Biological Immortality w/ Dr. Andrew Steele
EPISODE #32
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Computational biologist Dr. Andrew Steele shares his insights into the latest scientific research dedicated to tackling age-related disease, the societal implications of extending the human lifespan, and the habits linked to a longer life.
Andrew Steele is a computational biologist with a PhD in physics. He is a Research Fellow at the Francis Crick Institute in London, using computers to decode our DNA, and unravel the secrets hidden in some of modern biology’s biggest data. He has a first-class degree and a DPhil from Oxford University, where he used particle accelerators to understand the inner workings of magnetic and superconducting materials.
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Luke Robert Mason: You're listening to the FUTURES Podcast with me, Luke Robert Mason.
On this episode, I speak to computational biologist, Dr Andrew Steele.
"We should go after the root cause of the biggest amount of human suffering. We've managed to extend lifespans in loads of ways in the past, but the frontier now is the treatment of ageing."
- Dr. Andrew Steele, an excerpt from the interview.
Andrew shared his insights into the latest scientific research dedicated to tackling age-related disease, the societal implications of extending the human lifespan, and the habits linked to a longer life.
You can also view a video version of this conversation at FUTURES podcast dot net.
Luke Robert Mason: Ageing is the world's leading cause of death and suffering, but since getting older has always been part of the human experience, we've never felt the need to question it. That, however, could soon be changing, with the development of new medicines, procedures and interventions offering us the possibility to both live longer and to live healthier. So what might some of these innovations look and feel like? Well, luckily they've all been catalogued in Andrew Steele's exciting new book, 'Ageless', where he investigates the myriad of ways that science might soon slow the ageing process and by doing so, fundamentally transform the human condition. So Andrew, since we're on the topic of death and ageing, let's start with a fun question. When and how do you want to die?
Dr Andrew Steele: Oh, that's a fascinating one. I'd like to die as late as possible and as quickly as possible. I'm sort of not so worried about death itself, it's the suffering that really bothers me. If you look at people who are more our grandparents’ generation, I've watched my grandparents slowly getting older, getting more diseases, getting frailer, getting less able to manage doing stuff about the house. It's that period of time that I really don't want to be experiencing.
Mason: There's the funny thing with the longevity community. They're quite happy to have immortality; to live forever. In a funny sort of way, when I think about how long I want to live, I always think about David Bowie. He lived to 68 years old and he lived a really good life. I would rather take 68 David Bowie years over immortality any day of the week.
Steele: I'm not really sure. I mean, the thing that I feel is that I don't want to die now. I've got stuff to do and I'm quite enjoying being alive. I'm not saying there is no point in the future at which I would wish to die because that's a ridiculous thing to say. Maybe if I were to live to 1000 or 5000 I'd get bored or some bizarre thing could happen to the world where it would cease to be an interesting place. Anything could happen. But honestly, the way I think about it is day by day. I think that I don't want to die today, I don't want to die next week. More than death, I think that I don't want to get Alzheimer's next week, I don't want to get cancer next week. I can't imagine - whether I'm 68, or 168, or 1068 - why that would change. I think immortality, but one day at a time.
Mason: That's the interesting thing about reading the book. When you talk about ageing, you're looking at ageing from a scientific perspective. To help our audience, what do you mean when you talk about the thing called 'ageing'?
Steele: Well I've got two different ways of thinking about it. The first of them is a statistical definition which I think is the broadest and most catch-all, but it doesn't really cover the nitty-gritty of what's going on inside our bodies. Let's start with that one. Ageing is just the fact that some organisms increase their risk of death as they get older, and humans are obviously an example of this. I'm in my thirties and that means my risk of death every year is somewhere around one in 1000. I'm pretty happy with those odds. If you could imagine projecting that out into the future, on average I'd live into my 1030's. Obviously that isn't the case. Those odds change quite dramatically, quite quickly. Actually, humans have what's called a mortality rate doubling time; time in which their risk of death doubles. That's about every seven or eight years. Although it starts out very small when you're a young adult, it can get very big, very quickly. By the time you're 65, it's somewhere in the region of a one per cent chance you won't make your 66th birthday. By the time you're 80, it's about five per cent. If you make it to your 90s, then you're looking at something like a one in six chance that you won't make your next birthday. It's almost a wall of mortality. It creeps along pretty slowly for the first four or five decades of life and then suddenly shoots up once you enter your 60s. That's the statistical way that I think about ageing.
Of course, as I was saying, it's not just about death. The good thing about death - if that's something I want to say - is that it's very easy to measure and it's very hard to game. You can argue about definitions of disability or frailty, or even perhaps definitions of states of disease, but whether or not someone's dead or alive is pretty unambiguous, even probably to a non-doctor. So that's the statistical way of thinking about things.
The biological way is to look at that...and this is what inspired me into this field. Sometimes I tell people that I changed my career because of a graph. That graph is increasing mortality with time. What that says to a scientist isn't just: Oh God - there's a level of existential terror. It's also the fact that there must be, in order for all of these different diseases - cancer, heart disease, stroke, dementia, frailty, grey hair, wrinkles - in order for all of those things to be happening at around the same time in our lives, there must be some underlying biological processes that are driving all of those things to happen at the same time. The modern, accepted biological definition of ageing is to look at what are called the 'hallmarks' of ageing. These are the underlying cellular, molecular processes that cause us to grow old. They're things like damage to our DNA. They can be damage to the cells and the molecules inside of our bodies. Some of our cells become senescent so they actually become aged themselves and stop dividing. The aggregate sum total of these things is all of the consequences of ageing that we're more familiar with: cancer to wrinkles.
Mason: This is the important thing. When you talk about 'agelessness', what you're really talking about is something called 'negligible senescence'. It's really important to note this difference because what you're talking about in the book isn't immortality. It's this thing, negligible senescence. What is the difference?
Steele: Actually, sometimes negligible senescence is confusingly but quite alluringly called 'biological immortality'. What it means is that it's a risk of death that doesn't change with time. That might sound like something that's a bit strange. It's certainly not happening in any of the animals that we're familiar with day-to-day. We observe our pets, our cats, our dogs, mice. They can all age in a very similar way to humans, actually. Mammals all get cancer, they all get cataracts, they lose their hearing and they become frail as they get older. If you look at some other species that are a little bit more distant from us, some of the tortoises - the reason a tortoise is on the front of my book is that tortoises have this property of negligible senescence; this biological immortality. Their risk of death actually isn't as low as a human's when they're a young adult. It's something like one or two per cent a year. But by the time a tor-, tur-, tor- I can't say turtle or tortoise, I just can't make my mind up.
Mason: When we get later on and I start saying 'biogerontology', then we're even.
Steele: I said antagonistic pleiotropy on breakfast radio the other day and I managed not to screw it up, so that's a feather in my cap, yes. But...tortles.
Mason: Tortles. New species discovered by Andrew Steele.
Steele: By the time a tortoise is in its 150s, it's risk of death is still one or two per cent. What that means is that basically, no matter how long ago they were born, that risk of death stays the same. That means that although their risk of death isn't as low as a young adult human's, they can just carry ongoing for longer and longer because they don't hit that wall of mortality when they get to a certain stage of life.
Mason: You say in the book that ageing is the world's most important problem. Why should we cure ageing?
Steele: It's just the sheer scale of the suffering. If you think about that mortality rate doubling time, doubling every seven or eight years, that means that when you get into your 60s, your 70s, and your 80s, lots of bad stuff is happening to your body. You're becoming frail and you're losing your independence. You can start to become forgetful and maybe even get into the early stages of dementia, or full-blown dementia. You can lose your personality, your memories, and everything that it is to be you. Those are all the things that I care about.
Then, you look around the world. I think life expectancy, globally, is higher than a lot of people expect. In 2019, which I think is the latest figure that we've still got available, global life expectancy was actually 72.6 years. What that fundamentally means is that most people in most countries are going to live long enough to experience these diseases of ageing. It's the biggest cause of death and it's the biggest cause of suffering.
To put that into slightly more concrete numerical terms, if you look at the 150,000 people who die every day on planet Earth, over 100,000 of them effectively die because of ageing. They die of all these age-related conditions. Over two-thirds of deaths are being caused by this single thing and all the decades of suffering. Cancer doesn't kill you overnight. You don't just wake up one morning dead because of cancer - or rather not wake up one morning. It can affect you over years, over decades as the tumour gets bigger. You have all the treatment. If you look at heart disease, you're less able to get around and do stuff because you're slowly losing your fitness because of heart problems. Then eventually, a heart attack can take you out, or heart failure. It's just looking at this. Two-thirds of deaths, the billions and billions of people who are going to suffer a slow decline. I think it's almost inarguable that this is the world's largest problem.
Mason: To tackle that problem, a new field has emerged. That's one of biogerontology, which I think I've absolutely butchered.
Steele: Biogerontology.
Mason: Biogerontology, there we go. What was it that actually kick-started this field, and what has it discovered about the process of ageing?
Steele: I think looking back at the history of it is really fascinating. There are a few times when you just think: why didn't scientists do more of this? I think the fundamental problem is that throughout a large fraction of the 20th century, ageing was seen as this inevitable process. If you go back to the beginning of the 20th century, this is the sort of age when physics had really firmly established the idea of thermodynamics. We knew that things tended to increase in disorder with time; this idea of increasing entropy. It didn't seem that unlikely that living organisms had exactly the same problems that machines do. We know that if you have a steam engine and you leave it running for a long time, eventually it's going to get rusty and some of its components are going to start to break. Unless you get in and maintain it, it's going to break down. It just didn't seem that weird to extend that idea to living things as well.
As I say, if you think about the sorts of animals that we're familiar with, most of them are mammals. Humans, for their entire existence of age to death - if you think about our farm animals and pets - they've all had the same thing. It looks like this inevitable process of falling apart. As we came to understand a bit more about it and a bit more about evolutionary theories of ageing, strangely this increased understanding doubled down on this idea that the whole case was completely hopeless. The evolution of ageing is incredibly complicated. That's why you end up using words like antagonistic pleiotropy...almost screwed that up.
Mason: Almost!
Steele: It's just this fantastically complicated idea. Evolution is survival of the fittest, so how do we end up evolving to become old? To cut a long story short, the output of these theories was that ageing is going to be the result of many dozens - hundreds even, perhaps - of different processes. The idea that you could study it in any meaningful, coherent way was just, it seemed, for the birds.
I think what really changed things was in the 1990s. It sort of started in the 80s but the real revolution was in the 90s. There were experiments done in labs which looked at individual genes and they found that if you disable a single gene in a nematode worm which is a commonly used model organism - a simple organism that we use to extrapolate, to understand biology - you can disable a single gene and you can increase the lifespan of a worm. In the 90s when we discovered it, it was by a factor of two. Actually, the current winner, you can increase the lifespan of a worm by a factor of ten. What this means is that suddenly this was accessible to lab biology. This wasn't some incredibly complicated process involving hundreds and hundreds of different sub-processes that were completely impossible to understand. You could go in, you could surgically disable a single gene and have these massive effects. That was the cultural shift that was required. This wasn't some immutable, complicated thermodynamic nightmare. It was something you could actually do in the lab.
Mason: You just said there that there is a complicated relationship between this thing called evolution and ageing. Humans have developed over millions of years of evolution so surely there must have been some sort of evolutionary advantage to ageing, and to eventually dying?
Steele: The current theory says there isn't really an advantage. It's more of a process of evolutionary neglect. The irony is that the reason we age is actually that we can die of things other than ageing. If you imagine you're a prehistoric human, there are loads of dangers in your everyday environment. There are sabre-toothed cats, there are infectious diseases which are probably the main one. There's other humans out to kill you because they want to have your territory or have your food. That means that we think life expectancy back in those days was about 30-35 years old. That actually reflects a large burden of infant mortality. There were some prehistoric humans making it into their 50s and 60s but nonetheless, there were lots of different ways that you could die before you got properly old, in modern terms.
What that means is, imagine you're an organism and you're trying to work out: I'm going to evolve. I've got to allocate the amount of energy that I've got - you've got a fixed amount of energy that you take in with your food - I want to allocate that in the most efficient way. You can use that to give your animal stronger muscles or you can use it to grow larger. There are so many different ways you can allocate that energy. One of them is that you can use it to maintain your body. You can create defences against cancer or heart disease to keep the body in pristine condition to old age. The trouble is by doing that, you're taking energy away from other things. The key thing is thought to be reproduction because obviously that's a huge energy-intensive process. Growing a baby inside you if you're a woman and taking care of your kids regardless of your gender. That means that there's definitely a preference in animals to reproduce before you're dead. You've got to gear up, you've got to have that kid. You've got to get it out into the world and get it - in the case of humans who have a long childhood period - you've got to get it capable of taking care of itself before you get taken out by a disease or before you get killed by something else.
The incentive is to move some of that energy away from maintaining our bodies in perfect condition until the end of time, effectively, and put it towards reproducing, getting your kids out, and getting your genes spread around. We call evolution 'survival of the fittest'. I actually think we should change that and call it 'reproduction of the fittest'. It's passing on your genes to the next generation. That's the crucial thing here.
Mason: Is that why - and you mention in the book - is that why historically it seems like eunuchs have a longer lifespan, because they're not worried about reproducing?
Steele: It's a fascinating question. I think the honest answer is that we don't know, but there's definitely an argument for that. If you look at the difference in life expectancy between women and men, women tend to live about five years longer than men. It depends a bit on the country, but I think there's only two countries in the world where men live longer than women. What you find is that if you look back at historical examples of castration - removal of the testicles - men who have been castrated seem to live longer lives. This study of the eunuchs is particularly impressive.
Perhaps the reason we're not a hundred per cent sure is that men are constitutionally able to live as long, or maybe even longer than women, but testosterone is a sort of kamikaze hormone. It gears us up very fast to be big, strong reproducing machines, but at the same time it diverts energy away from those processes of maintaining our bodies. Although we can't be a hundred per cent sure that's the reason, it's certainly a leading theory as to why castration is a way to make yourself live longer.
Mason: Yeah, I'm not sure whether that is something that I will be willing to do.
Steele: Neither am I.
Mason: I mean, you go through the book and you show us all of these wonderful ways in which we might be able to cure ageing. Do you think we're actually close to curing ageing? Do you think that it could happen in the next, say, a hundred years?
Steele: I think it's a really difficult question. I certainly think there's a distinct possibility it could happen in the next hundred years. There are just so many unknowns. The reason I'm confident it could happen in the next hundred years rather than in the next thousand or the next ten thousand years of human future is that we can make it a lot easier for ourselves. When I talk about a cure for ageing, exactly as you say, what we're really talking about is negligible senescence. We're talking about a risk of death that doesn't vary depending on how long ago you were born. If I could snap my fingers and get to that state, that's just not possible, because the understanding of biology we'd have to have in order to be able to engineer ourselves to be negligibly senescent is just completely way beyond anything we could possibly conceive of today.
However, if you look throughout history one thing that's definitely happened is that because life expectancy has been extended by a particular treatment, people then go on to benefit from future treatments that are developed during their lifetime. One of the examples I give in the book is that people who were born in the 1930s or 1940s were born into a time where there was much less infectious disease. Back at the beginning of the 20th century, there was a lot more awareness of hygiene and so that was already starting to stamp out the infectious disease. We're also getting vaccines. The first antibiotics were developed in the forties and started to be rolled out. Those people lived through a period where they didn't die, as children, of infectious disease. What that meant is that by the time they were getting old, by the time it was the 1990s or the 2000s, there was medication for heart disease or treatments for heart disease that simply hadn't even been conceived of when they were children. That means that by living a bit longer earlier in life, they were then able to live longer to benefit from these future medical advances.
We could do the same with treatments for ageing. It could be that we could have the first drug against ageing in the next 10 years, potentially. If that happens, that then means that people who are alive at that point will be able to take that drug and extend their own healthy life a little bit into the future. If you take care of your health, if you exercise and if you eat enough, if you eat right, if you don't smoke and all of that sort of thing, you can keep extending your healthy life and potentially give it more time for more advanced anti-ageing treatments to be developed. It's not as though we develop a cure all at once. We don't have to come up with some magic, incredible computer model of human biology that allows us to completely reprogramme ourselves. All we need to do is stay one step ahead of mortality. I'm not saying it'll happen this generation or next generation, but I think ultimately that's how ageing is going to be cured. We're going to end up adding a year to life expectancy every year. Such that you're just growing up normally, maybe they'll expect to die at 80, maybe they'll expect to die at 150, or whatever life expectancy is for their society. Gradually, as more and more of these treatments get developed, their funerals will just be receding into the future far faster than they're chasing them. I think that's the point at which we can be said to have cured ageing. Even if the true negligibly senescent humans won't exist for maybe hundreds of years after that, as long as you can stay one step ahead of things.
Mason: You do such a wonderful job in the book of summarising some of the latest scientific advances for curing ageing. They broadly fall under about three categories. There's either the removal, the replacement, or the repair of our cells. Which of those three do you think is the most effective way, currently, to prolong our lives.
Steele: I think the best example at the moment - by head and shoulders, basically - is a removal therapy; senolytic drugs, they're called. There are these cells in your body - I actually mentioned them earlier - they're one of the hallmarks of ageing. Accumulation of senescent cells is one of the reasons that we grow old. These cells were first discovered in the 1960s. There was a chap called Hayflick who was messing around with cells in a dish, in the lab. He was watching them divide and he noticed that after about 50 divisions, they just stopped dividing. Worse than that, they looked really weird under the microscope. I'm not an expert cell biologist by any means, but it's blindingly obvious looking at these things. They're these horrible, distorted shapes. There's clearly something a bit amiss.
These cells seem to be old, they've divided too many times. They were christened 'senescent cells', after the scientific term for 'old'. That begs the question: is it because our cells inside our body are ageing, that our bodies as a whole are ageing overall? The consensus, basically, over the intervening decades of research, has been that yes, it is. We know that organisms do accumulate these senescent cells as you get older. The problem isn't so much the cells themselves - they're sat there not dividing and in theory they're not doing any harm. The problem is that they emit this toxic cocktail of molecules that basically accelerates the ageing process. The purpose of that cocktail is usually to attract the immune system. It's saying, "Over here, I'm a senescent cell. I'm not dividing anymore. I'm not really doing my job. Can you come and clear me up?" In most senescent cell cases, a passing immune cell will come and gobble them up. Problem solved.
The problem is that as you get older, your cells are divided more times. We now know that there are more ways that cells can go senescent. They can get damaged, they can have problems with their DNA, they can be under cellular stress. If any of these things happen, the cell goes senescent just to be on the safe side, in huge part to stop it becoming a cancer. A cell that isn't dividing can't divide infinite numbers of times and become a cancerous cell. That's thought to be the evolutionary underpinning for this.
The problem is they sit there emitting these molecules, telling the immune system to come over and clear it. As we get older, we know that the immune system also gets less effective. That's one of the reasons why coronavirus, for example, is so much deadlier in older people. Their immune systems are less strong than those of people who are younger. That means that the senescent cells are appearing more frequently, they're being cleared less frequently, and so overall they increase in number.
That's a long story, but the conclusion of that is that finally, we've now got ourselves into a position where we can remove those cells. Scientists have identified drugs that you can use to delete these cells while leaving the rest of your cells in your body intact. If you give these drugs to mice, the mice just get biologically younger, and so obviously they live a bit longer. If you give them to 24-month-old mice, these drugs, they live another few months. Mice don't live as long as us. 24 months is about 70 years in mouse years. That means that maybe they live another few years, in human terms. They're not just hobbling along, geriatric and having the horrible end of their life extended. They get less cancer, they get less heart disease, they get fewer cataracts. They can run further on treadmills. They even have better fur. It really does look like you're globally reversing the ageing process by getting rid of these aged cells. I think that shows us the way. It shows us that by removing one of these hallmarks of ageing, you can take away one of the fundamental causes of all of these different biological changes and slow down or even reverse the ageing process, overall.
Mason: This sounds very exciting, but still, the science of aging is one that is very complicated. There are sometimes problems with some of these solutions. Instead of helping us, they may actually cause new diseases or even cancers, in the case of telomeres.
Steele: Yeah, it's a really complicated area. The thing that makes me most optimistic about senolytics - so these drugs that remove senescent cells - is that in all of the studies, there are very few side effects reported. There's an extent to which you have to take this with a pinch of salt because scientists want their big flashy Nature paper and so they're not going to report every single caveat or every little small problem that they saw. What it suggests is that even though these first therapies are quite imperfect - they're not clearing all the senescent cells - and even though on the other side, they're becoming quite indiscriminate - it's not as though we're only targeting particular tissues - it looks like almost everything about these mice gets better. We're going to just have to cross our fingers and hope the same is true of humans.
There are some caveats that we do know. For example, there are some parts of the body where you might not want to remove these senescent cells. A really good couple of examples are the heart and the brain. We know that heart cells and brain cells don't get replaced throughout your life in the same way as other parts of your body. You can literally be born with a neuron - a brain cell - and die with that same brain cell. If these cells aren't being replaced, we don't want to go removing them. We might want to try and fix whatever caused them to become senescent.
As I say, the good thing is that so far at least, these senolytic drugs have pros that far outweigh the cons. As we get better at understanding why cells turn senescent and how to identify senescent cells in different parts of the body, we'll be able to target these drugs even more precisely and make sure we only take out the senescent cells that we do want to take out, and then hopefully rescue the ones we don't or leave them intact in some other way.
Mason: Why isn't there just a gene for longer life?
Steele: It's interesting. There may be some genes that extend your life spans really dramatically. I said that in worms, we saw this gene where you can actually make a change of a single DNA letter. A worm gene name is hundreds of millions of DNA letters long. It's a huge, huge thing, yet you can change a single letter in that genome and cause the worms to live 10 times longer. Rather than living for two weeks, they can live 20 weeks, or 30 weeks or something. That's absolutely incredible, but it probably doesn't translate quite as simply to humans. There was a lot of head scratching when these kinds of discoveries were made. Scientists thought: oh, worms, they only live a fortnight. They're a very simple system. A worm has exactly 959 cells whereas humans are made up of tens of trillions of cells. Surely this sort of thing isn't going to transfer across?
Something that made me quite excited that it might, was actually a discovery in the last five or 10 years which is a gene called SERPINE1 which was found in the Old Order Amish community in North America. It was discovered by this really rather roundabout route. A girl came into the hospital in the 1980s and she'd bumped her head. The bleeding just wouldn't stop. Even though it was quite a minor injury, she just kept bleeding and bleeding and bleeding. Doctors eventually managed to save her life. There are quite a lot of different things called bleeding disorders that can cause blood not to clot normally when you have an injury. As the doctors looked through this girl's medical history and looked through some of her genetics, they couldn't find any of the classic bleeding disorders that they knew about. Eventually, they did drill down and find this new gene, SERPINE1. She had two altered copies of it, one from her mum and one from her dad. What that meant was that her blood wasn't able to clot normally. There was a scientist who was particularly fascinated by this and wanted to study what was going on in the whole community. They found that her parents had one copy each and lots of other people in the Old Order Amish community had a single, or two copies as well.
When they went back and looked through all of their family trees, they found that people who had a single copy of this gene didn't seem to have any problem with blood clotting - that was the first good thing. It appears you can get by with one copy. Secondly, these people lived on average 10 years older. That's not a factor of 10, but it's a start. I'd certainly take 10 extra healthy years. They also found that they were less susceptible to things like diabetes. It really does seem as though this gene, in some way, accelerates ageing.
It's going to be tough trying to identify these in humans because we have a lot of genes. The way that these things are identified in worms is that you just randomly mutate them and see what happens. Obviously, that's not quite so ethically acceptable in humans, but it really does open the possibility that there are these single genes. We can make a single genetic change and potentially add a substantial amount to life span. This certainly came as a surprise to me, and I think it came as a surprise to a lot of scientists as well.
Mason: Doesn't nature already have a way to preserve our genes, or at least our germline? We might have a form of immortality but it might not be immortality of our body. It's about the preservation of a germline by having children.
Steele: Yeah, so the phrase 'germline' has sort of distinguished a type of cells in our body from what are called the somatic cells. Those are the cells of the body. Eggs and sperm are germ cells and when they combine, obviously, you can make a baby. The very fact that we're having this conversation right now actually tells you something incredible about us and of course, all living humans - it's not us who are special. What it means is that there's been an unbroken line of reproducing creatures, all the way back potentially billions of years into the Earth's past. That means that three and a half billion years or something, when the first life is thought to have emerged - we're not a hundred per cent certain of the dates - it's not immortality, but it's not a bad start.
Clearly, nature has got some way of making sure that those cells at a very minimum are protected enough so that we can have children, they can have children, they can have children. It's not as though our species slowly ages over time. I think it's obvious that nature does have some tricks up her sleeve to try and prolong the life of cells and make sure all of that genetic information is preserved. The question is can we adapt those tools and use them in our adult bodies? There's this quote that it seems weird that nature is so capable of producing this incredibly complicated body and yet not able, seemingly, to do the much simpler task of maintaining that body once it's built. The question is can we work out - with our technology, with genetic modification, with drugs, with other kinds of treatments and whatever it is that we use - can we work out who to keep what we've got, going?
Mason: It seems there's still so much excitement about longevity technology. Are there any recent breakthroughs in the longevity medicine that we might soon see on the market? Is there a pill for longevity coming soon?
Steele: I really think the best example of this is senolytics. The drugs they used in mice are actually human drugs. They're human approved drugs, already. One is a chemotherapy drug called dasatinib and the other is flavanol, which is sometimes used in a nutritional supplement called Quercetin. The combination of these two things together seems to be the most effective to kill the senescent cells - that's what they ended up using. There are trials of that going on now.
There are actually 20 or 30 biotech companies - at the last count - which are trying to commercialise this stuff. They're using a variety of approaches. Some of them are drugs. Some of them are special packets of a suicide gene, effectively, that will go in and if a cell is senescent, activate a suicide programme. We've got loads and loads of different approaches. If I had to bet on something being the first, that would be a pretty good contender.
Mason: Andrew, are you a pill popper by any chance? You look at people like Ray Kurzveil, the transhumanist, and he has these stacks of drugs that he takes. I think he's been claimed to be taking about 250 different forms of pill and drug to try and help him live longer. Do you think that's actually an effective way to do it?
Steele: I don't think at the moment we've got the evidence, to be honest. A lot of people take vitamin supplements and the best evidence that we have for vitamin supplements says they either have no effect, or sometimes they actually reduce your lifespan. We've got incredibly big, incredibly rigorous trials showing that unless you've got a specific vitamin deficiency that you might talk to your doctor about, basically for most people there's no point popping vitamin pills.
I think the same is probably true - at least for now - of any medical interventions. There are some things that we think might have benefits. There are things like metformin and rapamycin which have been shown to extend lifespan of animals and that may extend lifespan in humans. The thing I was just about to mention, actually, is that metformin is my second contender for a near-term longevity drug. I just think at the moment, the evidence probably isn't quite there to go around recommending people take these things. Especially in the case of metformin, there's a big trial that's going to happen. A proper randomised clinical trial which is the gold standard of clinical research. It's actually been delayed by coronavirus, unfortunately. It was supposed to have already started. It's not going to be five years before we know whether or not metformin is a longevity drug or not. Although I can understand why people might want to take that gamble, I personally think it's better to sit it out and wait for the results because they're not going to be that far away.
Mason: Every so often we get an exciting-sounding story coming out of Silicon Valley that brings renewed attention to longevity technology. In fact, Peter Thiel, the investor, claimed that he wanted to inject young people's blood to live forever. I'm surprised to read in your book that there's a little bit of truth behind that claim, isn't there?
Steele: There is. I think the example of young blood transfusion is probably not going to stand up. The clinching thing of that for me is that it started out with these rather macabre experiments. Let's rewind before I explain why I don't think it's just going to work transfusing young blood. It started out with these macabre experiments where you get an old mouse and a young mouse, and you sew them together. You sew them together in such a way that they actually end up sharing blood supply. Some of these experiments were done in the 70s but they weren't quite rigorous enough. The first proper demonstration that this was doing something was in 2005. What they showed was that the young mouse was effectively making the old mouse younger by being attached to it. It was rejuvenating the stem cells inside that mouse. That meant that if you gave the old mouse a little muscle injury, it would recover more quickly than an old mouse that was attached to another old mouse, or just an old mouse that was scurrying around on its own.
The problem with making the analogy then to young blood is that there are a whole load of things going on in that experiment. It's not as clean as you might like. When the mice are sewn together, they've got completely shared organ systems. That means that the old mouse is benefitting from the young mouse's heart. It's benefitting from the young mouse's lungs which means it might be getting better-oxygenated blood all around its system. It's got better kidneys and a better liver that are clearing all the toxins out of that blood at the same time.
I actually spoke to the two scientists who did this, Irina and MikeConboy. What they said was that they noticed that the old mouse was effectively being dragged around the cage by the young mouse, because younger mice are known to be more active. There's a sort of enforced exercise programme. Of course, we all know how good exercise is for our health. There are just all these different things going on that could be causing the old mouse to be getting benefits above and beyond simply the transfer of blood.
The clinching experiment in 2014 involved them trying to inject young plasma into old mice. They basically found that it didn't extend their lifespan, and it didn't make them any healthier. I think the young plasma idea of just literally having young blood transfusions is too simple. What's really cool, though, is that they've then really extended that work. They've gone far beyond the heterochronic parabiosis ideas. They've started looking at drugs that might be able to mimic its effects and all of that sort of stuff. I think that although that was a really good proof of concept, it's just another way to demonstrate that ageing is malleable. I think ultimately the way we're going to capitalise on that research isn't going to be by directly injecting young blood, which I guess is a relief for all of the young people listening.
Mason: Also I'm not sure how I feel having a stroppy teen surgically attached to me, following me around 24/7. There are companies, aren't there, like Ambrosia - in Peter Thiel's case it was Ambrosia promising this injection of young blood - and even Google had a company called Calico. We're beginning to see the emergence of these longevity technology companies. What are your thoughts on some of those?
Steele: I think it's great news in the sort of big picture. I think it shows that there's some real excitement around the field. When Google started pouring money into Calico, I thought wow, this is fantastic. Maybe ageing is going to be a solved problem because finally we've got enough money looking into the research. With Calico, it's hard to know. I think the aggregate opinion is that it's probably been a bit of a disappointment. That's tempered by the fact that we don't really know what they're doing. They've been quite secretive and haven't released a huge amount of results. It's very hard to know. Maybe it's a disappointment, or maybe they're sitting on something enormous and they just haven't told us yet.
Although it's cool to see all of this investment in the biotech and venture capital side of things, what we really need right now is more investment in the basic research. That's because there are some investable opportunities - things like senolytics. There are going to be some companies that I very much hope will create successful senolytic treatments, and they're going to have a huge potential market. There's still an awful lot of this stuff that just needs the hard graft of doing the basic research at the beginning.
If you look at how much you look into basic research on ageing, it's just absolutely minuscule. The US is the place it's easiest to get numbers because the US has a National Institute for Ageing. It's got a specific research funding body; a government funding body, dedicated to researching ageing. The fact that that is such a unique thing in the US is itself a problem. I tried to find out similar numbers for the UK and had a very hard time.
There's a sort of in-joke in biogerontology that NIA actually stands for National Institute on Alzheimer's, because their neuroscience vision gets the vast majority of their funding. If you then look at how much goes into the basic biology of ageing, I think it's a few hundred million dollars a year. To put that into some sort of context, the US spends four trillion a year on healthcare. Not billion, but four trillion on healthcare. You realise that quite apart from any of that, the biology of ageing part of the NIA is investigating the mechanisms. Only a fraction of that is looking at developing treatments. We've got probably somewhere in the region of a ten-thousandth of the US' spending on healthcare is going into researching ageing, even though a huge fraction of that four trillion dollars is going to the chronic diseases of ageing.
Those two numbers just don't make any sense, even from an economic standpoint. You can imagine developing therapies that would save huge, huge amounts of money in health and social care but the US isn't doing it, and other countries around the world aren't doing it either. I think although this is going to be an enormous industry because these drugs are going to have a potential market of every living human, we've really got to put some money not just into the biotech side of things, but also into the basic research that's going to give us the ideas that we can spin out into companies.
Mason: It's impossible to talk about ageing without mentioning the wonderful wizard who is Aubrey de Grey. He's made grand proclamations that the first human beings who will live to a thousand years old have already been born today. The thing with grand statements like that is that they help that sort of cause. It helps draw attention and funding to the cause. Do you think statements like that, from Aubrey, help the ageing science movement, or perhaps hinder it?
Steele: I think it's a really difficult one and I think actually, he's decided to sort of change his tack in recent years, as well. That's the sort of stuff that got him some big press in the 2000s when he was first starting out trying to make a bit of noise about this stuff. Since then, he's retreated to a slightly more moderate position. I think that's probably for the best. The fact is that when you talk to people - often as a result of talking about my book - a lot of people ask you about immortality. They ask you about whether you'll get bored. What's it going to be like having a society of loads of people living to 1000 years old. Actually, what really excites people and what really excites me is the health side of things. Aubrey has started talking a lot more about the health benefits, a lot more about dementia, a lot more about cancer, a lot more about these diseases that we're going to end up preventing.
It's a really difficult thing. You've got to try and tailor your message to your audience. Also, you have got to have some realism. That statement came with quite a lot of caveats. Aubrey, if you asked him about that, would explain how it requires a certain amount of research funding and there's only a 50 per cent chance we'll make it to that stage, based on a certain amount of research funding. Whereas obviously when you talk to the press, a lot of those caveats get stripped away. It's a really, really tricky one. The most important thing in ageing, I think, is to get the word out and to get people engaged with this. To realise this isn't some kooky sci-fi mad thing. It's something that even if we fall far short of thousand-year lifespans, it's going to be of huge economic and social benefit to people who are alive today. My preference is to focus on the much nearer term, most weird sounding benefits.
Mason: The interesting thing I've always found with Aubrey - I first met him when I was 18 years old in the famous Eagle pub in Cambridge. I sat and watched him drink about six or seven beers and talk about living forever which seemed like cognitive dissonance to me. The incredibly interesting thing about Aubrey is not just his enthusiasm for anti-ageing, but the fact he developed these strategies for engineered negligible senescence. You look at some of these strategies in the book. I just wonder what your thoughts are on something like SENS?
Steele: I think it's a really powerful framework in terms of thinking about how we're going to treat these things. I think that actually, The Hallmarks of Ageing - this paper that was done in 2013 - is in some ways along quite similar lines. I think it's a much more useful way of breaking down the problem into smaller problems, each of which we can potentially individually solve. A lot of the ideas in SENS are still difficult to pass judgement on because they're going to require technologies that don't yet exist. At a very minimum, they haven't been proven.
To take the thing that probably he has been most instrumental in driving forward, which is an idea to try and prevent the ageing of our mitochondria which is the powerplant inside our cells. His idea is to prevent them from impacting on our ageing is to back up a copy of their DNA. Mitochondria, the only part of our cell outside of the nucleus that has its own DNA. He thinks that the DNA damage to mitochondria is what causes these problems that they experience with age. By putting a backup copy inside the nucleus, we'll be able to leave our mitochondria functioning entirely the same as they would in youth. The SENS Research Foundation has managed to get furthest in doing this. They've managed to get all 13 of the mitochondrial genes being expressed in the nucleus, and they've managed to get them to the mitochondria, and demonstrate that on some level, they work.
The problem is that this is on cells in a dish, and obviously it's going to be a huge thing to try and transfer that up to full-size living and breathing organisms. I think it's a really exciting idea and it's really good to break the problem down into these various particular chunks that we can do research on. There's still a lot that remains to be proved about SENS, and actually, a lot that remains to be proved about any attempts to solve every single one of these hallmarks of ageing as well.
The key contribution, in my mind, is breaking it down in this way. It's allowing us to tackle the problems one at a time, rather than seeing ageing as this sort of massive, messy process of slowly breaking down. Here are, in his categorisation, seven different problems that we need to solve. Maybe it's not everything, but it's a damn good start.
Mason: The other interesting thing about Aubrey is all his predictions are within his own lifespan. I do wonder whether that's deliberate as a way to generate funding from very rich individuals who potentially want to live forever. There might be something very strategic about that strategy.
Steele: Yeah, and as I said all of his predictions do actually come with these percentage chances. He's trying to hedge his bets a bit. They also come with the caveat of 'with sufficient funding', which is a bit of a malleable thing.
Mason: Give us money. It will happen.
Steele: I think that both of those things are a fair way to try and look at things. The fact is that if we sink a load of money into this stuff, I would find it absolutely mind-blowingly unlucky if literally none of the SENS strategies or ideas that I lay out in the book came to anything at all, and we didn't see some kind of improvement in human health and lifespan.
Of course, you have to accept that that is a possibility. Biology and medicine are really, really hard. So many drugs work in mice but then fail, somehow - often for no obvious reason - when we try and translate them to humans. This whole thing is very probabilistic and his predictions say that we've got a 15 per cent chance of having what he calls 'longevity escape velocity' - this one year of life expectancy being added every year in 25 years. It's very, very hard to assess how accurate that is, but he's not saying it's definitely going to happen. I think he still says there's a 10 per cent chance it won't happen within this century. Whether or not you subscribe to those exact numerical predictions or whether or not you think it's plausible that it's going to happen in our lifetime or during the next generation's lifetimes, I think this idea of, "We've got a certain percentage chance of making it with a certain level of funding." is the way to look at it. Rather than as it's often boiled down and simplified, "it's going to happen in 25 years.", because that's just now how science works.
Mason: One of the problems is that in the medical and scientific community, it just feels like they're biased against ageing. The idea of dying of old age is just considered normal and unremarkable by the scientific community.
Steele: Yeah, I think that's a huge problem. I've actually had that happen in my own research. When I was working at the Crick Institute, I was doing some work using machine learning to try and predict from patient's medical records when they were likely to have a heart attack. I was working with a doctor on this. At one point, I'd made a very simple model to try and compare against my machine learning model - sort of as a baseline to say, "If we can't do better than this, we're not going anywhere." - and that was literally to say the older you are, the more likely you are to have a heart attack. I spent a bit of time going into the details of that in the paper draft that I wrote. This doctor just said, "There's no point writing this paragraph. Everyone knows older people are more likely to have a heart attack. It's completely non-news." I thought yes, we do know that. But isn't it remarkable that doctors are so willing to discard the single largest predictive factor in that model? "That's not interesting. Let's look at something else that only explains 10 per cent of what's going on." whereas this huge, huge predictive factor we just ignore and put to one side.
I think that's really reflected in the education system, as well. If you talk to an undergraduate biologist, some of them get a great degree from a great university, and they might not have any lectures at all on the biology of ageing. It's certainly true of doctors. My wife is a doctor. When I first started talking to her about this stuff, she thought I was a bit crazy. It's certainly not something they cover in their training to the extent that they do understand gerontology. It's more from a geriatrics point of view - the sort of complexities, the social difficulties of dealing with patients with huge numbers of different comorbidities, taking loads of different drugs. It's a very practical way of looking at things. It doesn't explore the idea that ageing is the underlying root cause of these things. It sort of ignores it. Because it's so big, it ironically becomes invisible.
Mason: It feels like we would just learn so much more if we were allowed to do autopsies of our grandparents.
Steele: Yeah. Something that I found while researching the book was that there's a cause of death that's thought perhaps to be the single largest cause of death in supercentenarians- that's people who make it beyond 110. It's called 'transthyretin amyloidosis'. The details aren't particularly important, but it's sort of protein clumping that particularly affects the cardiovascular system. This was discovered by doing autopsies of incredibly old people. The problem is that if someone dies in their 80s, we commonly don't do an autopsy because it's pretty unremarkable, in some sense, that they've died. We probably know the cause of death that we can write on a death certificate without cutting them open.
Whilst I don't think we should necessarily cut up every single 80-something who dies, it would certainly give us a much deeper insight into what kinds of conditions they died of, and with. Subsequently, looking at this transthyretin amyloidosis, it's been found that it's much more common in people who are in their 80s and 90s than we previously thought. Although it's not maybe a cause of death, it's sort of giving us a heads up that if we do manage to treat or cure some of these other problems that cause ageing, transthyretin amyloidosis is waiting for us in our 110s. That's something that we'd definitely like to have on our radar. I think by doing more autopsies of older people, we'd potentially be able to discover more of these things and catch them before they kill us.
Mason: It sounds like there are more and more ways of keeping the body healthy, but what about the mind? What about things like mental illness? Even if our bodies survive, will our brains be able to or will we see extreme forms of depression, or perhaps anxiety, or Alzheimer's? As you previously said, we are born and we die with many of the cells in our brain that we were born with.
Steele: The good news is that all the causes of ageing are basically the same. Whether you're looking at wrinkles, whether you're looking at cancer, whether you're looking at heart disease or whether you're looking at brain ageing and dementia. Although the sort of balance at which the most significant will change from place to place, fundamentally if we can treat senescent cells and treat problems with mitochondria, if we can treat DNA damage, these are all things that affect every single part of our body. We would be mind-blowingly unlucky to come up with a set of treatments that somehow preserved our entire physical body in perfect, pristine conditions, and yet let our brain completely deteriorate.
That said, I think it's really important that we do specifically concentrate on the ageing of the brain. I'd far rather have a youthful, aware brain, without dementia, free from any mental impairment and with a slightly more ragged body than the other way around.
Mason: I'd one hundred per cent agree.
Steele: It's crucially important. More neuroscience and generally looking at the brain and how it ages and how we can tackle that is crucially important, as well.
Mason: When we talk about putting more money into these sorts of technologies, it just feels like we already have radical life-extending technologies. Those technologies are sanitation, education, regulation, contraception, universal healthcare, clean water, participatory economics, participatory political systems. Instead of putting money into stopping something natural like ageing, shouldn't we put our attention towards these societal things?
Steele: I'm going to take issue with your characterisation of ageing as natural and therefore by implication, you're saying good. If you were to go back 150 years, these things like infection - before we had sanitation - that was a natural process. Before we had germ theory, even in the 1830s or something, we didn't understand what was causing these diseases. We didn't understand it was bacteria. We didn't understand it was viruses. What that means is that you could have made exactly this argument 150 years ago, but you'd be talking about tuberculosis rather than ageing.
I think I want to do whatever will minimise human suffering. Evolution is reproduction of the fittest. We've been optimised to be reproducing machines, to reproduce babies, to survive long enough and pop out some kids. Evolution has no ethics. Evolution doesn't care about you. All it cares about is you as a vehicle for sperm or a vehicle for babies. What we've got with our technology is the ability to go beyond what natural selection has imbued us with. Exactly the same way as we've tried to treat infectious disease and in exactly the same way as we've tried to treat individual diseases of ageing, we should go after the root cause of the biggest amount of human suffering. We've managed to extend lifespans in loads of ways in the past, but the frontier now is the treatment of ageing.
Mason: Surely you've heard the critique that ageing and death is key to what it means to be human. Doesn't death have meaning?
Steele: I really don't think so. The reason I don't think so is that as I said earlier, I think that we live our lives maybe not always day-to-day - but at least day to day, week to week, month to month, year to year. I'm saving for a pension, but I'm not at many points in my life considering its whole sweep. Particularly, I'm not considering the fact that one day I will die, when making a decision. When I decided to write a book, or if you decide whether or not you're going to ask someone out on a date, or if you're going to go for a job promotion, or whatever it is you're thinking about, you're not thinking: I'm going to do this because I'm going to be dead at the age of 80 or at the age of 90. That's not factored into your thought process.
Again, you could make very similar arguments when people are dying in their 30s and 40s of infectious disease. You could say, "Without that motivation, maybe these people wouldn't have produced their great works of fiction" or whatever it was. The fact is, I think most people live most of their lives on a relatively short term basis. You're thinking about what you're going to do that day; you're thinking about where you're going to go on holiday in a few months' time; you might have a five-year plan for your career or where you want to live. Honestly, given the unpredictability of life, none of us can make a full life plan. You couldn't get to the age of 18 and see exactly how it's going to look. Quite apart from anything else, because our lives are getting older.
I just can't understand this idea that death gives life meaning. I think it's a backwards explanation to try and justify something. Death can be scary, because you're going to cease to exist. It's going to cause a lot of grief to your friends and family. To try and rationalise the existence of this scary and potentially horrible thing in the world, we try and imbue it with some sort of philosophical significance that I just don't really think it has.
Mason: Is a long life necessarily a good life? My favourite way to annoy the longevity advocates is to say that I want to die at say, 69, but with all my mental faculties, but live a really, really good life. Living 69 years of incredible experiences versus just having to be on the planet for 200 years living in a very banal existence, surely you'd pick the shorter life. I do wonder in the future - if this sort of technology is available and is rolled out to the population - whether we'll have cultist deathists who will go, "You know what? I just want to live fast and die young", and young will be like 80 by then. A long life will be 200 and it'll be a tragic life because you're just running the clock out until you finally have to leave the planet. Will death become more tragic if we cure ageing? Do you think we can live fast and die old? Will living longer make us increasingly risk-averse, perhaps?
Steele: I think what I would think about is: say you're 69. Say it's the day before your 69th birthday and you know you're immediately going to keel over in some wonderful, painless death having lived an amazing life. You'll presumably still be having an amazing life aged 68 and 364 days. Why wouldn't you want to have another day of that, or another month of that? Why at the end of that month wouldn't you want to have another month? Again, even if you were to be immortal, you're living the immortality month by month. There's still going to be loads to experience.
I was thinking perhaps in a slightly glib way about this. If you think about the countries in the world, say I were to visit a country each year, it would take me almost two centuries to visit every country. Obviously, that's a bit of a stupid thing to say because there's more than one interesting thing per country. If you think about the number of films there are to watch, the number of books there are to read, the amount of music there is to experience - as we all live longer, musicians and artists will get better and will have longer careers over which to build their skills. Perhaps to develop entirely new artforms. Technology is always changing. We're going to have space travel. We're going to have a virtual reality that's completely impossible for us to conceive in 50 or 100 years time. I just can't imagine running out of things that I'd want to do.
Mason: So basically, Andrew, what you're saying is the reason you want to live long is so you can watch all of Netflix.
Steele: The entire thing, if I could become a completionist.
Mason: I wonder what happens when you've watched it all. I wonder if they send you a notification or a surprise. Some party or secret content. It's so easy to talk about living long, but if we got to the point where we could start to choose how long we want to live then surely the people who are advocating for longevity also have to advocate for euthanasia: the ability to select when you want to die. If you can just stay constantly negligible senescence ad infinitum, surely you want to take that power into your hands and go you know what, maybe my birthday was this date but maybe I'm going to start planning for my death day where I'll invite all of my friends around and they'll jump out from a sofa and stab me in the back. It'll all be over, a celebration. Surely we need to talk about euthanasia and what it means to have a good death in the same way we talk about what it means to have a good life?
Steele: I guess we could. It's just really hard to imagine from our standpoint with our fixed lifespans and this period of degeneration at the end. I think this is something we need to have a conversation about as a society, if and when we get to that stage. The fact is, the first treatments for ageing might add five years to healthy human lifespan. They're certainly not going to be talking about immortality. If we do get to a point where we're negligibly senescent, maybe you'll just want to take 100 years off. You might want to get cryogenically frozen if we've got that technology by that point. You can be reawakened in a centuries' time when you've had a bit of a rest or when something you've been waiting for has come to pass.
I think it's basically impossible because sometimes people ask things like, "Won't you get bored?" If your friends and family are still alive, you've got loads of social interaction. You've still got all these things to do, films to watch, blah blah blah. The fact is, I just don't know what it'll be like being 400. The fact is that nobody does. No one knows. Maybe you'll be crushed by the weight of a lifetime's memories by the time you get to 207 and that's just an immutable physical limit on the human mind. My guess is that none of this is going to be a significant problem. It's actually going to be more mundane than we imagine. We imagine some total transformation of the human condition. Actually, all we're going to find is that there is a lot less suffering and people are living a lot longer, and everyone's still facing the same trials and tribulations as we do in current life.
If we do get to a point where there are loads and loads of people who are youthful and therefore not dying, I'd far rather be killed in some sort of painless euthanasia than I would by stopping taking my anti-ageing medication and degenerating over a period of a few decades into a position where I've got horrible heart disease, cancer, and dementia, and finally get taken by some combination of those diseases in the middle of the night.
Mason: Apart from the obvious problem of overpopulation - we're not going to bring up overpopulation because I know you're asked about it constantly and I know there are ways that we can deal with the overpopulation problem. In actual fact, it's not quite as bad as we think. From a cultural perspective, German physicist Max Planck is credited as saying, "Science advances one funeral at a time." Similarly, Thomas Kuhn argued that true revolutionary progress happens only when a generation dies. Death is almost needed for generational change and for scientific progress to occur. Don't we need death to ensure that new ideas emerge? Don't we need death to ensure that there's a new generation of scientists who might think of new ways to extend lifespan, for example?
Steele: Yeah, I looked into this a little bit when I was writing the book, and unfortunately it didn't quite make it in because it was just too many words in the end. What you find is that there is some evidence for this. There was some research that was done looking at the impact of people who are 'research stars', they called them. People who had a really, really, unusually high number of very highly cited scientific publications. They looked at these people when they had premature deaths. They didn't just retire and die of old age. They died of something else in their prime, effectively. What they found was it did have an effect on the scientific field. It basically allowed a thousand flowers to bloom. It allowed a load of younger, less influential scientists to come and do more new research.
The other effect it had was to have a negative effect on the particular paradigm or field of research that that research star had previously been looking into. Depending on the field of science, I think you could argue it multiple ways. Should we go really, really deep into a single topic that is really current and trendy at the moment? Or, is it better to look into a wider range of things? That answer will vary by field and it'll vary by the progress of that field. What that really illustrated to me was that this is a problem that we need to solve anyway, potentially. It's certainly something that science policy people should be thinking about. If they can discern this effect within current human lifespans - shorter than the current research career, because these people's research careers were being cut short by them dying - maybe we need to do something about this already. This is something that really recurs with these ethical and moral quandaries that associate with curing ageing. It's something we're going to have to solve anyway.
If you look at population for example, one of the big issues with that is that if you look at climate change and our carbon footprints, the richest billion or so people on planet Earth - dependent on how you count it, it's a bit complicated - they emit something like half of carbon emissions globally. If we want to bring the other six or seven billion people up to a Western standard of living, we're going to have to come up with ways of producing that standard of living with a far smaller footprint on the Earth - and we're screwed. So actually, adding a few more people because people are dying less frequently is going to be a much smaller contribution to that massive change that we're going to need, than people think.
It's very very similar, this funeral by funeral thing. I actually was really convinced looking at that research that maybe we need term limits on professors. So you can only be a professor of physics for a certain time, and then after that point you need to become a musician, or change your field to biology, or just do something that's completely different in order to free up some space. It's happening within current research careers. It's happening before we all live to 150.
Mason: You're basically arguing for the death of tenure. That needs to get removed before death. In fact, the only way PhDs can get a job right now is when a professor who has tenure does pop his clogs and move on.
Steele: It's not so weird because if you look at politics, we have term limits. We have elections every four or five years. Presidents in the US can only serve two terms. It's not so crazy, yet for various cultural and historical reasons, that's not something we do in academia. Maybe it's something we should? Interesting question.
Mason: But what about lack of genetic diversity? If we have the same sorts of people living for longer periods of time, what we are essentially doing is fixing - not repairing, but freezing or fixing our current genetic state. Won't that leave us open to new forms of virus, bacteria and disease? If we don't have a recycling of the population every now and then, surely we won't evolve or get better? We'll be fixed as we were 400 years ago and that will leave us open to anything else in the environment that may choose to cause us some harm.
Steele: It's a really interesting argument as to whether that factored to some extent into the evolution of ageing and death, actually. As you say, an organism that doesn't age or doesn't die can't evolve because those animals - at least the parent animals - will keep on living forever and ever and ever. If their environment changes around them, they're doomed aren't there. You've got to hope they've had some kids with a bit more genetic diversity.
I think the question of humans is quite different. The fact is, we've already transcended evolution in a number of ways. There are people who would have fatal genetic diseases who are now living among us, living full and happy lives, which is a great thing. There are people who would have died in childbirth. There are people who would have died of infectious diseases as young children, who again are living as adults and contributing to society. They're composing great works of music and all of those great things that humans can do.
I think evolving your way out of problems is a really really painfully slow process. Imagine we had to evolve our way out of the current coronavirus pandemic. The fact is, it would have affected everyone on earth before we've had a couple of generations in order to try and weed out the people who are going to die and the people who are therefore going to be immune. I don't think evolution is a viable solution to most of the problems that humanity is going to face in the future. I think you've got to get to a point where our technology is the way that we succeed. Otherwise, a new virus could emerge and kill us all. It would be generations and generations and generations before civilisation recovered. Obviously vaccines and surveillance - all of these different ways of sorting out viruses - are far better than the glacial selection of natural evolution.
Mason: The problem with these sorts of conversations is that it assumes that there's always been something wrong with the human. That thing being wrong, being ageing. Is there a danger in seeing the human condition as a sort of problem that needs to be solved?
Steele: I don't think so, because I think - again, this is called in philosophy 'the naturalistic fallacy' - the idea that just because something is natural, it must be good. Again, the clearest rebuttal to that is just to look at infection. Look at smallpox. This horrible disease that killed millions and millions of people over human history. Maybe even billions, I don't know the statistics. It killed them in a really horrible way and it was incredibly contagious. There's just nothing good about that. There's nothing good about that fact of nature.
If you look at the solar system we live in, it doesn't care about us. It could smash us with an asteroid any day and eradicate the whole of civilisation; eradicate all life on Earth. We're just incredibly fortunate that we're in this sort of benign Goldilocks zone around our star that allows us to live. Nature, at an absolute minimum, doesn't care. It's not difficult to look around and think that actually, it actively wants us to die. I'm quite chilled about trying to make the absolute best of what we've got, and improve upon what natural selection has given us.
Mason: Well, let me ask the question in a slightly different way. Andrew, your background is in computational biology. Does that affect and impact the way you think about human beings? Do you see us as computational machines? Aubrey is being accused of the same issue. He sees human bodies as comparable to cars that can have their parts replaced. Does that lens on what a human being is? Does that create a dangerous circumstance? Isn't that sometimes a problematic metaphor?
Steele: There are two ways of thinking about that. As physical beings, we are subject to the laws of nature. At the lowest level, the laws of physics. They then integrate somehow into the laws of chemistry which then somehow integrate into the laws of biology. Ultimately, I think we are going to have computational models for humans. It might not be in 10 years, it might not be in 50 years. At some point, we're going to have a computer simulation advanced enough to understand the ins and outs of human biology. Human biology is really complicated, but at the end of the day we've only got 20,000 genes. There are only, maybe, 100,000 proteins inside a human. Those are big numbers - it's not going to be a cinch and you can't just do that on your laptop - but ultimately there's going to be a point at which we can simulate that on a computer. I'm absolutely confident of that.
However, to think of us as sort of moral sentient conscious beings, I don't know where we are with consciousness - it's not my field of expertise at all - but it's far from clear exactly what consciousness is and exactly what it means to be self aware; to be worthy of moral consideration. I think that you can understand that humans are, in a sense, machines that can be fixed when it comes to illness or suffering, but we're more than machines when it comes to what we're capable of thinking and feeling.
Mason: A lot of this stuff might just be around the corner, but it might be a little further away. We just don't quite know yet. What can we do today to live long enough so that potentially, we could live forever?
Steele: Well, you can read my book.
Mason: Nicely done!
Steele: I think the thing that's really surprised me about ageing biology is that it's encouraged me to look after my own health in a variety of different ways. The first of which we already alluded to, which is this idea that the longer you live, the more likely you are to live to benefit from more technologies.
The second way in which it's helped is that by understanding the ageing process, it really imbues old health advice - or classic health advice - with a new meaning. It shows you that a lot of the boring stuff that we know we should do like eating the right sort of food, not eating too much of it, not smoking, exercising - these things legitimately slow down the ageing process in quite a real sense. It's really encouraged me to watch my diet a bit more, make sure I go for a run a bit more often than perhaps I used to.
Finally, it allows you to illuminate perhaps unconventional bits of health advice that you wouldn't expect. To give one example, brushing your teeth is something that can increase your longevity or healthy lifespan. The reason we think that's the case is that although you might not think there's a direct connection between teeth decay and heart disease, for example, studies have shown that people with better dental hygiene have better cardiovascular health. When this was first uncovered in the 1990s, there was a lot of scepticism from scientists. This sounds like a classic example of what scientists say: "Correlation doesn't mean causation." You get an association between two things but actually, one isn't causing the other. There is some third factor. Let's take that example of tooth decay and heart disease. What you could find is that people who are poorer have less time to invest in their fitness, less time to invest in cooking good food, and less time to look after their teeth. They can't afford their dental bills. All of this combines together to mean their health is worse, and their dental health is worse. They get heart attacks and they have bad teeth and bad gums. That would mean that there was no causality. There's no benefit to brushing your teeth. It's just that people who are bad in one respect also have problems in the other, for unavoidable reasons.
However, as we've understood more about the underlying biology, it's looking increasingly likely that there is some sort of causal connection. That connection is what is thought to be chronic inflammation. Inflammation is the process by which your body responds to threats. You get an infection, and you'll get inflammatory molecules being given off at the site of that infection. Basically, your cells are calling for help. They're saying, "Come on over here. There's stuff going on. Can you come and clear out this infection, or help us heal this wound?" or whatever the problem is. The problem with age is that you often get what's called chronic inflammation. In fact, the toxic chemicals I alluded to earlier in the senescent cells are inflammatory chemicals, by and large. They're chemicals that spur the immune system into a heightened, low level of alert. A constant fizzing and buzzing of panic, which makes it less effective at its other jobs, and also directly affects ageing.
Imagine in your mouth, you've got gum disease. These are bacteria that are attacking your gums. It's very very hard for your immune system to eradicate those. There's this constant low level skirmish going on inside your mouth, emitting all of these inflammatory molecules. What it means is that this is increasing your likelihood of things like heart disease. In fact, we think it could even be related to cognitive decline. If you look at the plaques - the bundles of molecules that are found inside people's brains when they have dementia - sometimes we find these bacteria embedded in the plaques. At the moment, it's not clear if correlation and causation are going on here. Are the bacteria actively driving the dementia? Are they just managing to get in there because the brain is so badly damaged? The fact is, the evidence is suggestive enough that for your lifespan - as well as to minimise visits to the dentist - it's worth brushing your teeth.
Mason: Well I'll tell you what Andrew, this book has a lot to answer for. You've suddenly guilted me into being slightly healthier, especially during this time of lockdown where it's so much harder to move and to do these healthy things. Especially when you're tied as I am to a corner of a room, recording podcasts. There are so many health studies out there. There are so many ways we can potentially improve our health. How do we do a better job, individually, of looking critically at scientific research and health advice, and deciding what's good for us? One week it feels like coffee's going to kill us, and the next week it feels like it's going to help us live until 90. All of these things are so confusing as a member of the general public. How do we do a better job at looking critically at this research and advice?
Steele: I think the first thing to say is that when you do find these studies that are contradictory, often that's a warning sign that the effect one way or another probably isn't that large. If you've got a study that shows coffee extends life, and a study that shows it makes things worse, the truth is probably somewhere in there. It's probably not a very big effect. Often scientists in good faith try to reproduce a particular result. If they get it going completely the other way, it's probably just quite a small effect that's going to be very hard to tie down.
The other thing you can do is try and look in scientific literature. Not at these individual small studies. Particularly with various diets or supplements, you might find that a study only involves 20 people or something like that. That means it's going to be very hard to generalise, particularly because those small groups of people are often chosen for a specific reason. Perhaps they're people who are overweight in a particular way, or they're people who have got a particular condition. It might not necessarily benefit everyone in the entire population who have different ethnicities or those with different health backgrounds and different ages. They're often only tested in young people, so does that really apply to people who are in their 60s and 70s?
The best sort of health advice to follow, I think, is that which is supported by the gold standard of scientific research, which is something called a systematic review. It's not an individual study, but it's where some scientists have searched the entire literature in a systematic way. They've tried to find every single study on a particular topic and then they've said, "Okay, if we aggregate all of this evidence, can we say that it goes one way or the other?" Where you can say that, then you can be pretty confident in the conclusions. That's the sort of evidence that I've tried to draw upon in the health advice in the book.
Mason: I mean, I'm one of those people who only really listens to my body when something's wrong, when something's hurting, when it feels like oh, blimey, I should probably pay attention to that thing. What we're talking about with anti-ageing or ageless medicine is preventative medicine. How do we culturally get people used to the idea that they've got to take medicine for diseases that they don't already have?
Steele: I think it's going to be easier than it might sound, the way you've posed that as the question. People already take a huge number of nutritional supplements. If you look in the US, I think it's over half of US adults say they regularly take vitamin supplements. These are things that don't work, basically, by and large. You've got this huge fraction of the population who are clearly interested enough in their health to take a supplement, even though, actually, we know it's not going to have a great deal of effect. I think if you can present people with medications that are actually going to work - demonstrably improve their healthy lifespan - I think it's going to be easier than people think.
Mason: How this is rolled out is quite interesting to me. Do you think the ability to live longer will eventually be seen as a human enhancement? If so, do you think it'll be a selective enhancement or a therapeutic enhancement? Will it be a choice to live longer, or will it become a universal basic human right?
Steele: I hope the latter. At the end of the day, this is about postponing your health. It's not about living longer, although that's always the easy way to understand it. The reason you're living longer is because you're healthy. It's because you're not getting cancer. It's because you're not getting heart disease. It's because you're not getting dementia. All of these things that are currently the leading killers in the modern world. We want to defer those until later and later in life.
Quite apart from anything else, from a purely pragmatic point of view, ageing is hugely expensive. If you look at the global cost of dementia, I think it's about a trillion dollars a year at the moment. As the global population ages, that number's going to go up and up. For governments around the world, if they've got access to these anti-ageing medicines that can push the process of ageing further back into the future, it's going to be a huge cost saver, even from a purely economic standpoint. There was a study that was done a few years ago in the US. They said that if we could come up with quite a modest intervention that could extend life by about 2.2 years and do so by delaying the ageing process by the same period of time, that would be worth seven trillion dollars, just to the US, by 2050. That's just an incredible, incredible amount of money. There's a huge incentive to sort this thing out. I think it's very likely to be universal, just because the economic and social benefits are so, so large.
Mason: It would be wild if the NHS was just something there for when you were injured. Just when you cut yourself or fell, or maybe broke a bone or did something stupid. That's the reason the NHS exists, to protect us from the silly things we do as opposed to the things that happen to us over periods of time.
Steele: Yeah, I think that some of this stuff is going to be still done by doctors in hospitals. When you're talking about drugs, obviously you can pop a pill at home without necessarily needing too much supervision. Some of these things are going to be intermittent treatments. It might be like visiting your dentist. You might pop in every six months and your doctors will have a look at your concentrations of senescent cells, and different tissues and how your DNA is doing in various parts of your body, and if you need a top-up of a particular kind of stem cell or whatever. Then, some of these treatments - depending on what works, depending on how we end up rolling this thing out in practice - some of them could require being in a hospital setting, like having a stem cell transplant, for example. You might want to be under medical supervision for a few days after that, at a minimum.
It's very hard to know how it's going to pan out in practice, but I lord the vision that by and large, these things are going to be routine. It's going to be like a dentist trip or an optician trip where you just go in, you have a check-up, you get sent away with a few pills. Every few years, you might be given a bigger procedure. It's going to be no crazier than the sort of stuff we have done at our dentist surgeries.
Mason: Yeah, it's going to be like getting an MOT for your car, basically. On reading the book, it feels like there's so many things that contribute to ageing. There are so many possible ways that ageing could be solved that it feels like it's a massive interdisciplinary challenge. It feels like we need more communication between different medical fields, and bring those fields together and encourage them to do cross-disciplinary work in science. As a scientist, do you think that's ever going to be possible?
Steele: Yeah I do. The reason I think it's possible is because scientists will, to a large extent, follow the money. I think there's a sort of self-fulfilling prophecy with ageing research at the moment, which is: let's take the example of cancer research. Cancer research, by the way, I think, is also grossly underfunded. It's at the same time, vastly greater in terms of its funding than ageing research is. Imagine that you do a degree in biology and you wonder what you're going to do in your PhD. You might well be interested in cancer because you've had lectures in cancer as an undergrad. You go and do a PhD in cancer. You get to the end of that period of time, what are you going to do as your postdoc - which is the next stage of your career after your PhD? Well you're probably going to stick with cancer aren't you, because that's where your knowledge is. You might have a few papers that can back up that you've got the skills in that area, and so you're going to get a postdoc in that. Now when you go on to try and start a lab of your own, again, you're not going to deviate wildly from your preceding expertise. You're going to carry on as a cancer researcher. Ultimately, that means that when you go back to lecture the undergrads who are being trained 10 or 20 years later, you're not going to tell them about ageing either, because you're a cancer expert. You haven't got anything to contribute in terms of ageing biology. You end up with this sort of vicious circle where I feel like cancer being big, and ageing being small can be a self-fulfilling prophecy.
I think if we start to have some more directed funding streams - so things that have to be used for proper ageing research. Something you also often find is a stream of funding that is labelled for 'ageing research', just like the National Institute of Ageing in the US, actually ends up being directed towards specific diseases at the endpoint of the ageing process, rather than the fundamental causes at the beginning.
I hesitate to say 'command and control' because that sounds like we're going to have some sort of terrible communist overseeing every single minor detail - but if we were to direct scientists' attention to ageing and show them some of these incredible results - that's why I wrote this book: to show that this field has so much promise. To try and excite scientists about this stuff. I don't think there's any reason why this research should be any harder than cancer research or heart disease research is now. It's just that it needs that focus, that money. It needs people to understand how important it is in order to get anywhere.
Mason: So in that case, how do we approach it from a slightly different angle? How do we engage the policymakers and the public in the science of biogerontology?
Steele: Good work. Very well pronounced. I think the way to do that is basically just to explain to people what this actually means. This isn't some freakish immortality quest by a handful of lunatics. This is a hugely important socio economic problem. It's going to tackle all of the diseases that everyone cares about - for themselves, for their relatives, for their friends - because no one wants to get cancer. No one wants their mum to get dementia. No one wants their dad to have a heart attack. If you can couch it in those terms and explain to people that this is the best single way to try and cure and to try and tackle some of these problems, I think suddenly it changes it from being a sci-fi freakshow where we're all going to live in some sort of immortal dystopia, and makes it much more accessible.
The other thing that I think it's really important to emphasise is that we aren't talking about extending the old part of life, as we currently understand it. There's a common misconception that if we start treating ageing, you're going to live your first 70 or 80 years as normal and then you're going to spend 50 years in a nursing home. That isn't what is going to happen, either from a theoretical or from a practical standpoint. When we do slow and reverse ageing in the lab, what we see in the animals is that they stay healthier. They effectively stay younger for longer.
Even from a theoretical standpoint, what do you die of? You die of diseases. I've listed them before so I won't list them again, but the point is if you're free of those diseases, you're not going to die. If you do have all of those diseases and you do have all of that frailty, you're going to die. It's not even theoretically possible to extend the unhealthy, frail part at the end of life. I think by explaining that to people and making it seem less weird, and making it seem appealing, then that's ultimately how we're going to make progress with this stuff.
Mason: We're both in our thirties. Do you think we will be the generation who gets to live agelessly, or do you think we'll be the last generation to actually die of age?
Steele: I do wonder about this and I'm not sure. It's very hard to be certain. I'll end up hedging my bets to some extent. What I found was that as I wrote the final part of the final science chapter of the book, I talk about reprogramming our biology, and the idea that we can build these huge computer models that would allow us to simulate an entire human being. We've got huge DNA sequencing datasets. We've got huge proteomic datasets that look at every single protein inside a cell or inside a tissue. There's going to come a point where we're going to be able to integrate all of that into some sort of systems biology model of what a human being is. I think that's the point at which we can truly think about curing ageing. We can understand the whole of the system as a whole. We can come up with interventions that will stablise that system and that will maintain it in a youthful state.
As I was writing this, I was thinking this sounds bonkers. This sounds like some kind of far-future sci-fi machine learning, artificial intelligence, ridiculous, implausible quantities of data. But then, you think: imagine this is going to be 50 years away, which maybe is optimistic but it's not a ridiculous timescale. If you look back at what's happened over the last 50 years, it was only in the 1950s that we discovered the structure of DNA. Now we can sequence a genome for about a thousand dollars in a few hours. We've totally transformed our understanding of how the genetic code is stored. We've got incredible new microscopy techniques. We've got incredible ways to look at human bodies on a big scale and on a tiny scale. I wouldn't bet against having some of those systems biology models in 50 years time.
We just had another great example from the last month or two. This is a strange thing to phrase and the protein biologists get cross, but we've solved the protein folding problem with machine learning - is the sort of popular science interpretation. There are nuances and subtleties underneath that, but basically we've used neural networks which are this incredible way to understand vast quantities of data, to understand the way that proteins fold up inside our cells, which is something that we've been making incremental progress towards for decades. Finally, machine learning has come along and basically turned the problem on its head. We may be able to make much bigger strides than we ever thought were possible in a much shorter time than we thought.
Even if you think this stuff is going to be 50 years away, then you think about the fact that we're in our 30s. I very much hope to still be alive in 50 years. Even if nothing else happens, assuming I live a relatively healthy life and I don't get hit by a bus, I should still be alive at the age of 80 or 85. That means that potentially, I could be around to benefit from the first systems biology models of ageing. Actually, I hope that if I live a healthy life, maybe I'll start taking senolytics in my 60s because we'll definitely understand that by that point. I might start taking metformin, or I might be taking better drugs that aren't even on the drawing board right now. Even if you think gene therapy is 30 years away, I might have gene therapy when I'm in my 60s. What that means is that I'm going to be living longer and longer. That gives us more time to develop these systems biology models. It's a foolish scientist who makes a hard prediction and says that ours is going to be the last mortal generation, or we're going to make it, or whatever the cut-off is going to be. But it's far from crazy to suggest that we're going to live substantially longer than we get to now, if you just think about the timescales that are involved.
Mason: Well if AI helps us to achieve longevity escape velocity then maybe I'll reframe my hope of dying at 69, and hope for that 90 or perhaps even 100. Folks listening into this podcast or watching in on YouTube, they want to get educated on the latest science behind ageing. How can they go about doing that?
Steele: I honestly think - and this is going to sound like a plug, because it is I guess - but my book is a really good way of doing that. What I've tried to do in the book is to summarise all of the leading developments in the field. I've tried to take a big review and make it accessible to as many people as possible. You don't have to have a scientific background to read this book. I use a slightly different instruction of hallmarks of ageing. The original 2013 paper had nine. My book's got 10 because I've switched a few things around. Basically, I look at all of the different ways that we can treat all of these different fundamental underlying causes of ageing. I think there are 400 references in the back, so if you want to take a deep dive on any particular topic, there is plenty of additional reading material. Not all of that is hardcore scientific papers. I've tried to reference other articles in the popular press, or videos and things that are a bit easier to get your head around, as well. Honestly, I wanted this book to be the best summary of the field that it could be. If I've done justice to it, that's very much what I hope it is.
Mason: Andrew Steele, it is a book that makes me feel hopeful about the future, and I do highly recommend it for anyone who wants to live just a little bit longer. Andrew Steele, thank you for your time.
Steele: Thanks for having me.
Mason: Thank you to Andrew for sharing his thoughts on how we might cure ageing. You can find out more by purchasing his new book, 'Ageless: The New Science of Getting Older Without Getting Old', available now.
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Recorded, Mixed & Edited by Luke Robert Mason
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