultimately mean that, um, the environment inside our body is very different by the time we're 60 or 70 or 80 than it is when we're 20 or 30. And that is what causes us to age fundamentally.

11. 17:56 – 19:21

    Cells

    1. ASDr Andrew Steele17:56

    2. CWChris Williamson17:56

       It's bizarre, isn't it? Because I think we're not conscious of the fact that our cells are constantly replacing themselves. I think is it every seven years you don't have a cell left in your body that was there seven years ago. Is that right?

    3. ASDr Andrew Steele18:08

       Mm-hmm.So, it depends on the tissue. It's really interesting because like, so our guts are literally turning over every few days.

    4. CWChris Williamson18:14

       Okay.

    5. ASDr Andrew Steele18:15

       And our red blood cells in our blood, they last about three or four months. But then if you look in other parts of the body, bones I think probably are on about the 7 or 10-year mark. But if you look at some neurons in the brain and some heart cells, you are literally born with them and die with them, so they last your entire life. And it's actually really fascinating why these different organs have chosen these different sort of levels of turnover, because obviously in an environment like your guts, it's, it's rough and tumble in there. You're getting lots of toxins in your food. You've got bacteria, you've got your microbiome, you've got all sorts of stuff going on. And clearly evolution has decided the optimal way to deal with that is to constantly replace those cells. Whereas in your brain it's, um, it's all protected. There's something called the blood-brain barrier that keeps almost everything out of your brain that isn't needed, and that means that a neuron is in a really quite a safe environment. And so apart from a few special cases like your- the olfactory neurons, the neurons that are responsible for your sense of smell, they turn over really rapidly because they're, um, exposed to the outside environment basically. They're exposed to all kinds of dangers. Whereas a neuron that's like deep somewhere inside your skull is so well protected that evolution, for whatever reason, has decided it's better to leave that neuron completely intact and never change it for your whole life.

12. 19:21 – 21:03

    Lifespan of animals

    1. ASDr Andrew Steele19:21

    2. CWChris Williamson19:21

       That's fascinating. I thought I've seen something probably on Instagram that was like e- e- every seven years or so, your, all of your cells turn over. But now, everybody that's listening has it in the tank to say, "A- a- a- actually there's a, there's some neurons-"

    3. ASDr Andrew Steele19:36

       (laughs)

    4. CWChris Williamson19:36

       "... are in the blood-brain, brain barrier and, uh, uh, I think you'll find they're exactly the same." Um, so did your research uncover any animals that live for ridiculous periods of time? Obviously, we know our life expectancy at the moment. What about other animals?

    5. ASDr Andrew Steele19:51

       I think the craziest t- in terms of actual lifespan tend to be a little bit further from humans. So the longest lived vertebrate, which means animals with a backbone, is actually a kind of shark called the Greenland shark. And it's hard to be exactly sure of their age because it's not as though we've like tagged a shark 400 years ago and then like watched it until it died. But they think from various sort of chemical analysis that the oldest Greenland shark ever found was about 400 years old, so that's crazy. But then as you move a bit further away from us in the, in the sort of tree of evolution, I don't know, tree was an appropriate choice of word actually because we think the longest lived single organism on the planet is a tree called a bristlecone pine. Um, it's in the White Mountains in California. It's a top secret location because they don't want vandals to go and chop down this like incredible piece of Earth history. And it's-

    6. CWChris Williamson20:32

       It's a secret tree? Shit the bed.

    7. ASDr Andrew Steele20:34

       Yeah, a sec- a secret tree. (laughs) Um, and it's, they think it's about 4,850 years old. They took a core out of it and count- they counted the rings just as, you know, tree rings just as you'd expect, and it was, I think it was about 4,800 in the 1950s. And so sort of moving that forward, that tree was a sapling before the pyramids. Like, uh, that's just absolutely mind-blowing to me, that, that tree has basically seen the whole arc of human civilization from atop this sort of windy, arid mountaintop in California.

13. 21:03 – 22:23

    Hydra

    1. ASDr Andrew Steele21:03

       (laughs)

    2. CWChris Williamson21:03

       That's unreal. What about this hydra thing?

    3. ASDr Andrew Steele21:08

       Hydra are fascinating, that's another example I was going to suggest actually, and that's another one where we don't actually know how long they live, but we can extrapolate from how long, how long we've watched like loads of them live to how, how many would still be alive after a really long time. So hydra, they're these tiny freshwater creatures. They're incredibly simple. So they've basically got a mouth at one end and a bum at the other and not a- (laughs) not a great deal else going on. Um, and the, the thing that really captured scientists' attention about them initially was that you can chop any bit off a hydra and it will turn into a new hydra. So you can chop it in half, you'll get two hydra. You can chop it into four, you'll get four hydra.

    4. CWChris Williamson21:38

       (laughs) Holy shit (laughs) .

    5. ASDr Andrew Steele21:39

       And so it has, has this incredible... You know, if you think, if you think salamanders are good at regenerating, it's got nothing on a hydra. You know, you can't chop a salamander's leg off... They'll get a new leg, but the leg won't grow into a new salamander. (laughs) So they, they've got this incredible power of regeneration. And, um, as the, as scientists started watching them more in the lab, they realized they're actually living a surprisingly long time as well. And, um, they... It's been extrapolated, though again, we obviously haven't done the actual full length experiment, that 10% of hydra would still be living after 1,000 years if the death rates we've observed so far are accurate, which is just bonkers because there's... The- We, we sort of imagine the bigger and more complicated and more humanlike an organism is, the longer it's gonna live, like in general as a rule of thumb. But these are literally like microscopic organisms and they can live 1,000

14. 22:23 – 25:32

    ardigrades

    1. ASDr Andrew Steele22:23

       years.

    2. CWChris Williamson22:23

       Is this like tardigrades as well? They're pretty hardcore, aren't they?

    3. ASDr Andrew Steele22:27

       They are pretty hardcore. I actually don't know if we've got any good longevity data on tar- tardigrades. I've not seen it. They, they're certainly hardcore in the sense that they can like survive ridiculous environmental hazards-

    4. CWChris Williamson22:36

       Vacuum of space.

    5. ASDr Andrew Steele22:36

       ... like insane levels of radiation, vacuum, horrible chemicals, and they just basically, um, I think they just, um, dehydrate themselves and turn themselves into this like super hardcore remnant tardigrade that as soon as you just, you just add water, you get the tardigrade back again.

    6. CWChris Williamson22:51

       (laughs) Yeah, it is, like those sea monkeys that you used to get as a kid.

    7. ASDr Andrew Steele22:54

       Yeah. (laughs)

    8. CWChris Williamson22:54

       You said that the effect of fasting is one of the most universal in all of biology. What's that mean?

    9. ASDr Andrew Steele23:02

       So we've observed... The fir- the first proof that we had that aging could be changed in animals were some experiments that were, that they were sort of kicking off a bit around the early 20th century but the first proper formal, uh, experiment on this was done in the 1930s by a guy called Clive McKay, and he was looking at rat development. And he was really fascinated by if you feed rats different amounts of food but you give them... Make sure they get the right amount of nutrients but you feed them different numbers of calories, what does that do primarily actually to their development? Because back in those days people weren't living quite so long, I think there was more of a focus on the beginning of life, optimal nutrition when you're growing up sort of stuff. But what they noticed was, in these experiments, that the rats that were given substantially less food, and we're not talking like a diet here, we're talking like half the amount of food that the other rats were being given, um, they just kept living. So they were... They lived about 40 or... No, hang on, they lived about 80% longer, the rats. And, and they, not only did they live longer, they lived longer in good health. So these rats that were dying almost twice as late as the rats that were eating a normal diet, um, when they did an autopsy after those rats were dead, they basically looked the same. They looked indistinguishable from the rats that had died, you know, 600 days previously to c- you know, a couple of years previously. Um, and what that suggests is that this process was slowing the aging process down by, you know, by eating less, you slow down aging. And we've since discovered this works in all kinds of different organisms ranging from yeast, so the stuff that you use to make beer, um, all the way up through flies and mice and dogs and, uh, you know, bizarre-... creatures that live in pond water. And the only question mark really is, oh, how, to what extent it works in humans. And we've got some experiments in monkeys that show that it certainly makes them live healthier, but it doesn't seem to make them live longer. So, there's, it's this really fascinating universal effect. But one of the things I found most infuriating reading about this, 'cause I was thinking, "Can I do this?" And, like, on the one hand, I almost certainly can't 'cause I just like food too much, (laughs) to be totally honest. You know, I've, I've tried doing a bit of fasting. I just get very, very hungry. I, I get very grumpy. (laughs) You know, it's not a good look. Um, but the second thing is th- th- it's, it's hard to motivate yourself to do something so difficult when the evidence is so mixed for humans, and we just don't know whether you're gonna be putting yourself... So, there's, there's this sort of joke in the biogerontology community, um, fasting doesn't actually make you live longer but it certainly feels like longer. And so, (laughs) you, you don't wanna, you don't wanna get yourself in a position where you're putting yourself through absolute hell, feeling hungry literally all the time, and then, you know, you get to the age of 80, drop dead exactly on cue, and the scientists announce, "Oh, you know, we've done the study now. (laughs) We've, we've worked it out, the dietary restriction works in every other organism apart from

15. 25:32 – 26:22

    the best evidence

    1. ASDr Andrew Steele25:32

       us."

    2. CWChris Williamson25:32

       Where's your money on this, if you had to put a bet on?

    3. ASDr Andrew Steele25:39

       I think it's probably gonna turn out that it improves health but doesn't do that much on lifespan. I'm not gonna say it wouldn't give you a year or two, but it's not gon... Because, and I think the, the, the best evidence for this, quite aside from any, like, complicated studies, because, you know, there, there have been attempts to do this properly, proper medical research type randomized trials where you give some people... uh, you may, you know, reduce some people's diets and leave other people eating normally and see what are the differences. Um, but quite apart from these sort of, you know, proper high-octane studies, the fact is, you look around the world, there are people in different religions, people in different cultures. We've got such a variety of diets globally, and the fact is, there's nobody living to 150. Um, so what that probably suggests is that there's nothing we can really do to our diets or our lifestyles within reason that's gonna have a dramatic effect

16. 26:22 – 29:16

    fasting doesnt do anything

    1. ASDr Andrew Steele26:22

       on our lifespan.

    2. CWChris Williamson26:23

       Hmm. It would be, I mean, for the longevity... r/Longevity on Reddit, if, if it's true that fasting doesn't do anything, there are a lot of people... I mean, they've spent half the amount of money on food that they would've done, but they-

    3. ASDr Andrew Steele26:37

       There's that bonus, yeah. (laughs)

    4. CWChris Williamson26:38

       ... potentially been twice as hungry. So, yeah, it is a-

    5. ASDr Andrew Steele26:41

       Yeah.

    6. CWChris Williamson26:41

       ... it is a big trade-off. Um, just going back to that rat, rat study, there was-

    7. ASDr Andrew Steele26:48

       Hmm.

    8. CWChris Williamson26:48

       ... calorie restriction and fasting are two different things. You can eat-

    9. ASDr Andrew Steele26:53

       Yeah, they are.

    10. CWChris Williamson26:53

        ... half the amount of food just as frequently, or you can eat less food or a similar amount of food, uh, less frequently or more frequently. How, how, what are the effects-

    11. ASDr Andrew Steele27:03

        Mm-hmm.

    12. CWChris Williamson27:03

        ... that were seen from that?

    13. ASDr Andrew Steele27:06

        So, this is, this is so knotty, and I think the real... there's a real problem, actually, with the animal experiments. So, mice is the one that they've, they've done a bit more experimentation in now. They're the more common lab animal. And, um, there's, there've been, you know, scientists trying to distinguish the d- the effects between dietary restrictions, so eating less all the time, and intermittent fasting. And that can... Again, this can come in a huge load of forms. Like, do you eat every other day? Do you do the 5:2 diet and eat five days a week and take two non-consecutive days off? Do you go for a week without food every few months? Like, there's just a huge spectrum. There's even this, um, 16:8, um, time-restricted feeding idea where you only eat during an eight-hour window during the day. Um, so there's just this huge range of different things to test. And I think there's a worry in the comm- in the science community that actually, the mouse experiments haven't tested any of these things very reliably. The reason being, mice are nocturnal, and PhD students are not n- nocturnal. (laughs) So, the way that the PhD ch- students tend to feed the mice is they'll go in at the end of their, uh, you know, at the end of the workday, give them their ration, so half their food if they're on dietary restriction or their fu- you know, whatever they want if they're eating what they like, and then they'll come back the next morning and the food'll be gone. And if you actually watch the mice that are doing that, the mice that are on dietary restriction, they're starving. So, they run in, they eat all their food in one go, and then they don't eat for 23 hours. So, effectively, they're doing sort of this weird combination of dietary restriction and intermittent fasting. And it astonished me, I was chatting to a scientist about this, and they were saying, "Oh, actually, you know, so this is obviously... we, we've recognized this problem." And just now, like, literally in the last few years, they've started doing some experiments, I don't think any have yet been published, with automated feeders, like you get for your, your dog or your cat if you're away from home. And it, it just, I just... it was head-slapping. Like (laughs) how have they only thought? It's not as though this is 2010 technology. (laughs) You know, we've had automated pet feeders for decades, haven't we?

    14. CWChris Williamson28:49

        Well-

    15. ASDr Andrew Steele28:49

        And yet, for the first time, you know, there, there's been enough interest in sort of distinguishing the differences between DR and IF to actually do the experiment properly and find out.

    16. CWChris Williamson28:57

        We only put wheels on luggage about 30 years ago.

    17. ASDr Andrew Steele29:00

        (laughs)

    18. CWChris Williamson29:00

        So, if that's, if that's a start to remind us just how shit we are at innovation sometimes-

    19. ASDr Andrew Steele29:05

        (laughs)

    20. CWChris Williamson29:05

        ... then that's all we need. So, how can we treat aging? We've said it's a big problem, we've said that downstream risks from it are essentially endless. It is the...

17. 29:16 – 32:41

    senescent cells

    1. CWChris Williamson29:16

       how would you say? It is the axis of so much suffering in life, right? Like-

    2. ASDr Andrew Steele29:21

       Mm-hmm.

    3. CWChris Williamson29:21

       ... if you live for long enough, all of the people that you care about, all of the people who care about you are going to die, and it's going to be incredibly traumatic. So, obviously, holding that off or stopping it entirely would be a universal good. How can we treat it? Where do we start?

    4. ASDr Andrew Steele29:36

       I think the way to start is to look at the hallmarks of aging and to look at ways to slow and reverse those. And my favorite example, because it's the one that's furthest forward and it's quite an intuitive one, is looking at senescent cells, which you might have heard of before. So, these cells, um, they were first discovered in the '60s, and they were discovered by a guy called Leonard Hayflick, and he was doing... these are very sort of cells-in-a-dish-type experiments. They're very far removed from actual, you know, organisms in humans. He was just growing these cells in a dish. And what he noticed was they'd divide and divide and divide, what cells do, and then after about 50 divisions, they'd just stop. And not only did they stop dividing, they looked weird under the microscope. They started out as these quite sort of ordered-looking things, but if you look at a senescent cell, even, you know, a non-expert can see, it's this sort of weird, blurgy, splayed-out lo- you know, it, it looks radically different from a non-senescent cell. And as a result, because these cells seem to be old in the sense they've divided a lot of times, and because they looked weird, and because they'd stopped dividing, they were christened senescent. And senescent is just a scientific term for aging, basically, so it was aged cells.And these were of interest and people wondered, you know, that, that set the train of thought in motion. Could it be that the ageing of our bodies is driven by the ageing of the cells inside them? Could it be that cells inside us have divided too many times when we get to the age of 60 or 70 or 80 and that's one of the drivers of the ageing process? And so this was sort of observed for the next few decades, but I think the real excitement about this started in 2011 when, for the first time, some scientists got, um, at the Mayo Clinic in the US, got, uh, uh, some mice that had been genetically modified, and they'd been genetically modified such that they had an extra gene. And what that gene did was it meant if they were given a drug, which is otherwise, uh, pretty, you know, it's innocuous, it's something that if you and me took, nothing would happen 'cause we haven't got this special gene. But if you do have this special gene in your cells, then it, it, it, the gene basically goes, "Am I in a senescent cell? If I am, I'm gonna kill it." So it's sort of a suicide switch, but just for senescent cells. And so the mice took this drug, activated the gene, and the senescent cells in their bodies committed suicide. And what they found was this made the mice healthier. Actually, it didn't make them live longer because this first experiment was done in a special, uh, an- uh... They had another genetic modification that made them age really quickly and so they all die after six months basically. So, that, that wasn't the big result. The big result was that it made them healthier. And so then subsequent experiments started doing this in normal mice that didn't have this premature ageing condition, and what they found was they can make them live longer, they can make them live healthier, um, they get cancer later, they get cataracts later, they, they have better fur, which is obviously crucially important to all of us. Um, they are, you know, they're more cognitively... Uh, they, they, they age cognitively more slowly. So if you get one of these mice and put it into a maze, a young mouse will be very curious and go exploring, whereas an old mouse will be a bit more nervous and probably not going, you know, run around, have a look to see what's going on. But an old mouse that's been given these senolytic drugs, drugs that kill senescent cells, is much more like a young mouse. It's more curious, it's looking around. And so it seems, from what we know so far, that removing these cells globally reverses the ageing process. And the idea would be then that, you know, this is one hallmark of ageing. If we can go after the rest of them, then we can start to slow and reverse ageing in a multitude of different ways and altogether that should slow our ageing down basically

18. 32:41 – 34:25

    getting the old out isnt sufficient

    1. ASDr Andrew Steele32:41

       overall.

    2. CWChris Williamson32:42

       I'm gonna guess that just getting the old out isn't sufficient. There must be something new that needs to be put in to replace that. How does that, how does that sort of fit in?

    3. ASDr Andrew Steele32:50

       So, in the case of the senescent cells, um, it'll be interesting to see if, if this pans out, like, in every part of your body, 'cause there might be some places where exactly as you say, getting rid of the old thing doesn't, isn't, isn't sufficient. 'Cause say for example you were just saying that neurons, uh, you have your neurons your whole life. If you were to kill your senescent neurons, then that's really bad news, right? You're gonna start losing brain very rapidly and there's nothing to replenish it. However, if you kill the senescent cells in your skin or your guts or your blood, none of these are really a problem. Because they're constantly refreshing, then other cells are just gonna divide, take their place. And so, you know, they're gonna very, very rapidly, um, replenish those senescent cells that have been killed. So it really depends on the part of the body, and yes, we probably will have to replace cells in some of those places. But what's surprising or is, is, is almost how lucky we've got with these first round of senolytic treatments in that they're imperfect, they don't kill all the senescent cells, and we are just naively killing cells, and yet it seems to make mice live longer, live younger. I don't think this is going to... this is gonna be the end of senolytics. I think we're gonna have to refine them. But we have struck surprisingly lucky, at least in mice, with these first treatments.

    4. CWChris Williamson33:55

       What about stem cells?

    5. ASDr Andrew Steele33:58

       Yeah. We're definitely gonna need more of those (laughs) . I think, um, yeah, so th- they're a particular example where if you were to, you know, say a large number of your stem cells became senescent and you killed them, then you might end up with a problem because you'd end up with, uh, what's called stem cell exhaustion. And, um, so what we're gonna have to do there is stem cell therapy effectively. We're gonna have to go into the body and replace those stem cells with new fresh versions that are able to keep your tissues r- you know, turning over at the rate they should be turning over.

19. 34:25 – 35:41

    ongoing repair running

    1. ASDr Andrew Steele34:25

    2. CWChris Williamson34:25

       It's going to be a increasingly complex system to continue to move. What about, like, ongoing repair running? Is there anything we can do there?

    3. ASDr Andrew Steele34:36

       Yeah, and I, I mean, the thing is, is this, this applies just across all the hallmarks of ageing and it depends how you choose to tackle each one of them. So with the senescent cells, I think probably getting rid of them is the most promising approach. But it might be that repairing them is another option, and there are various ways that you can go about repairing them as well. So, um, one thing that you can do, for example, you've probably heard of the epigenetic clock. I think you chatted with David Sinclair about that. And, um, the sorts of, uh, treatment that he works on where you insert these genes and it reverses the epigenetic clock can reverse cellular senescence as well. And it'll be interesting to see whether or not that's a wise move 'cause often senescent cells have gone senescent for a reason. The reason they've stopped dividing is 'cause they are at risk of turning cancerous or because they're badly damaged or broken in some other way. But it might be that rather than killing every single senescent cell, there are some that we want to rescue or there are some that we wanna replenish, and I think it's really gonna vary on a case by case basis. Exactly like you say, this is, it's, it's complicated. It's not gonna be as simple as taking a single pill that slows or reverses your ageing. It's gonna be a question of managing all these different effects, perhaps in different ways, in different parts of the body, in order to make sure that we can maintain young bodies overall.

20. 35:41 – 38:30

    gene therapy

    1. ASDr Andrew Steele35:41

    2. CWChris Williamson35:41

       Rather than adding a gene on, is there a way to upgrade genes wholesale?

    3. ASDr Andrew Steele35:47

       Yeah. So gene therapy is coming on. It's not quite at the point where we can, you know, inject a, a, a new gene into every cell of your body yet. That's a real challenge. But certainly, the dream is that you can, you'll be able to turn genes off, um, turn genes on, put new genes in, put new copies of genes in, and all of these things are certainly possible in the lab and they're becoming more possible in humans. So I was really excited last week as we record this, I saw a story about, um, the first gene therapy for something called sickle cell anemia, which is a condition that's particularly common in people of African descent. And the reason for that is that it's, um, it, it creates a, a sort of distorted form of haemoglobin, which is the protein that carries the oxygen in your blood.... and what that form of haemoglobin does is it creates, um, sickle-shaped, so sort of shaped like a, a sickle as in a hammer and sickle, so a C-sha- letter C-shaped cells. Um, and they're very, they're not very good at catching oxy- carrying oxygen 'cause they've got a much smaller volume than a normal round blood cell, and they also tend to get jammed up in really small blood vessels, so the tiny capillaries. They can jam it up and stop the blood flow entirely, which can cause incredible amounts of pain for people who have two copies of this gene, 'cause if all their cells are sickle cells, they're not getting the proper amount of oxygen to their tissues. Sometimes it gets jammed up entirely. It's a really, really terrible disease. The reason it's, um, endemic in Africa is because having one copy of this gene is actually quite good news if you're in a population that is historically affected by malaria, because these sickle cell can effectively jam up the mosquito's, um, b- bite. Uh, proboscis, I think, is the word. I'm not entirely sure. I'm not- Mm-hmm. ... not an insect biologist, but, you know (laughs) , so it jam- it jams up the mosquitoes and they're unable to take a drink of blood from you and they're unable to infect you with the malaria parasite, so that's why this evolved. But now, in the modern world, it's becoming less and less important. In fact, as I say, if you have two of these genes, it's very bad for you. Anyway, long story short, the scientists have come up with a way of extracting the stem cells from your bone marrow, which is the place that your blood cells are regenerated. They then reactivate a gene for something called fetal haemoglobin. So, we have a different kind of haemoglobin that works when we're inside our mother's wombs, and they reactivate that gene, which is normally deactivated in adults, and then re-insert those blood cells. And not only that, like, in the intervening time, they get rid of all the other blood cells, um, all the other blood stem cells with chemotherapy. So, at the moment, it's not a hugely pleasant procedure, but then they inject these new cells back in with this gene reactivated, and they're able to produce blood cells that are normal again, so they lose these symptoms of the sickle cell anemia, and it works. It's just been... I, I think the, it's the first successful tr- trial. I'm not sure it's been approved yet, but it's just, that's just so exciting 'cause it's an example of, um, a lot of the kinds of technologies that I talk about in my book, like, you know, removing cells, modifying them outside the body, doing gene therapy, putting them back in. It's not at the stage where we can, you know, enact all of the ideas that I talk about in the book, but it's certainly a serious step along the way to having actual gene therapy and actual cell therapy in the clinic.

21. 38:30 – 41:23

    the cure for aging

    1. ASDr Andrew Steele38:30

       Will the cure for aging arrive in time for me and you? I think it could do. I don't wanna make any guarantees. But I think what I, what I find most remarkable about this, and I, I... Toward the end of the book, I start talking about what a cure for aging is actually gonna look like, and I think it's gonna be much more complicated than anything we've talked about so far. It's gonna be more complicated than addressing those 10 hallmarks of aging. The reason I've got some faith that it's gonna happen is because we're undergoing a computational revolution in biology at the moment. You talked about AI earlier. Um, you know, even if we don't get to general intelligence, I think we're gonna get to a point where AI programs are able to interpret this huge sort of torrent of data that biologists are producing in, in a way that humans just can't understand. And to give another exciting thing that's happened in the last couple of weeks, DeepMind, uh, this company that are part of Google, announced that they've managed to get AI to fold proteins, to work out how biological molecules fold up in our bodies, which has been a problem that we've been struggling with for decades. And suddenly, they've come in and they've... They haven't solved it, I wouldn't quite say, but they're, you know, they've, they've made significant strides. And the fact they've done it in just a few years suggests there are significant more strides to come if they can keep on squeezing those performance gains out of the AI. And we're just gonna get to a point where we've got so much data, we can sequence genomes, we can s- sequence, you know, we can look at proteins, and we can combine all that together in a computer. And as I was writing this, I was thinking, "Wow, this just sounds like total sci-fi." We're gonna need a, you know, a huge model, a computer model that understands the whole of the workings of the human body, all of our DNA, all of our proteins. We've got, you know, like 40 trillion cells in our body all working together. You have to model every single one of those. And, you know, I just thought this s- this is crazy. We're not gonna... The cure for aging is never gonna arrive in time. But actually, you know, if you think that th- that kinda idea is a bit pie in the sky, it's 50 years away, imagine... I'm in my 30s now. I'm, you know, fully expecting, even if nothing happens in medicine, that I should still be alive in my 80s. And that means that even if you think that technology is 50 years away, it could be in time for a lot of people who are alive today. And actually, the way that you can get more optimistic about this is, um, because by the time we're 80, we're gonna have senolytic drugs that are able to kill our senescent cells. In fact, we're not just gonna have the first generation we have now, we're gonna have much-improved versions of those things. We'll probably have a few of the other hallmarks sort of ticked off the list at the same time, and that's gonna mean that we live longer and healthier lives. And I don't wanna put a figure on it, but let's, let's imagine that you live an extra five years as a result of all that stuff, and, and five years in good health. That means, you know, when we get to the age of 80, we might be biologically 75 or 70, so we're a bit more able to take whatever these new treatments are and, you know, we might be alive in time to take them basically. Um, so I don't think... You know, I, I don't wanna guarantee at all. We've just got no idea. It could be that this stuff's completely impossible. And although it seems like we've got an idea now, we might get ten years down the line and think, "Oh, Jesus, you know, we just, we completely underestimated hallmark number four. We're screwed." But even if you think that some of these developments are 50 years away, they could be in time to matter for a hell of a lot of people who are alive today.

22. 41:23 – 42:31

    the fermi paradox

    1. ASDr Andrew Steele41:23

       It's like biology or longevity's got a hard problem and that ha-... Or a, how would you say? You know the great filter hypothesis about why the Fermi paradox exists, why there's no aliens out there? Mm-hmm. There could be that and we may have got past it or we may be able to get to it or it may not exist. Uh, yeah, it'll be a fascinating area of research presumably as well- It's a really, it's a really weird time to be a- a- alive because we're, we're at a point in history where I don't... You know, we're not 1,000 years away from curing aging, I don't think. I... You know, if, if I wanted to be, like, really conservative, I think in the year 2000 people's risk of death is not gonna depend on how long ago they were born. Year 3000. So, the que- yeah, in the year 3000. Like, that definitely. There's, there's... And, and I'm saying that to be, like, so thoroughly uncontroversial. But the question is, is it gonna be 50 years, is it gonna be 100 years, is it gonna be 200 years? I think that's an open question. And because, you know, say, say we reach the age of 200 through whatever breakthroughs happen, it just seems remarkably unlikely to me that we won't have made such huge strides in biology and computation that we can effectively expect to live longer still. So, I'm not saying we will make it to 200, but if we do, the possibility of us living much, much longer is just wide open,

23. 42:31 – 44:26

    immortality

    1. ASDr Andrew Steele42:31

       I think.

    2. CWChris Williamson42:31

       ... presumably, for everyone who's listening to this, the longer that we all live, the better our chance at being alive longer if a cure is found.

    3. ASDr Andrew Steele42:42

       Exactly. And, uh, uh, even if it, even if we don't get as far as a cure, like, every year you live in good health additionally, there are gonna be new breakthroughs in medicine. It might not even be breakthroughs in aging. It might be a n- a new cancer treatment or a new heart disease treatment. And I think as, um, a lot of people, like, th- there's, there's a real risk of starting to talk about immortality and that kind of thing, and certainly a lot of journalists, a lot of podcast hosts are very keen to talk about, like, really, really long lifespans and stuff that's sort of on the edge of our ability to predict at this point in time, quite frankly. However, if you look back in history, this is, this is really uncontroversial 'cause people who were born in the 1930s, um, a lot of those people survived because vaccinations were starting to come online. You know, if they, if they got an infectious disease when they were 20, there would have been just the first few inklings of antibiotics, and that meant that when they were 70 in the year 2000, there were a load of heart treatments that were completely unimaginable in the 1930s. Like, w- what I'm t- talking of, you know, we didn't put wheels on suitcases (laughs) until the '70s. We didn't invent chest compressions until the 1950s or 1960s, and they certainly weren't in w- like, widespread use until the late '60s. I was stunned when I found that out researching the book 'cause you just think, it's the most obvious thing in the world. If your heart, which beats, stops beating, why don't you physically, you know-

    4. CWChris Williamson43:53

       Whack it.

    5. ASDr Andrew Steele43:53

       ... beat it for it, effectively? And yet, it took us thous- thousands of years (laughs) as a species to come to that realization. And so if you are... That, that, and what that means... I've got quite sidetracked, but what that means is that if you were alive in the year 2000 because of medical developments that happened in the 1930s, '40s, and '50s, you were then able to benefit from a whole load of new medical technology that simply didn't exist at the time of your birth. And I think, you know, whether or not we're gonna live to 1,000 or 10,000 or 102, the fact is, every year you stay alive longer is another opportunity for some medical breakthrough to happen that could benefit you.

24. 44:26 – 47:10

    health advice

    1. ASDr Andrew Steele44:26

    2. CWChris Williamson44:27

       Let's say I want to live as long as I can. What, what do I do? I want the Full Monty.

    3. ASDr Andrew Steele44:32

       (laughs) I think, at the moment, a lot of it is just follow the basic health advice. You know, make sure you don't get too fat. Make sure you get a bit of exercise 'cause what you find when you drill down, you know, don't smoke, you get down, you drill down into what all these different bits of health advice mean, and this is something that actually really fascinated me. Research, there's a chapter in the book about health advice, and what's really fascinating to me is that it's all of the things that are best for your health, all of the things that you've been told that you should do by your doctor or your dentist or whatever effectively slow down the aging process. So, smoking effectively, obviously, it, it hits your lungs the worst. It puts you at massively increased risk of lung cancer. It puts you at massively increased risk of other lung diseases as well. But it also accelerates the aging process globally. It increases this process called inflammation, which we know drives the aging process. It makes non-lung cancers more likely as well. It increases your risk of heart disease. So, effectively, what a smoker does, if you s- you know, smoke 20 a day, you're basically 10 years older. Your biological age is 10 years higher than your chronological age is, and so you suffer from all those diseases of aging that much sooner. And it's the same with all of this health advice. Like making sure you eat well, making sure you exercise is effectively slowing down the aging process, and you know, there's, there's five or 10 years to be gained by doing this stuff. But what I think is the most important thing, and it's easy to overlook because I think, you know, all of us are really... I, I'm fascinated by diet. Reading, as we were talking about dietary restriction earlier, I was, I got obsessed when I was writing that bit of the book, being like, "What is the optimum diet?" You know, if I just read enough papers, it must be out there. It must be in the literature somewhere, you know? And what I came away thinking actually was, we're gonna have cured aging before we know exactly what the optimal diet is because there are just so many variables. There's protein, there's carbs, there's fats, there's all the different vitamins and nutrients. There's when you eat them, there's how much of it you eat when, there's what you eat on which days. It's ju- the, the number of variables is just astronomical. And so, what I think is the single best bit of health advice, which doesn't sound like health advice, it sounds a bit weird, but it's to campaign for more research into aging. So, wherever you are in the world, write to your representative, write to your MP, talk to your friends and family. Um, I know this sounds like I'm promoting my book, but get them to read my book. The reason being, the more people who understand that treating aging is a thing that we can do and that we should be aiming to do, we're gonna get a critical mass. You need voters to know this. You need politicians to know this, and that means they can give money to the scientists who are working on this stuff. And then, you get to a point where what's determining the length of your life isn't exactly whether you eat the right combination of fruits and veg on the right day of the week. It is the progress in biology. It's the process in aging biology. Sorry, the progress in aging biology, effectively. And I ultimately think that's gonna make a far bigger difference than any of the lifestyle interventions that we could talk about.

25. 47:10 – 48:11

    exercise

    1. ASDr Andrew Steele47:10

    2. CWChris Williamson47:10

       What about exercise? What's the most optimal form of exercise that you've found?

    3. ASDr Andrew Steele47:16

       And again, that's so tricky. Um, I th- I think something that I, I certainly personally neglected was strength training. So, as you get older, um, your muscle mass and your muscle strength decreases. Um, and it starts off relatively benign, but from your mid-30s onwards, it starts to decrease, and when you get into your 60s and 70s, it really starts to fall off a cliff. But what's surprising is that actually, um, that is, to a significant extent, optional, which means that if you engage in strength training, you can ward off frailty in your muscles for a substantial amount of time. I even found one study where they gave some nonagenarians, so people in their 90s, strength training, and they were able to walk faster. They were able to lift heavier weights. Um, you know, it's not like they were going down the gym and powerlifting or anything like that. But they, you know, th- their, their quality of life was substantially improved by this strength training intervention. And so, it's never too late to start. And also, yeah, just, just make sure that you look after your muscles because they are one of the things that's gonna really impact on your quality of life.

26. 48:11 – 49:42

    intermittent fasting

    1. ASDr Andrew Steele48:11

    2. CWChris Williamson48:11

       Going back to the diet thing, and especially the intermittent fasting point that we came up with earlier, do you think there's a bit of a-

    3. ASDr Andrew Steele48:16

       Mm-hmm.

    4. CWChris Williamson48:16

       ... Pascal's wager going on here? It's like, I don't know-

    5. ASDr Andrew Steele48:22

       It's-

    6. CWChris Williamson48:22

       ... if, if it's going to work, but it's probably not not going to work, so I might as well do it.

    7. ASDr Andrew Steele48:29

       Yeah, and I, th- th- that's the, that's the really frustrating thing about it, isn't it? It's, like, infuriating because...... I would, I would go with that if it was easy to stick to. But the problem is, in addition to the fact it might work and you might as well give it a go, it is exhaustingly, you know, th- being that hungry is just so tiring all of the time. And it's not like there are no disadvantages at all. So the, in the, um, I think the best studies actually are of dietary restriction rather than intermittent fasting, which is just because intermittent fasting stuff is that little bit newer and so the human trials aren't quite there yet. I, you know, if you ask me again in two years, I suspect we'll have a bit more to go on. Um, but what they found in dietary restriction trials is that people sometimes lose a bit of bone mass, so they had a few people have to, like, drop out of the trial because they were losing bone mass. They had someone drop out of the trial because they were getting anemic, which means they didn't have enough red blood cells. Um, and the other thing it can do is reduce immunity. So, you know, there's no point living effectively indefinitely if you're then just gonna get the flu and die any- anyway. Or coronavirus these days, of course. So, the- the- the it's not a, uh ... Unfortunately, it doesn't come, quite come down to Pascal's wager because firstly, it's just tiring and really dull and secondly, there are these sort of, these, these nasty disadvantages that mean it's just not a no-brainer to try it.

27. 49:42 – 1:05:26

    calorie restriction

    1. ASDr Andrew Steele49:42

    2. CWChris Williamson49:42

       Hmm. It seems to me that those are exceptions rather than common issues. Um, certainly, after speaking to David Sinclair a couple of years ago in Harvard, I was like, I was so eating the, or drinking the Kool-Aid, the calorie-free-

    3. ASDr Andrew Steele50:02

       Mm-hmm.

    4. CWChris Williamson50:03

       ... Kool-Aid of intermittent fasting.

    5. ASDr Andrew Steele50:05

       (laughs)

    6. CWChris Williamson50:05

       And you're right. I, I know somebodies who find it really easy. Mikhaila Peterson is a good friend of mine. She consistently does, like, four-day fasts or seven-day fasts and stuff, which is just, uh, yeah, that's another, another level. But-

    7. ASDr Andrew Steele50:19

       It really is.

    8. CWChris Williamson50:21

       ... I don't know, man. I, I don't know. I was... You've thrown a spanner in the works. I was, I was all team, team calorie restriction now and I, it, it, the story is not as simple as-

    9. ASDr Andrew Steele50:30

       I'm, I'm really mixed. So something that happened to me in exactly this way. Um, so calorie restriction is really hard. Um, intermittent fasting is still quite hard. You know, trying to not eat for a full day is really difficult. But the 16:8 thing, I thought, "Well, that sounds quite doable." So actually, my wife and I decided to try that, um, at the beginning of, I think it was, I can't remember if it was last month or the month before, and literally the week we started doing it... And it's quite doable by the way. You know, just not having ... Just skip breakfast, start eating at 12:00, then make sure you get your food in before 8:00 PM. Um, it's, I was a bit hungry in the mornings, but I, I often used to skip breakfast, you know, as a, as a young, young adult, back when I was irresponsible. So that's, um, it's just not that hard to do. But then literally that week, a study comes out saying, "We've done a proper randomized trial of this." Admittedly, it's not necessarily applicable to everybody because they looked at only white people, they looked at people who were slightly overweight to see if it would reduce their weight. And what they found was basically it didn't do anything. The people who were in the control group and the people who were in the experimental group doing the 16:8, they both had about the same trajectory of their weight, their inflammatory markers in their blood were about the same, their cholesterol was all about the same. Um, and, you know, that's not nails in the coffin, but the scientist who, uh, who did the experiments, he said, "I was taken in by 16:8 fasting. I was completely convinced by it, but now we've done this experiment, I'm stopping today." And-

    10. CWChris Williamson51:42

        You are pissing on everyone's party today, Andrew.

    11. ASDr Andrew Steele51:45

        It's, it's real- it's really annoying.

    12. CWChris Williamson51:47

        (laughs)

    13. ASDr Andrew Steele51:47

        It's not like... And I don't want to. I mean... (laughs) It's, it's really frustrating. I feel like... (sighs) I, I, I don't know what we can do about it because it, I, I don't think we're gonna have the evidence that tells us one way or the other. And that means, I think there are, there are some really compelling arguments made by people who are, like, DR advocates that, you know... So, so for example, a study in rhesus monkeys. There are two studies done. One of them was done at, uh, the univ- uh, University of, of Wisconsin and one of them was done at the National Institutes for Aging. And one of them found that the monkeys lived longer and one of them found that they didn't. They both found the monkeys lived healthier, by the way. So let's, you know, park that. We can s- we can still potentially look forward to healthier lives, but let's talk about longevity now. There are, there's enough in, there's enough differences between those studies to, like, have DR advocates and skeptics arguing until the end of time.

    14. CWChris Williamson52:36

        What's DR?

    15. ASDr Andrew Steele52:37

        Because... Oh, dietary restriction. Sorry. The reason I'm pedantically calling it dietary restriction rather than calorie restriction is that recent work has suggested it might be proteins or amino acids who, which is the important thing to restrict. So i- it just shows you, there's just... This is so complicated, right? It's, it's, it sounds, like, alluringly simple when you hear, "Rats ate half as much, they lived almost twice as long." Boom. But actually, like, what is it about their diet that changed? In what exact way that conferred those particular benefits? And that's how you end up in this mess. And these, th- this monkey experiment is a, or this pair of monkey experiments is a really great example of that because ... So the NIA monkeys, they were fed a relatively u- uncontrolled is unfair, but they, they were, they were fed a n- a natural diet of, like, fish and grain and various bits and bobs, which by its nature is uncontrolled 'cause obviously you can't, like, create a fish that has a particular combination of nutrients inside it every single time. And the monkeys in the University of Wisconsin version were eating these sort of science-y, purified pellets, so they had, you know, fat and protein and sugar in exactly predetermined amounts. And, um, the University of Wisconsin monkeys, the ones who were on the control group, wh- who were allowed to eat what they like, were literally allowed to gorge on as many of these fatty, sugary pellets as they wanted. And you can sort of see where I'm going here. These monkeys were on, like, their fast food, McDonald's, soft drinks diet. They had fatty, sugary pellets, all you can eat, stuffing them in, and that meant that the dietary restriction group, who were on a restricted number of these pellets, was healthier and lived longer. However, in the NIA study where they were given this slightly more diverse, but slightly less scientifically precise diet, what it turned out was the dietary restricted monkeys were healthier for longer, but they didn't live any longer. And so the simplest explanation of this perhaps is, uh, um, simplest and perhaps simplistic explanation, I should say, is that there's a sort of sliding scale. So if you're eating hamburgers and fries and soft drinks all the time like the Wiscon- Wisconsin monkeys gorging on these, uh, these little pellets, then you can benefit from restricting your diet a bit. If you're already eating not too much of an unhealthy diet or a, a reasonable amount of a basically healthy diet, there's not much benefit to going further.... that is one interpretation. However, if you're a dietary restriction proponent, for whom I've got a lot of time, then you go, okay, well, actually, there are other problems with the NIA study too. One of them is their monkeys were from a much more diverse background and they were a much wider range of ages, so they started some of these monkeys on the dietary restriction when they were in, you know, late adulthood. And they also had monkeys from all different parts of the world. And this, if there is an effect, this could potentially obscure it because they found that dietary restriction works differently in different, um, in different strains of mouse, for example. And so you can imagine that an Indian macaque and an African macaque might have a slightly different response to it. And so all of this just muddies the waters and it means you can make quite a convincing argument that actually, if we were to go back and do these experiments properly, we would find an effect. But what it makes me think is that there might be an effect, I don't wanna, like, completely rain on everyone's parade, but if there is an effect, it's clearly not a doubling of lifespan like we see in rats because these are two groups of scientists who did these experiments. They were trying in good faith to replicate these ideas and they had slightly different approaches, granted, and there are various things you can quibble about, but if this doubles lifespan, we'd know about it, right? One of them might be a bit less than the other one, but we'd see it, we'd see the results in the experiments. But given that the results are a bit equivocal, you know, maybe at the absolute most optimistic end, you might get five or 10 more years, but if you're already eating a basically healthy diet, I think it's hard to expect that you're gonna, like, dramatically alter your lifespan through DR.

    16. CWChris Williamson56:04

        What's unique about us, every animal, the most comprehensive, reliable effect in biology is calorie restriction or dietary restriction to extend lifespan and then at some point in our, like, couple of recent history's worth of evolutionary change, someone just put a bit of computer code bug in-

    17. ASDr Andrew Steele56:25

        Turned that off. (laughs)

    18. CWChris Williamson56:26

        ... and now, and yeah, and now we're wrecked. What- what's different?

    19. ASDr Andrew Steele56:29

        Yeah, it's rubbish, isn't it? Uh, well, the, the way to sort of reassure yourself a little bit is part of the reason is probably that we are rela- we're, we're incredibly long-lived for our size.

    20. CWChris Williamson56:37

        We're pushing the limits of that already.

    21. ASDr Andrew Steele56:40

        There's a very good... Exactly. And there was even a theory that I think has now been debunked, but that maybe humans had already turned on a lot of the mechanisms that underlie DR in order to reach our extended lifespans that we have. They've actually gone back and had a look at that and it isn't true, but it's, it's the right sort of way of thinking about it because, um, so f- so firstly, I think these results are much more variable than is sometimes suggested. And I noticed this when I was doing some research for the book because there's, th- th- so I'll tell you the simple story, then I'll tell you why it doesn't quite work. The simple story is that the reason that animals have this response to reduced food intake is imagine you're a mouse. You've got a maximum lifespan of a couple of years. You might only have a lifespan of one year because you've got predators and you've got disease and that sort of stuff, so you've got a very, very short lifespan. Imagine there's a famine, so there's a season where for some reason there's not enough food. There are two things you can do in that season. You can either have a last ditch attempt at having some kids before you starve to death or you can hunker down, you can engage your dietary restriction response, and you can slow your aging in order that you'll live that little bit longer so you can survive until the next season when food's hopefully plentiful again and have some kids. And there's a serious advantage to that second approach and that is that your kids will then be born into an environment where there isn't a famine going on, so rather than just having them immediately in a last act- act of desperation. So the theory goes, and it's not entirely supported and there are DR proponents who will fight back against this, but the idea is that if you're a short-lived animal, it's really important to have a very flexible lifespan with respect to how much food you're eating 'cause if you're going through a famine, you need to survive much long- you know, a significant fraction of your lifespan in order to get to a point where you can have kids and it be useful. However, if you're a human and even in pre-history, as you rightly said, you know, 'cause of a lot of infant mortality, our life expectancy was 35, but actually if you made it out of childhood or you made it past 15, then you could expect to probably live into your 40s or 50s. And that means if you have a famine for one year, like, it's not ideal, but it's not a significant fraction of your reproductive lifespan. And so you'd expect that as organisms get longer-lived, they might get less of a response to dietary restriction as well. And what you also find when you look at the data which makes it more confusing is that this, this sort of tight correlation between lifespan and size and the tight correlation between, um, lifespan and dietary restriction response doesn't really hold very clearly. So dogs, for example, which we've also tried dietary restriction in, has, they, it has a surprisingly small effect and I don't think anyone really knows why. And actually, there are lots of animals that have a really big response and a really small response, and it's not quite as neat as it seems at first glance. Even though it is incredibly universal, the size of the response can vary very significantly.

    22. CWChris Williamson59:16

        I love that theory. It makes complete sense and I'm a, a, a big advocate for evolutionary biology and evolutionary psychology, so I'm seduced by that. It's plausible, but everything today's come with a caveat.

    23. ASDr Andrew Steele59:28

        Yeah.

    24. CWChris Williamson59:28

        There's not a single thing that's been definitive except for o- a couple of studies. And even the studies, "Well, this could've been different and that could've been different."

    25. ASDr Andrew Steele59:36

        Yeah, yeah, yeah.

    26. CWChris Williamson59:37

        So yeah, it's strange that something that's, let's say the prime vector of so much suffering and a universal, a ubiquity across all of our lives, is also something that we're incredibly ignorant and all of the waters are- are still very muddy about. Oh, that's something actually, what about supplements and drugs, NMN, NAD, resveratrol, metformin, baby aspirin, the- the- the David Sinclair stack?

    27. ASDr Andrew Steele1:00:02

        I think we haven't got enough evidence to go for those. I personally don't take any of them. I think that the evidence could get there in the next few years, but we need to see human trials. There have been a few experiments in mice that David's done that have shown some effect. I don't think they've shown longevity on any of those things. Um, and so-

    28. CWChris Williamson1:00:18

        It's like regrowing optic nerves and m- mad shit like that, isn't it?

    29. ASDr Andrew Steele1:00:22

        But, but, but cr- yeah, crucially, that was with gene therapy rather than with a drug.

    30. CWChris Williamson1:00:25

        Oh God.

Episode duration: 1:17:22