If I could turn back time - Andrew Steele

Photo by Tran Nguyen supplied by Andrew Steele

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Kat Arney: It was my birthday earlier this month, which I celebrated in lockdown with an excellent online winetasting. I don’t know about you, but every passing year makes me more acutely aware of my own mortality, especially as things start getting wrinkly and sagging a bit. So is age just a number, as the saying goes? Or is there something deeper going on at a biological level? To dig into the ageing process I had a chat with Andrew Steele, author of the new book Ageless:The New Science of Getting Older Without Getting Old, who has taken a deep dive into the processes that underlie ageing and - excitingly - whether we might be able to slow them down to live longer, healthier lives. First things first - what exactly is ageing?

Andrew: It's a good question, It's a tough one. There's a big long chapter in my book trying to sort of go through the nitty-gritty biological details of this. But I think the easiest, the simplest definition is actually a statistical one rather than a biological one, which is to say that your rate of ageing is the rate at which your risk of death increases as you go throughout your life.

So in humans that risk doubles approximately every seven or eight years, we call this the mortality rate doubling time, and by looking at that number for a different species, you get some impression of how fast they age. So, as I say, humans, every seven or eight years, if you look at animals like mice, we know that that happens in a matter of months, their risk of death doubles, but then right at the other end of the spectrum, there are some animals that don't age effectively.

So if you look at Galapagos tortoises, for example, they're one of a few animals that have what's called negligible senescence, otherwise known as biological immortality, and that doesn't mean they actually are immortal, they don't live forever, but their risk of death is constant no matter how long ago they were born.

Kat: I find this amazing. I think naked mole rats are very similar aren't they? They just like they're born, they look really horrible and old and wrinkly, and then they just stay like that.

Andrew: That's the delightful irony. They are also, we think, negligible senescence. It's very hard to get good enough data to absolutely nail it down. Exactly as you say, they look like these little sort of wrinkly penises with teeth. They look geriatric on day one, and yet somehow they're about the same size as mice, and size is often a quite a good determinant of how long you'll live in the animal kingdom, and yet a naked mole rat can live 35 years, whereas a mouse can live two or three at most.

Kat: So let's drill into some of this stuff. So you've talked about like the statistical definition of ageing, which is like the closer to the grave you are basically, but what's actually going on inside the body. You've mentioned this term like senescence. So what actually happens as a physical body ages?

Andrew: It's a variety of different processes and I think something that we've started to understand over the last 10 or 20 years, that ageing isn't one thing, it's a collection of things all happening together that happen too, in this sort of slightly morbid synchronised way, orchestrate our demise when you get to a certain age.

I break it down in the book into 10 hallmarks of ageing, there was a paper that came out in 2013 with exactly that name, and they actually list nine, I added one and combined a couple so it all got a bit messy when I was trying to work out how to do it because the science has moved on a little bit since then. But basically if you look at these 10 different things, they're things that increase with age. If you increase the rate at which they happen they speed up your ageing, so that means you die sooner or you get diseases more quickly, and if you slow them down, and this is the bit I'm really excited about, you can slow the ageing process and defer those diseases.

So to give a few examples, one of them is DNA damage and mutations. So you've got like basically a chemical assault on your genetic code that changes the information that's stored in there over the course of your life. You've got senescent cells. So individual cells effectively getting old. You've got damage to the bits inside cells, things like the mitochondria, which generate the energy in there. And then you've got damage to the molecules, the proteins. And finally, you've got sort of overarching forms of damage. All of these things combine together to undermine the systems in your body. Things like the immune system, which are undermined by all of these different things happening together, and slowly conspire to make us less resilient and more likely to die as we get older.

Kat: It's really interesting that you talk about DNA damage because I've just written a book about cancer, Rebel Cell available now in all good bookshops.

Andrew: It's very good by the way.

Kat: Thank you, your cheque is in the post, but yeah, one of the key drivers of cancer is damage to DNA, and also, as I discovered, not just the mutations that gather in our cells but also, damage to tissue, inflammation, creating an environment in our bodies where, rogue cells become more likely to thrive. So it does feel like there's all these processes working together. I mean, interestingly, with cancer, would you consider cancer a symptom of ageing or disease of ageing?

Andrew: Yeah, there's this really fascinating debate about whether we should call ageing itself a disease, and I'm going to completely sidestep that because it's a philosophical and biological nightmare, but I think the way to think about it is it's something that predisposes you to a load of other diseases, and cancer is a really good example, like the sort of classic root cause of cancer is these mutations, it's because the cells accumulate these mistakes in their genetic code, as of course you know and you can read in your book, allows them to divide more and more times and eventually they can get so big they can form a tumour and that's what ultimately goes on to kill you.

But it's not just the DNA damage, we now understand, cells can accumulate this damage throughout our lives and obviously the longer they have, the more time they have to get that damage. So that's one way in which ageing can contribute. But also exactly, as you say, one of the things that goes wrong in our body as we age is we get this chronic inflammation, this constant sort of a low fizzing and buzzing of our immune system, which means it's always on slightly too high a state of alert, and that can predispose to cancer. And also there's a sort of irony because although our immune system is getting more hyperactive, sort of paranoid, it's also getting less effective at its real jobs.

So one of the other things that the immune system can do is sniff out sort of pre-cancerous cells and destroy them before they get to the point of forming a tumour, and there's a really interesting paper, which I think is probably a little bit on the reductionist side, but it's provocative because what it does is it looks at the size of an organ called your thymus, which is a crucial part of your immune system, which declines very rapidly in size with age. And it compares the size of your thymus to the incidence of cancer. And they're using a mathematical model to argue that the incidence of cancer is almost entirely driven by the decline in the function of your immune system. So as I say, I think that's probably a bit reductionist. There are multiple things going on.

Kat: Cause or correlation?

Andrew: Absolutely.

Kat: So one of the terms I think you use in your book is this idea of inflamm-ageing. Am I right? I don't know quite how you'd pronounce it, it's a bit that sort of portmanteau word of inflammation and ageing. So that's really this idea that as we age there are things just driving the inflammation in our bodies and that is one of the things that's making everything fall apart.

Andrew: Yeah, and I think the example I always go to with this, and it's very simple to explain, It's also the thing that's nearest term in terms of human treatments, is the accumulation of senescent cells. So we said earlier, senescence is just sort of the scientific word for ageing, and these were first discovered in a dish, in a lab back in the 1960s. A guy called Leonard Hayflick was watching cells divide and he noticed, after about 50 divisions, they just stopped.

Kat: Yeah, they kind of conk out. Right?

Andrew: And they look weird. I went to a lab and actually had a look at some of these things, I'm a computational biologist by background so obviously I don't look down a microscope very often, but yeah you can see even to the incredibly untrained eye like mine, they look bizarre. You can tell there's something weird going on.

So there are christened senescent cells, as in cells that sort of clapped out and old. And so there was a theory that perhaps accumulation of these cells within our own bodies could be driving their ageing, and what we found after studying it for the intervening few decades is that that is indeed the case, animals do accrue these senescent cells. Some because they've divided too many times, some are actually driven to senescence because of inflammation, so there's this complicated multifaceted process. But the thing that the senescent cells do is to emit a toxic cocktail of molecules, and that sounds counter-intuitive, why would I say I was being our bodies effectively killing us from the inside?

The answer is they're calling for help. They're saying to the immune system "over here, come and clear me up". But the problem is that, as we get older, our immune systems get less effective. The senescent cells get larger in number and all of these molecules that are secreting out into our bodies drive inflammation, which can accelerate the ageing process, make cancer and heart disease and dementia, more likely. And also ironically, it can create a feedback process where you can get more and more of these senescent cells. So that's sort of the downward spiral, thats associated with ageing. The reason that I get excited when talking about this, I keep looking at your face now, you're not excited at all.

Kat: It's my birthday next week. So, you know, the tick of mortality is upon me.

Andrew: It's happening to us all right now, as you listen to this. Yeah. But the good thing about it is that we've got drugs that can delete these senescent cells selectively. We can kill the senescent cells and leave the rest of the cells in your body intact. And when you give these to mice, we find that the mice basically get biologically younger, they have less cancer, they have less heart disease, they have fewer cataracts, they live longer, of course, and they even have better fur. So it looks as though these underlying hallmarks of the ageing process don't just impact on disease, they also impact on the more superficial stuff, the wrinkles, the grey hair that all of us get, because basically it's all caused by the same biology.

And what's really cool is that these drugs are starting human trials. And at first that's going to be for diseases where we know senescent cells to be a problem, so there are diseases like arthritis and age-related blindness and lung fibrosis that we know are sort of driven by senescent cells. But if those trials work, if the drugs turnout to be safe, if they turn out to be effective, then we could hope at some point to be giving them to people preventatively when they haven't got anything, "wrong with them" apart from the fact that they were born a long time ago. So we could clear out those cells and preventatively try to reduce the risk of them developing diseases in the future.

Kat: So I'm not going to get any for my birthday next week then?

Andrew: I think perhaps not this birthday, but it might not be that many birthdays before these are available.

Kat: Keeping my fingers crossed. Now this is a genetics podcast so it'd be remiss of me if I didn't drill into what we know about the genetics, because obviously we are all genetically unique and people do seem to age at different rates and in different ways and people do have different lifespans. We don't all get to exactly our three score years and ten and then you're done. So what do we know so far about some of the genes that are involved in ageing, like the genetic variations?

Andrew: So the first thing to say is that the genetics of ageing, it has surprisingly little effect. I think there's a lot of stuff in the press that might sort of lead you to believe that our fate is basically determined by what's written in our genes, but as we've done more and more detailed studies into the genetics of ageing in the general population, what you find is that somewhere between ten and twenty percent of our lifespan is heritable, which is sort of the biological term for written in your genes, and what that means is the other eighty to ninety percent is determined by lifestyle. So there's a lot that you can do to keep yourself healthy. A lot of the standard health advice you've heard before.

Kat: It's the boring stuff innit.

Andrew: A lot of it is yeah, and there's also just luck at the end of the day, things like cancer particularly, if you just happen across the wrong combination of mutations you can get cancer and die plus or minus five or ten years even. So there's a large component that isn't written in our genes. However, if you want to try and find some of the more exciting sort of longevity, genetic stuff, you need to go into weirder populations, and I mean sort of weird in a good way.

So if you look at people who make it to extremely old ages, people who are known as centenarians who make it to a hundred or above, It seems that the genetics of their longevity is much more heritable. So if you've got a parent or a sibling who's made it to a hundred years old, then you are about ten times more likely to manage that than someone in the general population.

So to clarify that a little bit, say your parents live to seventy or eighty, It's probably not putting a ceiling on your longevity, but if you've got a sibling or a parent who's made it to ninety or a hundred, or even beyond then suddenly that is something to get excited about.

Kat: Yeah, I really noticed that when I was researching rebel cell, the cancer book, it seems that your cancer risk it does start going up quite steeply after the age of sixty. But if you've made it to a hundred or into your late nineties without cancer, there's a really good chance that you'll carry on. So that does seem to be something in the genetics of those oldest old that is protective or cancer resistant in some way. I find that particular group of people really fascinating.

Andrew: Yeah, and there's a statistic I like to illustrate this, they effectively put off all these age-related diseases. They have about the same amount of ill health at the end of their life as the rest of us do, but they just push it back by ten or twenty years. Which means as a percentage of their lifespan, they are spending less time ill. And that's, I think, something we can all aspire to.

Kat: Yeah, too busy to be old right now, just got stuff to do. So what else do we know about some of the genes in maybe some other species? Because I know there's been loads of research going on in things like worms in particular, and people get very excited about this and they say, "Oh, look, we found the cure for ageing in worms". How translatable is this really from a species like a tiny nematode worm or a fruit fly to humans.

Andrew: I really credit worms with getting us to where we are in modern ageing research and actually it is entirely down to genetics. This is a revolution in slow motion that happened in the eighties and nineties, because if you go back to the sixties or the seventies or that kind of period of time, a lot of biologists thought that ageing was just a natural inevitable process of sort of wearing out and decay. And so it wasn't a particularly interesting thing to study because, if it is this sort of global process that affects every part of your body, every molecule, every cell, how on earth can you get a handle on that in the lab?

But in the 1980s, there was a gene discovered called, originally enough, age-1 that could extend a worm's life lifespan by fifty percent. Now, if we're talking about humans that are going from 80 to 120 years old, that would be amazing, obviously in worms, this is going from two weeks to three weeks so it's not quite the same sort of magnitude of life span increase. But what this did was it really lit a fuse. It showed scientists that you could do these sort of precision genetic interventions. You could go in and change actually a single letter of DNA in the case of age-1, and massively extend the lifespan of an organism. And that meant that suddenly, this rule book, the fact that ageing was something immutable, so complex you couldn't possibly study it in the lab that was just ripped up and that encouraged a whole load more experiments.

And so the one that really gets a lot of attention is one called DAF-2, which is discovered by Cynthia Kenyon in the early nineties, that doubled worm lifespan. And so if anyone had any doubts that age-1 "It's only 50%, it's in a worm, it's a bit of a weird situation, maybe just a one-off fluke" they were sort of banished. And so over the next couple of decades, more and more ageing retarding genes were found in worms and actually the current reigning champion, it's gone full circle and it's back to age-1. They found a different age-1 mutant that multiplies worm life span by ten.

Kat: Wow!

Andrew: Absolutely incredible, so it goes from two weeks to twenty weeks and the last worm in their experiment, I emailed the scientists he did the experiment while I was writing my book, and it almost made it to 300 days, which is absolutely incredible. Almost a year old worm.

Kat: That's absolutely amazing. I remember years ago doing a podcast about the genetics of ageing and I went to UCL to talk to the researchers there in the ageing lab and, yeah, they were talking about how they have this little Top of the Pops chart of the oldest one they've got, but it was nothing near that.

Andrew: Yeah, This age-1 mutant just like blew everything else out of the water. And I think there's nothing even within a factor two or something like that. So it's pretty impressive.

Kat: So coming back to the general field of ageing research, there's a lot of really exciting stuff in humans and in other organisms and there seems to be a lot of, put it one way, nonsense. So out of all the things that you were looking at, what do you think are the really exciting areas that have genuine potential? And also, are there a couple of things that you're like "nah, it's rubbish"?

Andrew: I mean, there's a lot of rubbish talked in anti-ageing, it's something that's been throughout the ages. Humans have been looking for sort of some kind of fountain of eternal youth. And so one of the most ridiculous examples I came across while researching the book is there was a researcher who thought in the 1920s that you could gain eternal life by surgically attaching monkey testicles to humans. And I think that's obviously quite a fraught procedure in terms of, you know, just hygiene.

Kat: For the monkey as well as the human.

Andrew: Absolutely, Yeah, Yeah. You've got to consider both sides of this, I guess, but yeah, nobody really wins in that equation and obviously it turned out it didn't confer eternal life after all. So that was a shame.

I think that particularly in the last ten or twenty years, we have finally got a biological understanding. Where if you're looking at the stuff that's coming out in proper reputable, scientific journals that's slowing down or reversing ageing in lab animals, a lot of this research is pretty rigorous. It's proved in multiple different ways. And we've got so many different ways to tackle the ageing process.

So, as I said, I break it down into these 10 hallmarks and we've got multiple ideas to treat each of those hallmarks. So even if one of them turns out to be, not quackery, that's unfair, but even if it basically doesn't pan out for whatever reason, because we know that biology is very hard to go from the lab into medicine, even if ninety percent of these things, fall at whatever hurdle, we're still going to have a huge range of treatments to choose from.

So I think we're going to be dealing with skin cream vendors, giving us all kinds of claims for a long time to come, but there's some really genuinely exciting stuff that's actually going to work and actually going to be available from your doctor rather than just some nutritional supplement that's available in the supermarket, certainly within the next five or ten years.

Kat: What's sort of the end game here? Because when I went to talk to Peter Campbell, who's one of the leading cancer geneticists at the Sanger Institute, I sort of said, "well, what's the end goal. If we do manage to find much, much better ways of treating cancer or preventing cancer." And he was like, "well, you know, I guess it's that you get old enough to die of something else." And like, we can't live forever. Can we? And there's also implications of having a much larger population of very old people. So how does this sort of pan out for society?

Andrew: So to answer the first question, I'm much more excited about ageing medicine than I am about medicine for specific diseases. There's an estimate done where it says demographers can look at what kills people basically and Peter's exactly right, if you look at what would happen, if we could completely cure all cancer, which is obviously a big ask from our current state of understanding, even though exciting stuff is in the pipeline, it would only add about two years to life expectancy and the same is true of heart disease. If you could completely eradicate all heart disease, then basically people live for two more years, but then they just die of something else. Because, say you do cure someone of cancer, the fundamental problem is that it's in an old body, it's in a body that's suffering from heart disease, a body that's, perhaps in the first stages of cognitive decline or dementia, they've got weakened muscles, they're losing their sight, they're losing their hearing, they're losing their independence.

All of these things are happening at the same time and so eventually one of them is going to get severe enough to kill you. Even if we pick off these individual diseases one at a time. And that's what really excites me about ageing research, because the plan is to defer all of these diseases simultaneously. So as I said, with these senolytic drugs that kill senescent cells, they don't just defer cancer, they don't just defer heart disease, they seem broadly to be a global reversal of the ageing process. And if we can come up with ways to treat these other hallmarks, they will have the same kind of wide-ranging effects on a number of different diseases.

And I think the end goal, and not necessarily saying this is going to be around the corner, but perhaps slightly controversially in the book, I talk about curing ageing. And as I say, it's not because I necessarily think it's going to be in the next five or ten years, but it's because I want to normalise the idea that ageing is something we should seek to cure whether or not we want to call it a disease. We want to try and defer the ill health, the frailty of old age until this latest medically possible. And so I think, in terms of human welfare, that's the single most important thing we can do.

Kat: It's this concept of health span rather than lifespan, isn't it?

Andrew: Yeah, I think the really important thing is just to emphasise, we want to maximise the health span and there is no scientist who wants us to live with our current decline of health and then spend fifty or eighty years in a care home. We all want to be living youthfully until the end, and then ideally just pop off of a heart attack one night without having any preceding pain. So yeah, that's definitely the way to look at it.

Kat: Yeah, that that's sort of my way to go. Some really exotic sexual tryst or something like that. Finally, I have to ask, so you've written this book ageless, you've looked into all this ageing research, are there any things that you have started to do personally with all the information you've had? Because I know for me writing a book about cancer it's made me take my health, and the health of my tissues, and thinking about inflammation, and making sure that I am actually exercising more and thinking about my own health. So is there things that you've started to do differently?

Andrew: Yeah, and I've actually got a chapter about health advice in the book, and it's motivated me in a number of different ways actually. The first of which is that understanding the biology behind some of this health advice really just makes it that much more salient. So if you think about some of the health advice is quite basic you've got to make sure you don't eat too much and eat a variety of food, make sure you get plenty of exercise, don't smoke. But understanding sort of nitty-gritty what's going on inside the molecules really, really motivated me to sort of pay a bit more attention to that stuff.

The second facet is that it revealed some quite unexpected health tips. So my favourite one is to brush your teeth, and obviously there are good reasons to brush your teeth in terms of not wanting to have too many expensive visits to the dentist, but also, it looks as though that could slow down the ageing process and the reason is, exactly as you say, to do with inflammation.

So back in the nineties, scientists are doing studies where they were looking at people's dental health, and they noticed that people who had better gums, better teeth tended to have less heart disease. And you know, at first you think this is a classic case where correlation doesn't equal causation, there's some third factor. So let's think about poverty for example, maybe people who haven't got as much money, they haven't got as much time to look after their health, they also haven't got as much time to brush their teeth, they can't afford healthy food. So maybe this has all just mixed up in some complicated social explanation that isn't really related to the biology. But as we've understood more about how these things are connected, it seems that there is indeed a connection between toothbrushing and ageing and that is because when you've got gum disease or when you've got tooth decay, it's something that your immune system can't ever quite get rid of, this constant low level skirmish going on in your mouth and over years, that's literally chronic inflammation.

So that means it can accelerate heart disease, it could accelerate cancer and there's even been some sort of tentative evidence at the moment where they found bacteria related to gum disease in the plaques of people who have dementia, So the Alzheimer's Dementia plaques in their brains, So obviously, again, it's correlation causation, are those bugs taking advantage of the fact that their brains are in a right state and sort of escaping into there, or are they a causative factor?

But the fact is I'm happy to take the risk and brush my teeth because obviously there's a load of other benefits at the same time.

Kat: It's a low investment brushing your teeth every night and morning.

Andrew: It really is, Yeah, and I think the third reason that I've got really excited about this is because I think these therapies are going to be available in the lifetime of people who are alive today. And so what that means is if I live for longer in good health, I could potentially get to the point where I live long enough to survive, to get one of these treatments and say there's a really good senolytic available by the time I'm sixty five, and I take that, that might add a couple of years to my life. And then if that gives me another couple of years for another treatment to be developed, It just means I'm going to live longer and healthier.

So it's a real motivator when you're out on a run on a freezing cold morning, like we've got at the moment, to just keep going, because potentially it means you're gonna get over the finish line for some of these amazing treatments that are in the pipeline.

Kat: I never expected that cleaning my teeth would be an anti-ageing intervention, but I’ll take it over a freezing cold jog any day. That’s Andrew Steele, and you can find his book, Ageless:The New Science of Getting Older Without Getting Old from all good - and evil - bookshops. And my latest book Rebel Cell, about the origins and evolution of cancer is also available from all retailers, with signed copies available from rebelcellbook.com  

Photos by Tran Nguyen and supplied by Andrew Steele