#118 Beat Ageing with Dr Andrew Steele

Dr Andrew Steel: So, I'm in my 30s, that means I've got a risk of death of somewhere in the region of one in a thousand per year. And I like those odds because let's think about what that would mean if that extended for the rest of my life. I'd live into my thousand and 30s on average. So clearly, that isn't what actually happens. And we all know that older people are more likely to die, but just how much really shocks me. So your risk of death as an adult in basically anywhere in the world doubles every eight years. It's shockingly universal. It's not just in rich countries, it's any period of time or any different part of the world you're looking at, that's about the same doubling time of mortality risk. And that means it's an exponential growth. And we've seen with coronavirus, exponential things can start out very small, they look like nothing's happening, and suddenly, boom.

Presenter: Welcome to the Doctor's Kitchen podcast. The show about food, lifestyle, medicine, and how to improve your health today.

Dr Rupy: I'm Dr Rupy, your host. I'm a medical doctor, I study nutrition, and I'm a firm believer in the power of food and lifestyle as medicine. Join me and my expert guests where we discuss the multiple determinants of what allows you to lead your best life.

Dr Rupy: Can we beat ageing? This is the topic of today's discussion. And whilst you might think this is yet another dive into our narcissistic tendency to want to live forever and reduce the appearance of wrinkles, the field of ageing and how to reverse it, also known as biogerontology, is actually about beating cancer, dementia, strokes, all the things that we become exponentially more likely to suffer after the age of 50. Dr Andrew Steel, PhD, is a scientist, writer, and campaigner based in London talking with me about this subject on today's podcast, and he is author of Ageless: The New Science of Getting Older Without Getting Old. And after a PhD in physics from the University of Oxford, he decided that ageing was the single most important scientific challenge of our time, and he switched fields to computational biology. Clearly a very smart person. And his latest book dives into the history of ageing research, what we understand about ageing today, as well as why in as little as the next few years, I, as a doctor, might be able to prescribe a suite of anti-ageing drugs. It is quite a phenomenal conversation that we have today. And we chat about the 10 features of ageing, how we measure it currently and why we need a biomarker for it. We define the terms senescence, autophagy, what fasting is, mitochondria, and DNA damage. So if you're new to ageing research, this is a really good refresher for anyone wanting to learn more about this subject. We talk about anti-ageing drugs and why senolytics are so exciting, metformin, the supplements that people are currently using for ageing and his opinion on those, gene and stem cell therapy too. Do check out Andrew's book, Ageless, and go to thedoctorskitchen.com for links to his YouTube channel and further work in the field of ageing. Plus, if you are not subscribed to the Doctor's Kitchen newsletter, you really need to be because every week I share something to eat, to listen to, to watch, just a few minutes or so that will keep you eating well every day and thinking about ways in which to increase the chances of you leading a healthy, happy life. You need to jump on that newsletter. You can find all the details plus links to a seven-day meal plan that is on the website, thedoctorskitchen.com. Here is my conversation with Dr Andrew Steel.

Dr Rupy: I'd love to start off chatting about how on earth you got into the official term, is it biogerontology?

Dr Andrew Steel: That's what I call it. Yeah, some people call it geroscience, but yeah.

Dr Rupy: Geroscience. I mean it's definitely a lot more communicable. Geroscience.

Dr Andrew Steel: Yeah, maybe I should have gone with that, but it's too late now, the book's in print.

Dr Rupy: It's too late. That could have been the title of the book. How did you get on with it? Because you're a physics guy and computational biology, right?

Dr Andrew Steel: Yeah, so I ended up, I was at the end of my physics PhD, and what I tell people is that I changed career because of a graph. And that's obviously a bit of a weird thing. I'm very statistically, mathematically driven. I guess that's how you end up doing a physics PhD. This graph is a very simple graph. It's a graph of your likelihood of dying depending on how old you are. So, I'm in my 30s, that means I've got a risk of death of somewhere in the region of one in a thousand per year. And I like those odds because let's think about what that would mean if that extended for the rest of my life. I'd live into my thousand and 30s on average. So clearly, that isn't what actually happens. And we all know that older people are more likely to die, but just how much really shocks me. So your risk of death as an adult in basically anywhere in the world doubles every eight years. It's shockingly universal. It's not just in rich countries, it's any period of time or any different part of the world you're looking at, that's about the same doubling time of mortality risk. And that means it's an exponential growth. And we've seen with coronavirus, exponential things can start out very small, and they look like nothing's happening, and suddenly, boom. And it's exactly the same with this risk of death. So you know, if you get to 65, your risk of death, not making your 66th birthday, is about 1%, still not too bad. But if you're lucky enough to make it into your 90s, your risk of not making your next birthday is about one in six every year. So it's sort of life and death at the roll of a dice. Now, you look at that as a human and you think, that's terrifying. I've got this sort of exponential wall of mortality just coming at me, you know, inevitably, there's nothing I can do about it. But you look at it as a scientist, and you think, that's really weird. Why is it that humans go wrong? They get cancer, they get heart disease, they get frail. All these things start going wrong with their bodies at this phenomenally synchronised time across time, across space, across cultures. And if we could understand that process, which is obviously the ageing process, maybe we could intervene in the ageing process itself and stop people from getting ill in the first place. So that's what really, really excited me about this stuff. And I started doing, we're going to obviously talk more about this, about we do now have ways to do that, to intervene in the ageing process. And I just thought, this is something I have to learn more about. Maybe I'm a physicist. You know, I last studied biology officially at GCSE, so I was 16 years old and I stopped studying it. I thought, you know, maybe I'm missing something really fundamental. I'm just a physicist sort of barging into this new field. But after working as a computational biologist for five years, I just thought, you know, this is legit, it's really important. And actually, speaking to biologists and speaking to people like you, my wife's a doctor as well. And what I found was that biologists, doctors, they don't know much about this stuff. And it's because you don't get taught about it. You know, if you had a geriatrics lecture when you were doing your clinical training, they'd have been telling you about all this social problems with dealing with older people, or they're taking five different drugs, and you've got to be really careful about whether those drugs are going to interact with each other. All that kind of really practical, important stuff. But nobody ever sat you down and said, you know, this probably isn't going to happen next year, but at some point in your clinical career, you might be prescribing people drugs that can extend their healthy lifespan. And you know, that's just a paradigm that you have to have in your head. No one ever said that. And that means that people haven't heard of it. Biologists haven't heard of it as well. They've got exactly the same problem. And so I thought, I've just got to, you know, get the word out there and write this book.

Dr Rupy: Totally, mate. I mean, I think certainly when I went to medical school, almost 20 years ago now, the the sort of creative side of medicine, the creative thinking that is essentially needed when tackling such a complex problem such as ageing, really wasn't inspired. It really wasn't something that we were enthusiastic about or told or motivated to to think about as much. Whereas what you're talking about, it sort of blows my mind, the fact that we've lost the fundamental vision of how we can actually get to the root cause of a number of different conditions. Because when people think of ageing, they think of exactly that description you made. They don't really think of, okay, ageing as a cause of cancer, heart disease, stroke, dementia, etc, etc. So if you can get to the root cause of ageing, you're actually thinking about improving the health span of people as well as the lifespan, rather than it just being some sort of, you know, narcissistic endeavour to to live for a thousand years.

Dr Andrew Steel: Exactly. And I think I think that word health span is just such a such a useful word because it encapsulates so clearly what it is we're going for here. Because the fact is, you know, if you are healthy, you will live longer. Because what is it that kills you? It's the cancer, it's the heart disease, it's the dementia that finishes your life ultimately. So if we can prevent those diseases or just at least push them a little bit back into the future, you are going to live longer. But that's almost as a side effect. You know, journalists love to ask me about immortality. You know, what's going to happen when people live for a thousand years? And I'm just like, well, I'm not really that interested in that question. What I'm interested in is, you know, what would happen if we could prevent people from getting cancer for five more years or 10 more years? You know, push that back into the future. Make people stay youthful and not frail for a little bit longer. So they can get around the house, they can play with their grandkids, maybe their great grandkids. You know, they can carry on with their hobbies, they can carry on enjoying life. So it's much more pragmatic than the sort of crazy, because I talk in the book about curing ageing, right? And I do that to be purposely provocative. But when you say you're going to cure ageing, or you want to cure ageing to someone, they think, you know, maybe you're some kind of transhumanist, maybe you're sort of, you know, imagining some sci-fi dystopia or something. But actually, I just really see it as something that, you know, I want GPs to be prescribing. I want this just to be an extension of, you know, how we do modern medicine.

Dr Rupy: Totally. What what kind of doctor is your is your wife?

Dr Andrew Steel: She's just finished her core medical training, which as you'll know, means that, you know, she's she's done a bit of everything basically. And in the UK that means she's actually, she's coming on to be a relatively senior doctor, but they still call her a trainee.

Dr Rupy: Yeah, yeah, totally. And is she going to be a med reg? Has she chosen a specialty yet or?

Dr Andrew Steel: She hasn't yet. No, she's actually taken a year out. She's she's doing a bit of medical editing and she's actually she's actually been managing a virtual COVID ward. So she's been um kind of med regging but on the end of the phone because there were so many COVID patients at the start of the year that they just decided they need to get some of them out of the hospital, the people who weren't quite so sick. So she's been in charge of that and it's been a really fascinating process. I actually think it's I think one thing that COVID has really done, well there are two things. Firstly to talk about my area is it's really illustrated the importance of ageing. Because what is the single biggest risk factor for COVID? It's being old. And so if we could treat the ageing process, maybe we could be ready for the next pandemic. But to talk a bit about my wife for a second, I think, you know, it's just really exciting that this COVID has like necessitated virtual care. And it's sort of kicked the NHS into gear a bit into trying to consider are there conditions that we could treat better at home, you know, in the comfort of people's own homes, rather than necessarily having to drag them and keep them into keep them in hospital, which apart from being unpleasant is expensive as well.

Dr Rupy: Yeah, yeah, a lot of my colleagues would certainly resonate with that. We've certainly accelerated the use of med tech that's always been around, but we just haven't been, you know, we haven't been motivated to use. And I think part some of my GP colleagues absolutely love having virtual consults because it allows them to sort of strategize their list of 40 odd patients every single day. Some people just really miss the face-to-face and I think there's going to be a blended approach in the future. But yeah, in terms of ageing, I think everyone is a lot more sort of cognizant of of what can happen when you age and what the risk factors are, as as we should have been for for many years. One question I did want to ask you actually is, um, is there evidence to suggest that we are ageing quicker now? Not to say that, you know, um, our our life expectancy is going down, but the degree to how many diseases that we have in old age, is that going up or is that is it just a a function of us living longer?

Dr Andrew Steel: It's a really interesting, naughty, difficult question. There's actually a paper that came out a few weeks ago, or maybe a few months ago now, um, that made the case, so the way it was reported was that ageing is unstoppable, I think was the headline. And they said, you know, the idea was that we're all getting older, the rate at which we're ageing isn't changing. But actually that was all they'd really shown. They'd shown that that mortality risk doubling time I talked about, the fact that your risk of death doubles every eight years, has been constant throughout the whole of human history, was basically what they were saying. And nothing that we've done with either changing lifestyles or modern medicine, none of that has increased that doubling time. Because what you'd like is to say, okay, um, so the reason there's a tortoise on the front cover of my book is that tortoises have this fantastic property, they're called negligibly senescent. And, um, what that means is that they have a risk of death that doesn't vary depending on how old they are. And that's really, really incredible. Because, you know, people know that tortoises live a long time. The oldest Galapagos tortoise, that tortoise that's on the book cover, was about 175 when she died, which is amazing. But what's more amazing is that she stayed youthful effectively, you know, although they look wrinkly, they don't have any teeth, they're not exactly the greatest ambassadors for longevity. Um, they stay sprightly, at least as sprightly as a tortoise can be, throughout their adult lives. And she was probably going running around as fast as she could at the age of 150, the same as she was at the age of 50. And they stay reproductively active, they aren't at any increased risk of disease and so on.

Dr Andrew Steel: Yeah, so what this study showed was that we haven't become more Galapagos tortoise. We haven't had our rate of ageing change. However, what you can do is, even though the rate at which our risk of death doubles has stayed constant, what you can do is you can reduce that initial risk. And if you've got a smaller number, it takes more doubling to get it up to be a big number, if you see what I mean. So the idea being that by things like reducing risk of infectious disease, um, by things like improved lifestyle, by things like, you know, making sure we've got exercise, making sure we're eating a good balanced diet, all that kind of thing. And obviously the contribution of modern medicine can't be neglected as well. We've effectively lowered the sort of baseline risk of death. And that means that although it carries on doubling at the same rate as it has throughout human history, that seems to be sort of a a fact of our species. By starting at a lower number, we can live longer in good health. And I think the the sort of question of whether we're getting more diseases now, I think it is largely the fact that we're living longer that's causing those diseases to to become more prominent. There's a huge debate about whether our our lifespans have obviously increased. So lifespans have been going up by about three months a year for the last 200 years with fantastic consistency in the best country in the world. So what that means, you know, we've effectively doubled what it means to be human. We've gone from a life expectancy of about 40 years old in the mid 1800s to a life expectancy of 80 in a lot of the rich world today. That's really incredible progress. But the question is has health span kept pace with that change? You know, are we just spending, you know, the last 20 years of our lives getting increasingly decrepit? I think the evidence is really, really difficult to tease out on this. Because one one way you can do it is you can say, you know, how many diagnoses, how many medical diagnoses do people in the population have? The trouble is we're a lot more aware of diagnoses now. There's a lot more medical care. So, you know, there's an extent to which maybe there's more dementia because what would have just been sort of written off as, oh, she's getting a bit senile back in the 1950s. Now people are getting a proper diagnosis of dementia. And they that means, you know, on the pro side, they're getting the care they need, they're getting the support they need. So if you just look naively at how many diagnoses people have got, it's very hard to know what's going on. The other way you can do it is you can ask people, how's your everyday life? Are you having trouble getting on with tasks at home, etc, etc. And what you find is that that seems to indicate that people are living longer in good health. But it really varies by country. And you just wonder if there might be some national personality stereotypes going on here. You know, maybe people in certain countries are a bit more stoic and so, you know, they're they're really suffering, they're in pain, but they just say, oh no, everything's absolutely fine. Whereas other people are a bit more whiny. I'll I'll leave everyone to choose which countries I think these stereotypes apply to at home. But you know, they might be going, oh, you know, I've got a bit of an ache in my knee, therefore I can't do any of my daily tasks around the house without huge inconvenience. So it's really, really difficult to tease these things out. I think the overall reading of everything that I saw when I was researching the book suggested to me that health span has increased, perhaps not quite at the same rate as lifespan, but it's not like we're, you know, it's not like all we've added to our lives is some horrible 20 years at the end. I think we have genuinely improved both health and lifespan throughout history. But it's a very difficult question as you can tell from that very long answer.

Dr Rupy: Yeah, no, no, no, it's it is a difficult one. And I think my sort of um uh my perspective is a bit warped, right? Because I've spent some time on geriatric wards as a junior doctor. I see a lot of patients as a GP who are on, like you said, like multiple different medications and you just think, what are you doing here? And you know, unfortunately seeing a lot more dementia patients as well. Um but on, you know, if you take like a sort of uh bird's eye view of of the trajectory of of human life, I think we've definitely made leaps and bounds when it comes to better care and better health in older age. Um and it's just about like optimizing that as much as possible considering, you know, the number of people that we now have on the planet. Um what let's let's talk about how we actually measure ageing because like there's some crude measures of like, you know, general health and well-being that we use in in clinics. So blood pressure, number of medications, perhaps, uh cognitive functioning, executive functioning, whether you can drive or not, etc. Um are there are there sort of like clinical measures of ageing that you think would become available to us as clinicians such that we can actually measure and intervene where appropriate when people are going past a certain point in their life?

Dr Andrew Steel: I think that's definitely coming down the line. And like, I think we've all got this intuition that, you know, some people seem to age better than others and some people are biologically older than what it says on their birth certificate. And actually, my wife calls this the end of bedogram. I'm sure you've performed one of these where you just you you go and see a new patient and you go, oh gosh, you know, she looks a bit older than it says on her birth certificate, you know, she's she's not long for this world or whatever. Actually, there's some scientific validity to that idea that patients, not just patients, but people who look older actually are biologically older. So there was this fascinating study done in 2009 where they got a panel of assessors to rate how old they thought someone's face looked. And then they correlated that with their future risk of death and disease. And it turned out that looking older actually corresponded to being biologically older, being at more risk of ill health, being at more risk of death. So clearly, and I mean, this isn't really surprising because actually, when you look at the causes of ageing, the sort of biological, molecular causes that, you know, cause everything, they they cause everything. They cause cancer, they cause heart disease, but they also cause the wrinkles, the grey hair, the sort of cosmetic external factors. So the fact that all of these things are driven by the same processes means, you know, in a way, it's unsurprising that your biological age is shown on your face. You know, effectively, it's it's sort of reflecting the wrinkles and grey hair as it were on your internal organs, even though obviously that's not exactly how they manifest inside you. Luckily as well, you know, we're not going to be consigned to doing end of bedograms for the rest of time. There are some sort of more hardcore scientific ideas as well. I think one of the most exciting is something called the epigenetic clock. Yes. And this is where you uh can take, you can do it with a blood sample, you can actually do it with a sample of any tissue in the whole body, but I guess, you know, often we go for blood because that's a nice easy one to get out rather than grabbing a bit of someone's liver or something. The idea is that you measure the uh you measure these things called epigenetic marks. These are sort of like bookmarks and notes all over your DNA. So in the middle of your cell, you've got your DNA, your instruction manual. And every single one of the cells in your body that has DNA has the same instruction manual. And that's sort of crazy if you think about it. Because you know, you've got brain cells, you've got liver cells, you've got lung cells, you've got skin cells. All these cells doing such wildly different functions, but they've got the same instructions at the center. So obviously the body has to have some way of saying, okay, you're a skin cell, what you need is activate these genes that are relevant to being a skin cell, to doing your job at your part in the body. And this is done with these epigenetic marks. These sort of little bookmarks going, you know, don't look at this bit, this bit's super important, make lots of this one, etc, etc. And it turns out that by looking at how those those bookmarks, those epigenetic marks change with age, you can judge how old someone is incredibly accurately. So you can take a sample from someone's blood, you can measure these epigenetic marks and you can work out their age to within three or four years. Now that's not that exciting. We already have a technology that's much better at working out someone's age to within three or four years because we can look at their birthday. However, what's more interesting is that if your epigenetic age is greater than your chronological age, so your birth certificate age, then again, you're at more risk of disease, you're at more risk of death than someone who's got a lower epigenetic age. So you can have either what's called an accelerated epigenetic age or a decelerated epigenetic age. And this isn't quite at the point where there's anything much that we can do with that clinically. Because if you if, you know, if someone's older quote unquote than their than their birthday suggests, um, you know, the advice you'd give them would basically be the same. They'd get some exercise, blah, blah, blah. But I think as we start to understand more about the ageing process, as we're going to develop drugs that can target particular facets of the ageing process, these biomarkers, as they're called, that tell us how biologically old someone is, they'll tell us if a treatment's working, and they'll tell us, you know, whether someone needs a treatment yet or and so on and so on. So I think these things are very much, you know, they're in development and they're not 100 years away from being applied at all.

Dr Rupy: Yeah, absolutely. And you know, even from like a very crude point of view, if someone had an accelerated ageing process, maybe, you know, as a clinician, I could be a bit more proactive with pinging that person to, you know, make sure they're doing exercise or perhaps even organize health coaching or have them come into the clinic for more regular tests and that kind of stuff in anticipation of, you know, there being these uh wonderful drugs that I'm sure we're going to get on to talk about a little bit later uh being prescribable. Um but before we get into that, why don't we talk about those features of ageing? So you've mentioned one, these these epigenetic alterations. Um I thought there were eight hallmarks of ageing, but I must have misread that. In your book, you you talk about the 10 hallmarks of ageing.

Dr Andrew Steel: Yeah, I was I've mixed things up a bit just to keep you on your toes. So there was a paper that came out in 2013 and it's it was called The Hallmarks of Ageing. And there are nine in that paper. There have also been a few other attempts to categorize the various sort of changes that are related with ageing. One has seven, I think one has five or six. There are basically biologists don't quite agree. And so what I did was I took that 2013 paper which has nine. I think I combined two, I added one. I I ended up with 10 somehow. It just it just it's a nice round number. I like it. It's a nice. Exactly. It was it was very fortunate. And I mean, one of the things that so one of the things that happened was in the intervening sort of seven or eight years, you know, since that paper was published, the particular thing we've learned a lot more about is the microbiome. So the sort of bacteria, the fungi in your guts, they seem to have an association with the ageing process that just wasn't mentioned in that paper. So anyway, I ended up with 10 of these things. I won't go through all of them, you know, to save your poor listeners' ears, but um they they just these are the fundamental underlying causes we think of the ageing process. And they range in scale across our whole body. So I mentioned already DNA, this instruction manual at the center of every one of our cells. That's one of the most changes in that is one of the most fundamental hallmarks. So you can imagine if you get damage to your DNA or you can get mutations, which are effectively spelling mistakes in that instruction manual. Because of those mistakes, that can then lead to various aspects of the ageing process. And the most obvious one, I think that a lot of people will know is related to DNA damage is cancer. Because cancer is essentially a disease where you accumulate enough mutations in a cell and that allows that cell to carry on dividing and dividing, you know, become a tumor and eventually potentially, you know, take your life. So that's the sort of very small scale. There are then other molecular things like the epigenetics we've just mentioned. There are proteins inside your cells that can either change or become damaged or or all kinds of various things as you age. Getting onto a slightly bigger scale, the cells themselves can age. So one thing that I love to talk about is senescent cells. I'm sure we'll get onto that a bit later. And these are effectively aged cells. Um which which we know accumulate as you get older and effectively accelerate ageing throughout your body. And then sort of zooming out even further, dysfunction in these sort of smaller scale hallmarks causes dysfunction across the body. And you can get problems with things like signaling, which is the communication between your cells that can happen. Um you know, and as that gets disregulated, your whole body can sort of fall out of regulation. And then, you know, bigger still your immune system. And this is I already mentioned coronavirus. We've got, you know, we've really seen how older people's immune systems just aren't as powerful as younger people's ones are when it comes to fighting off infection. So the combination of these various smaller hallmarks causes your immune system to age. And that doesn't just affect infectious disease actually. The other your immune system does a number of other things. Firstly, it seeks and destroys those senescent cells I was talking about. So as it gets less effective, it gets less good at that. So you can see how that sort of forms a vicious cycle. And secondly, your immune system is really important for cancer as well. Because it's constantly patrolling, looking for these cells that are on the route to becoming cancerous. And if your immune system gets less effective at that, that can make cancer more likely too. So you can really see, you know, I've just given a sort of a flavor there rather than a proper in-depth overview of all 10 of them. But you can see there are there are a variety of these changes. They're all quite interconnected. But what's surprising is, you know, 10, it sounds like quite a lot. I've just talked for quite a lot quite a long time about three or four of them. But actually, if you think about the number of age-related diseases you've got, you know, there are hundreds of kinds of cancer. If you think about the number of ways that your brain can go wrong as you age, you know, there are there are dozens of types of dementia, all with subtly different features, all happening at subtly different scales in your body. So although there are 10 of these hallmarks and that might sound like quite a lot, it's actually quite a lot less and it's quite a lot more fundamental than the the sort of diseases that we currently treat in medicine. And that's what really excites me is that we're going by going after this relatively handful of hallmarks, we could potentially address like dozens or even hundreds of age-related diseases.

Dr Rupy: Absolutely. Let's let's talk about senescent cells because um that that comes up quite a bit. What what are let's double click on the the actual definition of what a senescent cell is and why those are problematic.

Dr Andrew Steel: So senescent is just the biological word for getting older basically. So we talked about negligibly senescent tortoises, so that means, you know, tortoises that basically don't age. And these senescent cells are effectively aged cells, right? So they're cells that have um they've either got a lot of damage to their DNA or mutations. So we've already mentioned that. And that means your body goes, well, that cell is looking a bit suspicious. It's sort of looking as though it's on the path to cancer. And so what it does is it tells that cell to stop dividing. And you can have a similar effect where a cell has actually just divided too many times. So all the time in your body in places like your skin or your intestines or your blood, you need to have constant renewal of the cells in those tissues. And what that means is that you've got cells that are constantly dividing to replace the ones that are dying. And that means they divide and divide and divide. And over a lifetime, that can add up to a lot of cell divisions. And again, your body is suspicious of cells that have divided a lot of times. Because what divides a lot of times? Well, it's cancer again, isn't it? So if a cell has divided too many times, your body slams on the brakes, turns this cell into this non-dividing senescent state. And when you're young, the good news is your immune system comes over, gobbles up these cells. There's a sort of constant rate of production, there's a constant rate of them being gobbled up by the immune system, and everything's basically fine. But as you get older, you've got an increased risk of getting these senescent cells. And that's because you've had more time for you to accumulate the damage, the mutations in your DNA, you've had more time for your cells to divide more often. So there are more ways to produce these cells basically. And then on the other side of the balance, your immune system is getting less good at seeking these cells out. And in fact, ironically, it's partly because some of the cells in the immune system go senescent, you know, they they they stop functioning as they should. And so you get this vicious circle, the number of cells goes up and up and up in your body. And what's unfortunate is that these senescent cells, they don't just sit there not dividing, you know, not doing their job, but not doing any harm either. What they actually do is they pump out this toxic cocktail of molecules. And actually, its primary purpose is to say, hey, immune system over here, I'm senescent, you know, come and eat me up. But unfortunately, when your immune system fails to do that over time, those molecules can basically accelerate the ageing process. And I think, um, the reason that we know most about this is because, you know, that that might all sound quite depressing. But actually, we've done these experiments where you can remove these senescent cells. So there was a paper that came out in 2015 where scientists took a bunch of mice. They were 24 month old mice. Now, mice obviously, anyone who's ever had a mouse as a pet will know, live a lot shorter than human beings do. So 24 months old for a mouse is about 70 in human years. So these are sort of, you know, late middle-aged mice. And they gave them what's called a senolytic drug. So this is a drug that's designed to kill the senescent cells, but leave the rest of the cells in the body intact. And when you give the mice this drug, they basically get biologically younger. So, firstly, they live a bit longer. That's good. But they, you know, we don't want them just to be living longer in ill health, you know, sort of hobbling along, somehow prevented from dying. But the good news is that isn't what happens. They get less cancer, they get less heart disease, they get fewer cataracts. So this whole range of age-related diseases is prevented. And it's not just the diseases, they get less frail. So they can run further and faster on a little mousey treadmill, which they use in these experiments. They've got these incredible things. It's such fun reading these mouse experiments. They've got a sort of gym they send them to to work out, you know, what how how their ageing is progressing. It's like, how long can they dangle off a rotating rod? Can they walk along a tight rope? All these sort of various little challenges they set them. And by deleting the senescent cells, you get better at these challenges. They improve cognitively. So if you put an old mouse in a maze, they're often a bit anxious, they're not very exploratory. If you put a young mouse in a maze, then, you know, they're going and check everything out. And if you delete the senescent cells, you sort of restore some of that curiosity in the older mice. And honestly, these mice, you know, quite apart from any of these detailed biological measurements, they just look great. I was a computational biologist, so I didn't, you know, deal with mice directly in the lab myself. But even to my, like, wildly untrained eye, the mice that have had the senolytics, they've got better fur, they've got plumper skin, they just look fantastic. And what that means is, what these these things, these senescent cells are a root cause of this whole swathe of different age-related changes, you know, not just the lifespan, not just the disease, not just the frailty, not just the wrinkles and grey hair, sort of the lot. And that's really the dream of anti-ageing medicine is that we can go in, we can intervene in, you know, one or more of these hallmarks, and we can then prevent a whole swathe of different age-related changes and, you know, make people healthier for longer. So that's that's in mice. But now there are 10 or 20 companies trying to turn that idea from something that works on the bench in mice to something that works in humans. So this is something that could really be happening. I think we're going to see the first senescent drug, sorry, senolytic drugs on the market probably within the next few years. And at first, it's going to be for specific diseases where senescent cells are known to be a problem. But if those drugs are safe in those trials, then you could potentially start thinking about handing them out to people preventatively. So I really think this is something that's going to happen, you know, certainly within your medical career.

Dr Rupy: Wow, that that's incredible. I mean, I know I know the question that everyone's listening to uh is probably asking themselves right now is what was in that senolytic drug cocktail?

Dr Andrew Steel: Yeah, so what they started out with, they started out with a couple of existing drugs. One called Dasatinib, which is a chemotherapy drug. Oh, okay, yeah. And something called Quercetin, which is actually it's a I think it's a flavonol, so it's a molecule that's found in fruit and veg. And they just so the way they did this experiment was really pragmatic. They got a basically a dish full of senescent cells and non-senescent cells. And they dripped on a variety of drugs that they thought might help. And they just tried as many as they could and they found that the most effective combination was this D plus Q. And actually some people are taking forward D plus Q. You know, that's one of the companies is trying to like look into whether that's going to work. But other companies, you know, that's just sort of a first draft. It's just some stuff they happened to have in the cupboard basically. So they were trying that out because it was they had it to hand. But now we understand how important senescent cells are, people are going out and trying to develop new compounds that are going to be more effective. So they're going to target those senescent cells better, you know, kill more of them with fewer potential side effects. So it's just going to be a question of sort of watching and waiting and see which of the approaches is the most successful.

Dr Rupy: I guess when when people think of that, they might be thinking, this is amazing, you know, we can get rid of senescent cells and uh with this cocktail of drugs. Obviously, there are side effects associated with chemotherapy, but let's say we can better target specific senescent cells. What are the potential side effects that we should be worried about when using uh hypothetical senolytics?

Dr Andrew Steel: It's a really good question. And I think that's a very I think it's a very wise question, you know, medically to ask this because we know that all drugs have side effects. There's just nothing you can give someone that will make them better with absolutely no consequences. I'm I'm sure as anyone who's read the side of a pill packet knows, these senolytics are definitely going to cause nausea and headaches because that's just what literally everything causes. Um what's what's sort of fascinating and amazing is that in these studies in mice, they don't seem to be any negative side effects in that they don't, you know, they seem to affect everything in a positive way. Now, I think we should take this with a grain of salt for two reasons. The first is that when you're a scientist trying to get your big splashy scientific paper, you don't report every last single niggle and quibble that happened. You report the good results. So there's that sort of bias in there. And the second thing is, and this sounds stupid, but mice can't talk, which means if there are, you know, any headaches or nausea, for example, they can't like, you know, squeak to the experimenters that they're having a problem. So there are various places we might expect this could be an issue because although senescent cells are bad in a lot of parts of the body, let's take an example of the brain. One of your neurons in your brain, your brain cells could turn senescent. It might be that although that neuron is senescent, although it's, you know, it's not ideal that it's in that senescent state, it might be part of a memory or it might be part of some function that your brain is performing. And what we'd rather do with a senescent cell in one of these really important situations is turn back the clock and reverse whatever problem caused it to become senescent rather than just deleting it. Um at the moment, we don't know about those side effects. In fact, I think there are even some trials of senolytics to improve people's improve people's dementia. So it's really we're just going to have to watch and wait basically. But it's definitely worth being mindful, you know, these things aren't ready for the prime time. I'm not I'm certainly not running down to my clinic trying to grab myself some D plus Q, you know, trying to blag myself some from the pharmacist because I think we just got to it's the trials are happening now. So we're going to know the answer soon enough that we don't need to be sort of jumping the gun and trying these things out.

Dr Rupy: Yeah, yeah. You know, going back just it's come to mind now, going back to um your description of how exponentially we age after the age of 50 or 60. Um and looking at all the different hallmarks of ageing, you can understand that exponential increase because when you're if your microbiome is affected, your telomeres are affected, your immune system is affected, those things are all interrelated. So if they're consistently getting worse across the board, then that's going to be leading to a whole suite of inflammation issues, increased cancer issues, increased memory problems, dementia, you can sort of understand that if those are all the hallmarks of ageing and if they're universally getting reduced, then you're going to have this massive uptake in in number of diseases that leads to death.

Dr Andrew Steel: Yeah, I think that's exactly right. I think that's that's just such a a beautiful, simple way of thinking about it. And actually, there are there are a lot of mathematicians who try and model the body in really, really simple ways just to just to sort of see what happens. And um there's there's this branch of mathematics called reliability theory. And that's used to predict the reliability of everything from like, you know, steam engines and components in factories and people have even applied it to biology. And what they find is that if you just consider the human body as a bunch of abstract interacting systems and we won't specify what's inside the black box, but there's just these interacting systems. Because of the way that they interact, you end up with this exponential increase. Because as things go wrong, they cause these vicious circles. So this thing goes wrong and it makes this thing worse. And then that thing getting worse makes the first thing worse again. And round and round and round you go. So the human body, it's basically just a machine that like spirals out of control toward the end of life. I think that's exactly the right way to think about it.

Dr Rupy: I'm going to pepper like a whole bunch of like terms to you and feel free to define them as you go along and just like talk about how it's sort of related to the the hallmarks of ageing and and what might be in the on the future because your book goes into like great depth and it's really it it's written in a way that is um accessible and I think that's one of the things that I I want to make sure people listening to this, you know, understand because it's one of those books that I think everyone should have because everyone should really be thinking about ageing in a in a sort of more more of a positive light rather than something that is inevitable. Um autophagy, this is a a term that gets banded around quite a bit and I I believe it's related to senescent cells as well. What is autophagy and are there mechanisms to try and upregulate this uh or or or drugs on the horizon or even uh sort of uh lifestyle practices that we could do to to to change that?

Dr Andrew Steel: Autophagy is so so fascinating. It's so auto-phagy means self-eating. And it's the process by which your cells recycle uh components inside themselves. And the way that this process works is it seems to preferentially recycle the old and the broken components inside the cell and then break them down and make fresh new ones. And the sort of the way this was first observed is by looking at organisms that are doing something called dietary restriction. This is where you radically cut back the amount they eat. And what you find is that when you cut back the amount they eat, if you imagine you're a cell and there's no, you know, there's no protein, there's no nutrition coming in, you're going to have to make do with what you've got. And so what they do is they ramp up this process of autophagy. And as I said, it preferentially breaks down the things that are broken already. And what that then means is that we think it's breaking down some of those broken proteins, it's effectively slowing down ageing because one of the things that causes ageing is the accumulation of these broken components inside cells. Whereas if you're eating a, you know, plentiful diet, you're scoffing loads of food, you've got all this fresh protein coming in, like why bother recycling that stuff when you've got a load of fresh new material that you can use to manufacture your various components inside the cell. So the idea is that by by reducing the amount you eat or perhaps by fasting, you can activate this autophagy process. Now, the question is, you know, is this something that we can all try at home? And the answer is we it's frustratingly unclear. And I this I found this like one of the most annoying parts of the book to write because you're just reading all these studies about diet and you're just like, I know if I just read one more study, I'm going to find the answer. I'm going to find like diet Nirvana where I know exactly what to eat, how much to eat, when to eat it. Um this dietary restriction phenomenon, it's one of the most universal in biology. It works in single-celled yeast, that's the fungus that's used for baking bread and brewing beer. It works in nematode worms, which are these tiny little millimeter, sorry, yeah, millimeter long worms that are often used in ageing research. It works in fruit flies, which are again, classic biology organism. It works in mice, it works in dogs, it works in like just so many animals that we've tried it in. Um and yet, whether or not it works in humans is still uncertain. It just it's so frustrating. The the closest we've tried it in is monkeys. And so there was this 30-year long experiment that started in the late 80s, um looking at these rhesus monkeys and giving, you know, half of them were calorie restricted and half of them weren't. And it definitely improved their health span, but the lifespan results are ambiguous. And the real challenge with this, so we and we've also got a bit of human data as well. But these human trials, they're just too short. Because you know, imagine how long this study would have to be to find out if it improves someone's ageing. Ideally, you'd start someone on dietary restriction at I don't know, age 30 and watch them for what, 40 years? And what, longer if it works? So it's like it's genuinely problematic. And what you find is that these short-term studies, they seem to demonstrate that markers of health are improved. So you know, your your cholesterol goes down, you know, your your fasting glucose, these you know, sort of blood sugar goes down. These things are improved, but and the big but is there are side effects as with all medications as we were just discussing. So people, firstly, they report the hunger never goes away. They're just like hungry all the time. So that's something that I I would find very hard to deal with personally. And then there's the sort of more medical side effects. We know that there's a risk of your bones getting thinner if you stay on this kind of diet. There's a risk of anemia. So there are a handful of people in the trial had to drop out because they noticed that the the levels of iron in their blood were getting too low. Um what's the other thing I was Oh yeah, there's there's a risk of uh decreased immune function. So again, there's there's sort of no point potentially theoretically living five years longer if you're just going to catch the flu and die because your immune system's been weakened by dietary restriction. So it's really hard to know whether we should recommend people go away and fast or dietary restrict. I'm not even the right kind of doctor to be making these recommendations. I've got a physics PhD as we discussed, you know, I I really can't, you know, feel comfortable myself going out and making this kind of advice. What we need, I think, more importantly than that, firstly is to make sure we don't eat too much. That's definitely bad for us and that's absolutely unambiguous. And secondly, we need to develop drugs that can activate this process of autophagy without us having to do this sort of exhausting, bone thinning, blood thinning fasting process. And so what's really exciting is there are some drugs in the pipeline that are hopefully going to, you know, go in there, activate this process of autophagy in our cells and yeah, as I say, without the sort of the burden of having to fast in order to manage it.

Dr Rupy: Yeah, you know, one of the things because I get asked about this quite a bit with, you know, whether people should fast or not as it's become so trendy these days as a weight loss tool primarily, but you know, there might be some other benefits is um we don't know what the correct dose of fasting is appropriate for which person. Um and fasting itself is just so vague, you know, what is it? Is it 5:2? Is it sub 500? Is it water fasting for three days? Like there's so many variables involved in the process of fasting that it's very hard to cater for. And uh like you said, you know, we we don't have like a singular marker that is uh a a um a correlation with uh better ageing or or or less ageing. So it's hard to design like the perfect experiment to even test it out. And I know there's a group, I think they're colloquially called the cronies. Yes. Where they they've like been like calorie restricted for years and years. I don't know if they're still around or not, but um they're sort of like doing their end of one experiment or end of 100, however many there are of them or whatever. But I'm I'm not too sure about what their health status actually is.

Dr Andrew Steel: I think it's really surprising. I actually did a bit of Googling about this and was finding out about one of the sort of so there's the crony, the reason they're called that is it's calorie restriction with optimal nutrition. So the cronies. And I was I was Googling about one of the people who does this. And I I can't confirm this because it's internet forum rumors, but he hasn't been seen for a while. And the reason it's supposed to be the case is because he was trying to so the optimal nutrition is the really key part of this because if you cut back on the number of calories you eat, you're inevitably going to cut back on all the micronutrients you get as well. And so he had like tried to optimize his diet based in the absolutely, you know, approaching it pretty scientifically, I have to say, you know, these people, they aren't just messing about. They're really like trying to optimize their diet in every possible way. But he, it's thought that he got an iodine overdose from trying to add seaweed to his diet to increase his iodine levels. And that damaged his vocal cords. And whether or not that story is true, I think it's just so illustrative of how hard this is. Because these are, you know, I think they're pretty smart people. They're honestly trying to do this in the best possible way. And yet, getting all the right vitamins, you know, not being deficient in something, but equally not overdosing in something at the same time, it's just such a fine line to walk. And exactly like you say, you know, when you talk about fasting, there are just so many protocols. There are some people who are like, I literally don't eat for a week and I do it every three months. And then the other extreme, there's this sort of 16-8 time restricted feeding it's called where you say, okay, I'll only eat for eight hours a day, then I fast for 16 hours. And there are just, you know, some people, you know, do 12-12. So it's like, is that even that's not just normal eating, like that's not so wildly different from from someone just eating normally. So, I what I say, yeah, what I normally say is that I think we're going to have cured ageing like medically before we fully understand all the variables of diet. Because, you know, amount of protein, amount of carbs, different nutrients, when you eat, like there's just so much you can change in all of that, you know, there's so many variables. I just don't think we're ever going to get to the bottom of it to be perfectly honest.

Dr Rupy: Yeah, yeah. No, I I agree. And I think there's so many so many arguments as well that sort of like make it even more uh difficult for the average person to understand who they should be listening to, what they should be putting in practice, sustainability of diets is a key thing and sustainability of a fasting practice, I think is another thing. I think if we we could design a perfect experiment that didn't require, you know, following up people for tens of years, um it would be to find a uh a decent biological marker of ageing that everyone agreed on, almost like a credit score that that uh was sort of a contribution of all those different hallmarks of ageing, put them on different regimes, have a washout period and maybe, you know, do it with a different regime and then, you know, see what see what effect that had. But but like I said, there's so many different variables, you know, someone's microbiota status, their genomics, life experiences, all these different things. It's very, very difficult.

Dr Andrew Steel: I think you've really hit the nail on the head there because when I I talk about these biomarkers like the epigenetic age, and that sounds quite dry and scientific. Oh, we need to develop some biomarkers. But that, you know, actually the reason that's super important is exactly as you say. Like we don't want to do a 40-year long trial for an age, you know, an anti-ageing drug. Because quite apart from anything else, I'm going to be pretty old by the time that 40-year long trial is completed. And then they'll be like, yeah, it worked. And I'll be like, damn, I didn't take any of it. I've sort of blown my opportunity. And obviously, I'm talking about that in a slightly selfish way, but that applies to billions of people. What we really need is to be able to, you know, measure a bunch of people's biological age, give them a treatment, then they come back six months later and we go, oh, your biological age has gone down or maybe it hasn't gone down. Therefore the treatment does or doesn't work. And that's why these biomarkers are so, so important because although they sound sort of dry and nerdy, they're the thing that's going to enable us to develop these treatments like literally decades faster than doing the experiments in the sort of quite and quite conventional way.

Dr Rupy: Yeah, yeah, absolutely. And I think at the moment we just have sort of like adjuncts as to what is um a marker of of of ageing at the moment. You you mentioned glucose control that goes haywire after a certain age. That's why we see so many people with type two diabetes in clinic and stuff and we start them on metformin. Even though actually metformin is um uh potentially an anti-ageing drug as well. Have you have you looked into that yourself?

Dr Andrew Steel: Yeah, metformin is super interesting. And actually there's a there was supposed to be a trial starting on this already, but I think it's been delayed due to COVID. I think it's now going to start this year in the US. And the trial is called TAME, targeting ageing with metformin. Now, as I'm sure you'll you'll know far better than me, metformin is like this absolutely rock solid classic drug. We've been prescribing it in the UK since the 1950s. It's one of the most widely prescribed drugs. And it's a drug that's normally given to people with like you say, type two diabetes, so people who can't control their blood sugar, um you know, without without the assistance of the drug. But what people have found is they've looked back at they've looked back at medical records and noticed that people with type two diabetes who are taking metformin actually live longer than people in the control group of the experiment who aren't taking metformin. And the reason they aren't taking metformin is they haven't got diabetes. Now, what's really counterintuitive about that is that people who haven't got diabetes, they tend to be less overweight, they tend to have less heart problems. They tend to just be healthier in general than diabetics. And yet if you give a diabetic metformin, they seem to live longer. Now, the problem with this kind of study is because it's what's called observational, there can be all kinds of other things going on. So maybe the reason the diabetics live longer isn't because metformin is some wonder drug. It's because the fact that they're diabetic means they're going and seeing someone like you, you know, every few months. They're checking in with their GP, they're having their blood sugar, they're having their cholesterol measured all the time. You know, problems are getting picked up early. Whereas, you know, the the classic man, I'm I'm going to gender bias this, you know, they're in their 60s. They might have high blood pressure, they might have a bunch of things wrong with them, but because they haven't got a diagnosis like diabetes, they're not getting the checkups, they're not being seen. So maybe the reason that the diabetics live longer is just because they have more contact with doctors and problems are getting picked up early. So what we really need to do, this TAME trial that I talked about, it's what's called a randomized trial. So they're going to get a bunch of people, I think between the ages of 60 and 80. They're going to split them into two groups. They're going to give one group metformin, they're going to give one group a placebo, so effectively a sugar pill that doesn't do anything. And they're going to watch them over sort of three to five years. And they're going to see if they get one of a panel of age-related diseases. So cancer, heart disease, various other things. And also, of course, whether or not they die. And if the people in the metformin group get those diseases later and die later, then what you can say is metformin isn't just a diabetes drug. It's one that affects the whole ageing process. So that's something that's really interesting to watch. And the reason that's particularly interesting isn't because we think metformin's going to like double your lifespan or something. Because I think, you know, the expectations even of the scientists doing the trial is it's going to be, you know, a modest improvement at best. What's cool about this is they've developed this protocol for the trial in really close collaboration with the FDA, who are like the drug um Food and Drug Administration. Yeah, Food and Drug Administration. They're the drug regulator is the word I wanted. over in the US. And what that means is that therefore, this is sort of laying the groundwork for future anti-ageing drugs. So, you know, things that are more exciting than metformin basically are going to be able to plug into this protocol and say, okay, you now understand that we can actually because one of the big problems at the moment is you can't get a drug approved for treating ageing. You have to get a drug approved for treating a particular condition. So, you know, you say, I've got a patient with diabetes, I want to give them X or Y. And you can do this what's called off-label prescribing where you give someone a drug that's approved for something else. But there is no way to, you know, give someone a drug just because they're old. Like there's nothing wrong quote unquote wrong with them. They're just old. And so what those scientists were doing wasn't saying metformin is a wonder drug, though obviously I very much hope it is. But, you know, what they're doing is sort of laying the groundwork so that when the wonder drug does come along, there's a way to get it approved and a way for people like you to prescribe it, rather than it just having to sort of languish, you know, on the on the lab bench when we've got this amazing thing that we could be handing out to people.

Dr Rupy: Yeah, yeah. That that would be amazing. And I've heard that the potential mechanism behind metformin is its impact on mitochondria. Um is that is that something that you looked into in terms of the mechanism of why metformin?

Dr Andrew Steel: It's so messy. Yeah, doctors talk about like dirty drugs and metformin is just absolutely filthy if that's the criterion we're going on. So it definitely affects your mitochondria, which are these powerhouses, the sort of way that your cell generates energy. Um but there's also some evidence that it affects your microbiome. It might be a dietary restriction mimetic, so it might change autophagy by activating something called AMPK. So it's just it's all over the place. And I strongly suspect there are other and obviously also it can it has blood sugar control because that's the whole reason that we use it in the first place. So there's this whole variety of different effects and it probably intervenes probably in all of the hallmarks of ageing to be perfectly honest. So this is like this absolutely filthy drug. I don't think we're ever going to nail down exactly what the effect is that causes um causes it to help. But I think most of those effects do seem to be helpful. So it's probably some combination of stuff.

Dr Rupy: Yeah, yeah. You know, I think people in the nutrition world refer to foods as dirty drugs as well because there's so many different mechanisms by which they might be having an impact on your health and well-being. And you know, whether it be a dietary mimetic or sorry, calorie mimetic or um whether it's having an impact on your microbiota, whether it's having an impact on your signaling pathways or general inflammation, it's it's so hard to quantify. And and on the subject of mitochondria, I've I've heard of people, I know uh Professor David Sinclair talks about this quite a bit of um some supplements that impact mitochondrial function, uh namely, I think it's nicotinamide adenine dinucleotide, NAD. Yes. Uh and supplements that boost that, NMN. What what's your opinion on those?

Dr Andrew Steel: I think we just don't know. It's it's really frustrating because it's it's it's quite a complicated field again, it's all quite messy. But I feel like there's just not the evidence for these things yet. There were um so the idea is that NAD is this molecule that's used for a variety of processes in the cell. It's used by your mitochondria when energy is being generated. It's actually used for DNA repair as well. So if you get this damage to your DNA, it's not a one-way street, you can repair it as well. And NAD+ is really, really important in that. But the drugs that boost it, it's just really not clear what their effect is. So there's something called niacin, which is just a vitamin. So that's often been prescribed by doctors to people um with a deficiency and it seems to lower cholesterol. So it's sometimes used in heart disease. The problem is that's got loads of side effects. It causes uh you know, the sort of superficial and unpleasant stuff like skin flushing, so you end up feeling really hot. Um and it's also just not clear what the overall benefit on your health is. So then people are like, okay, niacin, it's it's a, you know, it's got all these weird side effects. Maybe we can come up with other stuff. So they come up with these other NAD boosters. Um NMN, just the evidence is just really, really not there in humans. There there have been a couple of recent trials that have finally come out in humans. And it was looking at, I think it was a group of 25 older diabetic women. So it was diabetic women over the age of 65. And you and me looking at this as young men, you know, we're thinking this isn't a group that we really fall into. Um and then, you know, so you've always got to remember this when these clinical trials are done, they're often done in this specific group. And that's the right way to do it so you can start to, you know, unpick and understand its effects, but it doesn't always generalize to the whole population. What they found was that NMN supplementation um improved the ability of their muscles to take up glucose, which sounds good, you know, it's going to help potentially with the diabetes. However, um there's there's this this absolute laundry list of other things in the paper that they tested on which it had no effect. So actually a sort of more honest title of the paper would be like 101 things NMN supplementation doesn't do to older diabetic women. Oh, and by the way, it improves their blood glucose. Right. So it's I just feel like this this thing is so, so messy. And there was a there was a trial of a different NAD booster in mice. And one of the problems with mouse studies is they're often quite small and, you know, particular labs have particular quirks. They're also different what are called strains of mice. So mice are different genetics basically. And sometimes the effects vary between these strains. And in the US, there's um this thing called the interventions testing program. This is three labs distributed around the country. They do the biggest mouse trials in three separate laboratories. So if there is a little weird quirk of one particular laboratory, hopefully it'll get averaged out. And they try um giving a whole different range of drugs um to these to these mice. And one of the things they tried was an NAD booster and it had no effect on the mice's lifespan. And of course, it might be the it might be the wrong dose. They might want to, you know, you might want to give it at a different point in life to where they gave it to those mice. But I just really feel like the evidence just isn't there. And there are things that I'm so much more excited about like these senolytics. I'm sort of tempted to, you know, I'm not saying we shouldn't do any research into these things because there is, you know, evidence that it can make a difference. But there are just things that I'm much more excited about than these NAD boosting supplements.

Dr Rupy: Yeah, yeah. Are you excited about any supplements at all that are currently on the market at the moment? Because it's a minefield. I mean, I get asked about all of these all the time. My my general opinion on supplements is, you know, make sure your vitamin D3 is in range, make sure you're taking a B complex if you're vegan. Uh, you know, unless you have uh severe um uh what's the word I'm looking for? Deficiencies in in certain other micronutrients or minerals, then you shouldn't really be supplementing. You should be getting most of it from your food and and focusing on your lifestyle. Are there any any ones that you think that may hold promise if they don't have human evidence at this point?

Dr Andrew Steel: Do you know what? I think I'd just reflect your answer straight back at you. What I've been saying when I haven't been doing a podcast with a doctor is that you should talk to your doctor and find out if you have any deficiencies. And then, you know, beyond that, I don't think there's an awful lot that most, you know, healthy people can do to deal with things. Um, I just I I just don't think the evidence is there. And there's there's sort of there is a so the reason that I say this is these randomized, not just randomized trials, but massive what are called systematic reviews, which is where scientists have gone through and said, let's take every single trial on a subject and pull it all together and do some clever statistics and work out like the absolute best possible answer. And what you find with most vitamin supplements is they have no effect on your risk of death. And in fact, there are a couple that even very slightly increase your risk of death. So there's just there's just really nothing to recommend these things unless, as we said before, you know, you have a specific deficiency. And actually, I think this all sort of dates back to an early theory of why it is we age, which has now basically been debunked. And that theory was that a lot of it was driven by free radicals, which is, you know, something you've probably heard of, a lot of your listeners have probably heard of. They're this they're often what are called reactive oxygen species. So as your mitochondria are generating energy inside the cell, they're dealing with very highly reactive chemicals. And one of those chemicals is obviously the oxygen from the air that we breathe. That's what it's sort of effectively we're burning our food in this oxygen. And sometimes it can fumble one of those oxygens and it can create what's called a reactive oxygen species. And this chemical sort of goes around the cell damaging stuff. It damages proteins, it damages DNA. And it was thought that this damage as it accumulated throughout your life is one of the things that caused the ageing process. And so if these free radicals are what's causing the problem, maybe what you want to do is take a vitamin C supplement, for example. That's an antioxidant. It'll go in, it sort of slurps up these reactive oxygen species without taking damage itself and it saves the rest of your cell. However, what we've since discovered is that reactive oxygen species are actually used by your body. And this shouldn't be a surprise, right? Because life has been dealing with this problem literally for billions of years. So the idea that evolution wouldn't have thought of this and like come up with its own internal solution is is just a bit crazy actually with hindsight. So what we think happens is that I think one of the most exciting um uses of reactive oxygen species is that your immune cells can bombard a bacterium with um reactive oxygen species to kill it basically. And they're also used for signaling. They're just used in loads of different functions around the body because evolution has gone, well, this this is created as an inevitable side effect. I'm going to come up with a use for it. And so if you take vitamin C and slightly reduce the number of reactive oxygen species, what your body probably does is it goes, okay, I'm going to produce some more to compensate for the fact that some of them are being removed. Or I'm going to reduce my own natural antioxidant production and again, in order to, you know, maintain that balance. And maybe even if you take too much of an antioxidant supplement, it's actually going to cause you harm. So I just think that that really simple story, it sounds so obvious that, you know, the food we eat damages our bodies, which goes on to cause our ageing. It's such a simple intuitive sort of tale. And unfortunately, the science has moved on. We've basically shown that doesn't work in the lab. The big trials have shown that these vitamin supplements don't extend people's lifespans. But nonetheless, you know, vitamins, they sound healthy. So a lot of people just carry on taking them even though the evidence just isn't there anymore.

Dr Rupy: Yeah, yeah. I remember talking about a study where they gave um I can't remember if they were athletes or they were trained individuals and they gave them vitamin C after a workout session and actually it blunted the hypertrophic effect on their muscles because the inflammation producing effect of uh exercise is actually something that causes resilience and actually leads to those beneficial outcomes. So if you blunt that inflammation after your exercise, it stands to reason that you're actually blunting the thing that causes the benefits in the long run. So again, it's this kind of it's this paradoxical concept of hormesis where a little bit of harm actually does you some good in the long run. Um that that people don't really get their head around and I think, you know, the convenient explanation of getting rid of all uh reactive oxygen species uh doesn't really hold true in a lot of circumstances.

Dr Andrew Steel: I think that's a really great example. And I think, you know, that's that idea of hormesis just crops up again and again. It's as long as it's only a little bit of harm. I've even seen some studies um that suggest that a little bit of radiation is good for you. Because we typically think of radiation as being a really bad thing, you know, it damages our DNA, it causes all kinds of problems. It's one of, you know, if you get a really big radiation exposure, obviously that can give you radiation sickness, which is terrible. Longer term, it can give you cancer. But maybe the optimal dose of radiation isn't zero. The research is very much still coming in. I'm not suggesting anyone go and sort of get a suntan outside a nuclear power plant or anything like that. But nonetheless, it's clear that um, you know, a little bit of something bad can be good for you.

Dr Rupy: Yeah, that's why I have a little bit of junk food in my diet every week. It's just totally justified by hormesis.

Dr Andrew Steel: Totally, totally.

Dr Rupy: Let's um let's talk on the subject actually because a lot of people who listen to this uh ask me about cold uh therapy as in cold shock therapy. Again, another very sort of trendy thing, whether it impacts brown adipose tissue, whether it impacts your immune system, is it something that people uh at an older age should be doing? Is there is there any evidence for that as a lifestyle hack?

Dr Andrew Steel: I've not seen anything that's really compelled me. Um so I I just I I don't think we really know the answer. And again, the problem is that you need the sort of ideal study until we get these biomarkers of ageing is going to be to give a bunch of 60-year-olds cold shock therapy for 10 years and like see what happens to their overall health. I think the thing that we've got a bit more um exciting evidence on is the other end of the temperature scale, so hot stuff. And actually saunas are quite an interesting example of this. The trouble is again, all these studies are what's called observational. I.e. you ask people how often they go to the sauna and have a look at their health rather than, you know, forcing and there's a sort of the practical and ethical issue of this like, are you going to force people to go to the sauna for 10 years in order to try and get the results of this? But the best studies for saunas come out of Finland. And that's obviously because, you know, Finnish sauna culture is a really integral part of their lives. And what they find is that the people who use the sauna more regularly seem to get less cardiovascular disease. Now, this could be it could be because of the heat. It could be because people who are using the sauna a lot just have a lovely relaxed lifestyle. They've got plenty of time to go down the sauna. It's a very social thing in Finland. So maybe it's just you know, like a destress thing. So it's very, very hard to like tease out cause and effect. And the other big problem with this study, which I found really, really funny, is that in Finland, they didn't have a control group because there is nobody who doesn't use the sauna. So they were like comparing people who use the sauna seven times a week to people who only use it once. And so there wasn't like there wasn't a proper control group. But what they found was, you know, I think it's pretty safe to say it's not bad for your health unless you've got a serious heart condition basically. And actually the the biggest um health problem they found associated with taking the sauna was that the single largest cause of burns admissions in Finnish hospitals is people, you know, burning themselves in the sauna. So I just think this is a it's basically a wonderful study of Finland as a country, but it also makes me a little bit excited that there might be something in the heat therapy side of things.

Dr Rupy: Yeah, yeah, yeah, definitely, yeah. All these different lifestyle hacks don't come out without their hazards, I'm sure. Um so looking at everything, I mean, we talked about senolytics and you talk about a whole bunch of other sort of studies in progress in the book as well. What are you most excited about when it comes to um the field of ageing and and where do you think the science is going to go? I mean, the the prospect of me being able to prescribe an anti-ageing drug is incredible. But I think there are a number of different hurdles to get there before, like actually defining ageing as a disease, for example, something that I don't think I appreciated before this. Um what are you what are you most excited about going forward?

Dr Andrew Steel: I'm actually, and it's this is a funny answer, I'm most excited not by any one thing, but I'm excited by the sheer diversity of approaches we have. And the reason that I sort of it sounds like I'm dodging the question, but the reason I'm not dodging the question by saying that is because if if senolytics were our one sort of dream about our hope, and if they fail, everything fails, that would be really depressing because although I am really excited about senolytics, I think they've got a strong chance, we know from drug development that so many things work fantastically in mice. You know, we've cured cancer in mice hundreds of times and yet often doesn't translate into humans. But what's really cool about this is we've got these 10 hallmarks that I talk about. We've got multiple ideas to treat each hallmark. We've got literally dozens of ways to slow or reverse ageing in the lab. And what that means is we've got dozens of bets. And that means that, you know, we're not relying on any single one of them to succeed. We can be hopeful that, you know, some some subset of those, you know, say we've got five treatments for each hallmark, we've got 50 potential ideas. And if only 10 of those work, that could still vastly increase our lifespan and health span. So we're not betting, you know, we're not putting all our chips on any one particular idea. The other thing that really excites me is that the more of these things that we can develop, the longer we can potentially live, and then the longer we can have for more of these treatments to be developed. So there's this sort of virtuous circle in ageing for once. So the idea being, you know, imagine you're in middle age now, imagine you're trying to optimize your lifestyle, you know, you're exercising, you're eating the right food. And obviously you have to get a bit lucky because, you know, various various things can conspire even if you have the best possible lifestyle. But you can realistically expect to live, you know, say you're in your 40s, you can definitely expect to live into your 80s, probably even your 90s if current life expectancy trends continue. Then imagine we're going to know the results of metformin in the next few years. We're going to potentially know the results of senolytics in the next few years. If you start taking some of those things, you could live a few years longer. And that gives scientists a few more years to develop even more treatments. And so in the book, I talk about stem cell therapy and gene therapy. These are things that, you know, they're definitely not ready for, you know, to be to be handed out to people who are just old. They're being used for specific conditions where, you know, where we know that stem cell loss is a problem or people who have single gene disorders they're called. So, you know, they've got a single gene that's wrong and we can go in and fix it basically. But to, you know, to use that for ageing, you're going to have a much higher bar because some of these single gene disorders, they're awful and there's nothing we can do to treat them. So obviously you're willing to sort of take a punt on something like gene therapy that isn't necessarily 100% ready for like prime time use yet. But we're really, really accelerating in these ideas. And I think they're decades away rather than centuries. You know, if in 20 years time, gene therapy isn't pretty widespread, I will be shocked. And what that means is that we can start to think about some of these, you know, things that sound a bit more sci-fi, they're going to be ready in time for most people alive today, especially if those people alive today can benefit from some of the early sort of simpler, you know, regular drug type therapies that we're developing. So I'm just really excited by this whole constellation of different treatment ideas we've got and the fact that every win that we have gives us more time to make the next win.

Dr Rupy: Yeah, you know, it's it's such an exciting area and it's a it's mind-boggling that it hasn't been given as much attention given, you know, how many issues we've had as a result of ageing. And when I look across the the the different hallmarks of ageing, the 10 different areas, I I always have my sort of diet and lifestyle slant on things, right? So when I look at DNA damage or telomere shortening, I'm thinking about, okay, how do you encourage a lifestyle that is least stressful as possible? How do you introduce mindfulness and meditation and reduce woes and and and worries and all the rest of it? When I look at things like the microbiota, you know, how do we increase the variety of different fibers, increase fruit and vegetable consumption, making sure that you're having adequate protein stores to make sure that you have enough of the substrate to make all the different enzymes, etc, etc. When I think of immune function, I think of the same sort of things, you know, there are so many elements in our lifestyle that can have an impact on the hallmarks of ageing. How much more as a as a as a function of those things on top of like a great uh lifestyle sort of suite of of tools. How much more do you think we'll be able to push lifespan as well as health span with with all the different arenas? I know you don't like to put a number on things, but I'm I'm going to challenge you on that.

Dr Andrew Steel: Yeah, I I think it's really, really hard. And the I mean, the reason is we've not actually obviously tried any of much of this stuff in humans yet. Um if you look at the mice, these mice that we gave senolytics, we gave them senolytics aged effectively 70 in human years. And the mice that were given the senolytic drugs, I think they lived about two months longer than the mice that weren't given the senolytic drugs. That's maybe a few years in human terms, but sometimes effects are a bit bigger in mice than they are in humans. The thing that makes it really, really hard to predict though is, you know, say senolytics are going to give us a few years. That's obviously great, especially if those few years are, you know, without the cancer, without the heart disease, preventing all that stuff in good health. But as exactly as you said earlier, these things are so tightly interacting. So maybe, you know, by improving our uh by getting rid of some of our senescent cells, we'll improve our immune system. And then we'll come up with another treatment that targets, you know, DNA damage. And that will then have another effect, a potentially synergistic effect. I.e. an effect that's greater than the sum of the parts. And the reason that seems optimistic is that I'm optimistic about that happening is there have been experiments in animals where we've made gene changes. So there are lots of genes that we know about in in animals where you can change that gene or delete that gene and it makes the animal live longer. And there are quite a few examples where if you take one longevity gene that adds, you know, say 20% to the lifespan and another longevity gene that adds 20% to the lifespan and make both of those alterations, you then add 70% to the lifespan, which is obviously bigger than 20 plus 20 just to, you know, ram home my point nice and clearly. So I'm really optimistic that by combining these treatments, we can potentially have a much bigger effect. And we haven't even tried combining these things in mice yet. So we just don't have any benchmark. And it's just it's just very hard to say because by changing that mortality risk doubling time, so to go go a bit nerdy and mathematical for a minute, if you reduce your risk of death by a little bit, the fact is that the doubling time is going to catch up with you because as we've seen exponential growth, you know, it starts out small, gets very big, very quickly. If you can change that exponential growth, then suddenly, goodness knows what we're going to do to lifespan. You know, if we can end up with, you know, a risk of death that is only changes by half as much with time, that could have a huge, huge impact. And that's why I just hate putting numbers on these things, not just because I'm a scientist, but because it's really, really hard to predict. And actually, I think my sort of question dodging but exciting answer is, this is going to happen in time for most people alive today. The reason being, senolytics are a few years away. Even if we think about stem cell therapy and gene therapy as being decades away, then, you know, that's still in the lifetime of most people on the planet now. And then, you know, toward the end of the book, I started talking about um what are called systems biology models. And this is getting like proper nerdy where we want to build these massive computer models that show and integrate and understand all those interactions and show us how the human body like different parts of those, you know, different hallmarks talk to each other. That's something we're not even close to being able to do now. But can I really say that we won't be close to doing that in 50 years time? I don't think I can because if you look back over the last 50 years of biomedical innovation, we've, you know, think about computers. And I I looked this up the other day. In 1971, the first 8-inch floppy disk was made commercially available. And yet now, I, you know, it's just hard to hard to grasp like how much computers have come on in that time. So what's that going to look like in 50 years time? So we're going to have so much more data from things like DNA sequencing. We're going to have so much more powerful computers. I think you'd be a fool to bet against these systems biology models being, you know, in existence in five decades time. I'm hoping still to be alive in 50 years. I think a lot of people are hoping still to be alive in 50 years. And as I say, especially if you've taken those senolytics, maybe you've had an early gene therapy, something like that. And what that means is you're going to be around to benefit from those systems biology models. And the computers are going to be much, much cleverer than we are at coming up with clever ways to intervene in ageing. So that's why I just hate putting numbers on this stuff because it's so dependent on what could be incredible revolutions in technology.

Dr Rupy: Yeah, absolutely. I mean, all those, you know, incremental gains, as small as they might be in each field, will compound over over time. And you know, if you if you're having those incremental gains in, you know, different areas of your lifestyle and then combining that with all these different uh areas of um uh biogerontology, it it could be incredible to see how long people live uh uh going forward. And what one of the things that I should ask about actually, I I wanted to ask about this at the start, but um uh is the large majority of the listeners are females aged 35 to 50. Um and I think they'd be very interested in the impact on fertility and actually whether any of these elements have been looked at with regards to prolonging the fertile period. Is that something that we've we've even begged to ask the question of at this point or is this are we quite a long way from that?

Dr Andrew Steel: I think it's a really neglected area actually because I the sort of the very basic principle, as I've sort of highlighted, is that all these hallmarks of ageing affect the whole body. You know, they affect the wrinkles, they affect the gray hair, they affect the cancer, they affect the frailty. The same biological processes are underpinning all of this stuff. And therefore, you know, it stands to reason that they would also affect the fertile window. However, I just don't think there's been enough research done specifically on that. And it's slightly annoys me and I know that I'm a bloke and I'm speaking out of place here, but I feel like this is a bit of a feminist issue because, you know, the fact is that women do have this biological clock that's, you know, ticking much, much faster than men in terms of having kids. And that impacts on their careers, it impacts on their life, it impacts on all kinds of different things. And I really think that, you know, as we as we go forward and as lifespans potentially get quite a lot longer, maybe you are going to want to spend a longer time, you know, developing your career or traveling or whatever it is you want to do as a younger person. And then that means that, you know, we need to extend that time for women to, you know, give them equal opportunity. So yeah, I think that this anti-ageing stuff is actually a feminist issue as well. But unfortunately, like so many areas of women's medicine, you know, it's just been, I think largely neglected. It's something we need to do something about.

Dr Rupy: Yeah, definitely. I spoke I spoke to Lisa Mosconi about this, Dr Lisa Mosconi, um who is an expert in in women's health and looks uh primarily at the brain, um but also menopause as well and estrogen's impact on uh neuroscience, um uh neurology. And um from a personal point of view, you know, I'm 36, a lot of my female friends are similar age, mid 30s. One of my friends is an ENT registrar, so senior registrar. And one of my male uh friends, same age, is now a consultant because he didn't have to take a couple of years out because he wanted to have children. His wife had children and then and, you know, he was able to progress through his medical career and become a consultant earlier than my my other friend who's had to take time out. Now, I'm not to say that, you know, she's uh a massive um disadvantage because of that, that was her choice to do. But had the fertile period, if we were able to extend the fertile period until much later on in life, would she have made the same decision? Maybe not. Um who knows? And I think given that we are living in ever um uh you know, a world where there is ever increasing opportunity for both genders, this is something that it could it could definitely have an impact on.

Dr Andrew Steel: I think it's really important. And actually one of the things that I've um one of the things I get asked most often when I talk about curing ageing, actually, you know, back when back when I used to go to dinner parties and weddings, and I guess that's going to be safe again. I might I might actually see some other human beings again soon. But back in those days, you know, when I said I'm writing a book on ageing, the first question I normally got was not, you know, how do I extend my lifespan? When are these drugs coming? You know, what can I do, etc, etc. It was what about overpopulation? Because I think a lot of people just imagine there are loads more people living longer, it's going to put huge strain on the planet. Um that's a whole podcast in itself. And actually, I think that the worries about it are, you know, the the point is that actually on the other side of the balance sheet, you've got ageing. You've got this thing that causes two-thirds of deaths in the world and causes billions of people to suffer over decades as they gradually deteriorate with these diseases. That's sort of another discussion. The reason I wanted to bring it up is um there's this there's this other control on population that we don't often talk about, which is birth rates. And birth rates are going down all around the world. And actually, if we extended that fertile window, we know that women are choosing to have children later and later in societies where they've got the option. So actually extending that fertile window could also help with population as well. So it's just it's such a multifaceted thing. I just think it's so shameful that we don't put more research effort into that. And I really hope that's something that's going to change.

Dr Rupy: Yeah, for sure, for sure. Absolutely. And you know, I think people look at ageing research in the same way they might look at um you know, rockets and uh and and space technology and think, oh well, that's just a narcissistic endeavor. Actually, you know, there's a whole bunch of different uh elements of science that could be repurposed into other um uh arenas, whether it be looking at hunger, whether it be mapping, climate change, whether, you know, all these different applications of that technology, but people people like to see it in their sort of uh narrow window. And I think we need to widen the perspective as it pertains to ageing because yeah, you know, it's a massive feminist issue uh as well as many more that we haven't had a chance to talk about today.

Dr Andrew Steel: Yeah. Yeah, yeah, definitely.

Dr Rupy: Mate, you're you're a fantastic uh science communicator. Um honestly, and your your YouTube channel is brilliant and I can't wait for for more videos for you to to put on there as well.

Dr Andrew Steel: Oh, thank you very much. Yeah, it's something I'm trying to develop in my in my massive amounts of free time.

Dr Rupy: Yeah, exactly. Yeah. I mean, writing books and what's your day-to-day now? What what what does it looking like?

Dr Andrew Steel: Oh, well, so the book came out in the UK um at the end of 2020, so in December 2020. And it came out in the US in March of this year, 2021. And it's been a bit of an endless publicity treadmill for that time. So just as the UK was dying down, the US sort of flared up. And you know, this is we're finally at a stage where things are starting to peter out a little bit and I am having a bit of time to do YouTube videos and other stuff. Nice. Um I've just so I've just submitted the corrections for the paperback version of the book. There are a few little tweaks I've made because that's coming out at the at the beginning of next year. So it's just there's so, so much stuff. Um I guess I'm sort of thinking in the back of my mind about the next book, what that's going to be about. Um and trying to do a few more YouTube videos. Um there's a bit of a discussion about a TV thing spinning off from the book. So I'm really hoping that's going to come to something. But it's just it's just incredible. You know, I I was a I was a full-time scientist before I started writing, then I got this book deal. And it just so happened, I just finished writing a paper. I was coming to the end of what's called the post-doc, so the post-doctoral research that I was doing. And me and my boss just said, you know, basically, you've finished one project, you might as well just, you know, quit and do the book full-time. And I am so glad I did because like it took me two years full-time to write this book. There's so much research involved. There's literally like 400 references in the back. And that's only half the papers I read. So it's just absolutely incredible. The and I you know, I think my mistake, if I can be said to have made a mistake, is to choose a subject that touches on literally every aspect of our biology. And I really wanted to get the research solid because what the most important thing I want people to take away from the book isn't necessarily to know like know every single thing about the nitty-gritty of how the mitochondria or the DNA damage or whatever it is affects ageing. I really want, you know, everyone, whether that's, you know, people on the street, whether it's doctors, whether it's biologists, whether it's politicians who are controlling the purse strings for funding of this kind of research, to come away and think, this is legit science. There are all these references. This this is actually something that's not sci-fi. It's genuinely happening in labs around the world now. So, yeah, that's the reason it took me two years full-time to write it because I wanted it to be absolutely solid. And writing a book, you know, it takes a while. Who knew?

Dr Rupy: Yeah. Yeah. Absolutely. Well, if the quality of your YouTube videos is anything to go by, your TV series is going to be awesome. And I think it will definitely uh absolutely catapult the field of ageing research leaps forward. So I hope that happens. Uh and I hope it's on Netflix or something like that.

Dr Andrew Steel: Me too.