[Transcript:] We are constantly being bombarded with health and lifestyle advice at the moment. I feel like I cannot open my social media feeds without seeing adverts for supplements or diet plans or exercise regimes. And I think that this really is a distraction from the big goals of longevity science. This is a really difficult needle to thread when it comes to talking about this stuff because I'm a huge advocate for public health. I think if we could help people eat better, if we could help 'em do more exercise, if we could help 'em quit smoking, this would have enormous effects on our health, on our economies all around the world. But this sort of micro-optimization, these three-hour long health podcasts that people are digesting on a daily basis these days, I think we're really majoring in the minors. We're trying to absolutely eke out every last single thing when it comes to living healthily. And I think the problem is that there are real limits to what we can do with health advice.
So for example, there was a study that came out recently that was all over my social media feeds. And the headline was that by eating the best possible diet, you can double your chance of aging healthily. But I decided to dig into the results table. The healthiest diet was something called the Alternative Healthy Eating Index or AHEI. And even the people who are sticking most closely to this best diet, according to this study, the top 20% of adherence to the AHEI, only 13.6% of them made it to 70 years old without any chronic diseases. That means that over 85% of the people sticking to the best diet, according to this study, got to the age of 70 with at least something wrong with them. And that shows us that optimizing diet only has so far it can go.
We're not talking about immortality or living to 120 here. If you wanna be 70 years old and in good enough health to play with your grandkids, I cannot guarantee that you can do that no matter how good your diet is. And that's why we need longevity medicine to help keep people healthier for longer. And actually, I think even this idea of 120, 150-year-old lifespans, you know, immortality even as a word that's often thrown around, I think the main thing we're trying to do is get people to 80, 90 years old in good health. 'cause we already know that most people alive today, when they reach that age, are unfortunately gonna be frail. They're probably gonna be suffering from two or three or four different diseases simultaneously. And what we wanna do is try and keep people healthier for longer. And by doing that, they probably will live longer but kind of as a side effect.
If you look at photographs of people from the past, they often look older than people in the present day who are the same age. And part of these are these terrible fashion choices that people made in the past. And we can look back and, you know, understand the mistakes they've made with hindsight. But part of that actually is aging biology. I think the fact that people can be different biological ages at the same chronological ages, something that's really quite intuitive. All of us know people who've waltzed into their 60s looking great and, you know, basically as fit as someone in their 40s or 50s. And we know similar people who have also gone into their 60s, but they're looking haggard, they've got multiple different diseases, they're already struggling through life.
In the last decade, scientists have come up with various measures of what's called biological age as distinct from chronological age. So your chronological age is just how many candles there are on your birthday cake. And obviously, you know, most of us are familiar with that. But the idea of biological age is to look inside your cells, look inside your body, and work out how old you are on a biological level. Now we aren't perfect at doing this yet, but we do have a variety of different measures. We can use blood tests, we can use what are called epigenetic tests, or we can do things that are far more sort of basic and functional, how strong your grip is declines with age. And by comparing the value of something like your grip strength to an average person of a given age, we can assign you a biological age value. And I think the ones that are getting the most buzz at the moment within the scientific community, but also all around the internet, are these epigenetic age tests.
So the way that this works is that you'll take a blood test or a saliva sample and scientists will measure something about your epigenome. So the genome is your DNA, it's the instruction manual of life. And the epigenome is a layer of chemistry that sits on top of your genome. If you think of your DNA is that instruction manual, then the epigenome is the notes in the margin. It's the little sticky notes that have been stuck on the side and they tell the cell which DNA to use at which particular time. And we know that there are changes to this epigenome as you get older. And so by measuring the changes in the epigenome, you can assign someone a biological age.
At the moment, these epigene clocks are a really great research tool. They're really deepening our understanding of biological aging in the lab. I think the problem with these tests as applied to individuals is we don't know enough about exactly what they're telling us. We don't know what these individual changes in epigenetic marks mean. We know they're correlated with age, but what we don't know is if they're causally related. And in particular, we don't know if you intervene, if you make a change in your lifestyle, if you start taking a certain supplement and that reduces your biological age. We don't know whether that actually means you're gonna dilate or whether it means you're gonna stay healthier for longer or whether you've done something that's kind of adjacent to that. And so we need to do more research to understand if we can causally impact these epigenetic measures. (...)
Machine learning and artificial intelligence are gonna be hugely, hugely important in understanding the biology of aging. Because the body is such a complicated system that in order to really understand it, we're gonna need these vast computer models to try and decode the data for us. The challenge is that what machine learning can do at the moment is it can identify correlations. So it can identify things that are associated with aging, but it can't necessarily tell us what's causing something else. So for example, in the case of these epigenetic clocks, the parts of the epigenome that change with age have been identified because they correlate. But what we don't know is if you intervene in any one of these individual epigenetic marks, if you move it in the direction of something younger, does that actually make people healthier? And so what we need to do is more experiments where we try and work out if we can intervene in these epigenetic, in these biological clocks, can we make people live healthier for longer?
Over the last 10 or 15 years, scientists have really started to understand the fundamental underlying biology of the aging process. And they broke this down into 12 what are called hallmarks of aging. One of those hallmarks is the accumulation of senescent cells. Now senescent is just a biological technical term for old. These are cells that accumulate in all of our bodies as the years go by. And scientists have noticed that these cells seem to drive a range of different diseases as we get older. And so the idea was what if we could remove these cells and leave the rest of the cells of the body intact? Could that slow down or even partially reverse the aging process? And scientists identified drugs called it senolytic drugs.
These are drugs that kill those senescent cells and they tried them out in mice and they do indeed effectively make the mice biologically younger. So if you give mice a course of senolytic drugs, it removes those senescent cells from their body. And firstly, it makes them live a bit longer. That's a good thing if you're slowing down the aging process, the basic thing you want to see. But it's not dragging out that period of frailty at the end of life. It's keeping the mice healthier for longer so they get less cancer, they get less heart disease, they get fewer cataracts. The mice are also less frail. They basically send the mice to a tiny mouse-scale gym in these experiments. And the mice that have been given the drugs, they can run further and faster on the mousey treadmills that they try them out on.
It also seems to reverse some of the cognitive effects that come along with aging. So if you put an older mouse in a maze, it's often a bit anxious, doesn't really want to explore. Whereas a younger mouse is desperate to, you know, run around and find the cheese or whatever it is mice doing in mazes. And by giving them these senolytic drugs, you can unlock some of that youthful curiosity. And finally, these mice just look great. You do not need to be an expert mouse biologist to see which one has had the pills and which one hasn't. They've got thicker fur. They've got plumper skin. They've got brighter eyes. They've got less fat on their bodies. And what this shows us is that by targeting the fundamental processes of aging, by identifying something like senescent cells that drives a whole range of age-related problems, we can hit much perhaps even all of the aging process with a single treatment.
Senescent cells are, of course, only one of these 12 hallmarks of aging. And I think in order to both understand and treat the aging process, we're potentially gonna only treatments for many, perhaps even all of those hallmarks. There's never gonna be a single magic pill that can just make you live forever. Aging is much, much more complicated than that. But by understanding this relatively short list of underlying processes, maybe we can come up with 12, 20 different treatments that can have a really big effect on how long we live.
One of the most exciting ideas in longevity science at the moment is what's called cellular reprogramming. I sometimes describe this as a treatment that has fallen through a wormhole from the future. This is the idea that we can reset the biological clock inside of our cells. And the idea first came about in the mid 2000s because there was a scientist called Shinya Yamanaka who was trying to find out how to turn regular adult body cells all the way back to the very beginning of their biological existence. And Yamanaka and his team were able to identify four genes that you could insert into a cell and turn back that biological clock.
Now, he was interested in this from the point of view of creating stem cells, a cell that can create any other kind of cell in the body, which we might be able to use for tissue repair in future. But scientists also noticed, as well as turning back the developmental clock on these cells, it also turns back the aging clock, cells that are given these four Yamanaka factors actually are biologically younger than cells that haven't had the treatment. And so what scientists decided to do was insert these Yamanaka factor genes into mice.
Now if you do this in a naive way, so there's genes active all the time, it's actually very bad news for the mice, unfortunately. because these stem cells, although they're very powerful in terms of what kind of cell they can become, they are useless at being a liver cell or being a heart cell. And so the mice very quickly died of organ failure. But if you activate these genes only transiently, and the way that scientists did it the first time successfully was essentially to activate them at weekends. So they produced these genes in such a way that they could be activated with the drug and they gave the mice the drug for two days of the week, and then gave them five days off so the Yamanaka factors were then suppressed. They found that this was enough to turn back the biological clock in those cells, but without turning back the developmental clock and turn them into these stem cells. And that meant the mice stayed a little bit healthier. We now know that they can live a little bit longer with this treatment too.
Now the real challenge is that this is a gene therapy treatment. It involves delivering four different genes to every single cell in your body. The question is can we, with our puny 2020s biotechnology, make this into a viable treatment, a pill even, that we can actually use in human beings? I really think this idea of cellular reprogramming appeals to a particular tech billionaire sort of mentality. The idea that we can go in and edit the code of life and reprogram our biological age, it's a hugely powerful concept. And if this works, the fact that you can turn back the biological clock all the way to zero, this really is a very, very cool idea. And that's what's led various different billionaires from the Bay Area to invest huge, huge amounts of money in this.
Altos Labs is the biggest so-called startup in this space. And I wouldn't really call it a startup 'cause it's got funding of $3 billion from amongst other people, Jeff Bezos, the founder of Amazon. Now I'm very excited about this because I think $3 billion is enough to have a good go and see if we can turn this into a viable human treatment. My only concern is that epigenetics is only one of those hallmarks of aging. And so it might be the case that we solve aging inside our individual cells, but we leave other parts of the aging process intact. (...)
Probably the quickest short-term wins in longevity science are going to be repurposed existing drugs. And the reason for this is because we spent many, many years developing these drugs. We understand how they work in humans. We understand a bit about their safety profile. And because these molecules already exist, we've just tried them out in mice, in, you know, various organisms in the lab and found that a subset of them do indeed slow down the aging process. The first trial of a longevity drug that was proposed in humans was for a drug called metformin, which is a pre-existing drug that we prescribe actually for diabetes in this case, and has some indications that it might slow down the aging process in people. (...)
I think one of the ones that's got the most buzz around it at the moment is a drug called rapamycin. This is a drug that's been given for organ transplants. It's sometimes used to coat stents, which these little things that you stick in the arteries around your heart to expand them if you've got a contraction of those arteries that's restricting the blood supply. But we also know from experiments in the lab that can make all kinds of different organisms live longer, everything from single-cell yeast, to worms, to flies, to mice, to marmoset, which are primates. They're very, very evolutionarily close to us as one of the latest results.
Rapamycin has this really incredible story. It was first isolated in bacteria from a soil sample from Easter Island, which is known as Rapa Nui in the local Polynesians. That's where the drug gets its name. And when it was first isolated, it was discovered to be antifungal. It could stop fungal cells from growing. So that was what we thought we'd use it for initially. But when the scientists started playing around with in the lab, they realized it didn't just stop fungal cells from growing. It also stopped many other kinds of cells as well, things like up to and including human cells. And so the slight disadvantage was that if you used it as an antifungal agent, it would also stop your immune cells from being able to divide, which is obviously be a bit of a sort of counterintuitive way to try and treat a fungal disease. So scientists decided to use it as an immune suppressant. It can stop your immune system from going haywire when you get an organ transplant, for example, and rejecting that new organ.
It is also developed as an anti-cancer drug. So if it can stop cells dividing or cancer as cells dividing out of control. But the way that rapamycin works is it targets a fundamental central component of cellular metabolism. And we noticed that that seemed to be very, very important in the aging process. And so by tamping it down by less than you would do in a patient where you're trying to suppress their immune system, you can actually rather than stopping the cell dividing entirely, you can make it enter a state where it's much more efficient in its use of resources. It starts this process called autophagy, which is Greek for self-eating, autophagy. And that means it consumes old damaged proteins, and then recycles them into fresh new ones. And that actually is a critical process in slowing down aging, biologically speaking. And in 2009, we found out for the first time that by giving it to mice late in life, you could actually extend their remaining lifespan. They live by 10 or 15% longer. And this was a really incredible result.
This was the first time a drug had been shown to slow down aging in mammals. And accordingly, scientists have become very, very excited about it. And we've now tried it in loads of different contexts and loads of different animals and loads of different organisms at loads of different times in life. You can even wait until very late in a mouse lifespan to give it rapamycin and you still see most of that same lifespan extension effect. And that's fantastic news potentially for us humans because not all of us, unfortunately, can start taking a drug from birth 'cause most of us were born quite a long time ago. But rapamycin still works even if you give it to mice who are the equivalent of 60 or 70 years old in human terms. And that means that for those of us who are already aged a little bit, Rapamycin could still help us potentially. And there are already biohackers out there trying this out for themselves, hopefully with the help of a doctor to make sure that they're doing everything as safely as possible to try and extend their healthy life. And so the question is: should we do a human trial of rapamycin to find out if it can slow down the aging process in people as well? (...)
We've already got dozens of ideas in the lab for ways to slow down, maybe even reverse the age of things like mice and cells in a dish. And that means we've got a lot of shots on goal. I think it'll be wildly unlucky if none of the things that slow down aging in the lab actually translate to human beings. That doesn't mean that most of them will work, probably most of them won't, but we only need one or two of them to succeed and really make a big difference. And I think a great example of this is GLP-1 drugs, the ozempics, the things that are allowing people to suddenly lose a huge amount of weight. We've been looking for decades for these weight loss drugs, and now we finally found them. It's shown that these breakthroughs are possible, they can come out of left field. And all we need to do in some cases is a human trial to find out if these drugs actually work in people.
And what that means is that, you know, the average person on planet earth is under the age of 40. They've probably got 40 or 50 years of life expectancy left depending on the country that they live in. And that's an awful lot of time for science to happen. And if then in the next 5 or 10 years, we do put funding toward these human trials, we might have those first longevity drugs that might make you live one or two or five years longer. And that gives scientists even more time to develop the next treatment. And if we think about some more advanced treatments, not just drugs, things like stem cell therapy or gene therapy, those things can sound pretty sci-fi. But actually, we know that these things are already being deployed in hospitals and clinics around the world. They're being deployed for specific serious diseases, for example, where we know that a single gene can be a problem and we can go in and fix that gene and give a child a much better chance at a long, healthy life.
But as we learn how these technologies work in the context of these serious diseases, we're gonna learn how to make them effective. And most importantly, we're gonna learn how to make them safe. And so we could imagine doing longevity gene edits in human beings, perhaps not in the next five years, but I think it'll be foolish to bet against it happening in the next 20 years, for example.
Image: Yamanka factors via: [ed. See also:
Researchers Are Using A.I. to Decode the Human Genome (NYT).]
