In his talk at Ending Age-Related Diseases 2021, João Pedro de Magalhães discussed the difference between longevity and rejuvenation along with the need for more ambitious research.
I think it’s a very exciting time to be working on longevity. I prepared a slightly different presentation like I did two years ago when I was in New York for the last in-person conference. On this topic, I’d like to bounce a couple of different ideas and thoughts, which I’ll do again today, but first, let me tell you a little bit more about my background, which is not on my bio, which is why I work on aging.
I’ve never made it a secret. I do mention it on my personal website. Basically, I’m sure you’re aware, but you probably don’t like to think about it, we are all going to die, and if we don’t do something about aging, it is going to be fairly soon, I would argue, from a cosmological perspective.
Back when I was a child, I realized this. I realized everybody ages and dies, and I figured I’ll do something about aging, I will find a cure for aging, just like we can find cures against diseases like infectious diseases, and we have antibiotics that can cure diseases that we couldn’t treat not that long ago.
I will fix aging. That’s what I’m going to do in my career. It’s not about just money or other goals. My goal is to find a cure for aging. That’s why I became interested in the topic, and I’m not the only one. I think Allison mentioned a similar story in your interview earlier today.
That’s the goal, and, of course, things have advanced a lot in the past few decades. We know, in particular, that aging can be retarded; actually, we’ve known that aging can be retarded for quite a long time. From the perspective of caloric restriction in particular, we know that we can retard, delay aging in mammals, specifically in rodents, by caloric restriction, so that’s been known at least 80 years. We know that aging can be retarded.
You see there a plot of rats that are ad libitum and caloric restriction; there is a significant difference. It varies between strains. You can see an increase in lifespan of 50% in some strains, and it retards the process of aging, delays age-related diseases.
We also know that aging can be manipulated; it can be retarded genetically in model systems like worms, flies, and mice. Lorna mentioned this a little bit earlier today in her talk. Thanks to the work of pioneers like Cynthia Kenyon and Calico, we know you can tweak genes and significantly extend lifespan in animal models, which is, again, quite remarkable.
Likewise, we now know of drugs that can retard aging in animals. We’ve heard a bit about rapamycin already and metformin. I’m sure this audience is familiar with these developments. We know that there are longevity drugs that, at least in animal models, they can retard aging, they can extend lifespan.
The only thing that’s important to mention here, to emphasize, is that the benefits, the longevity effects, are relatively modest when compared to other interventions like caloric restriction or genetic manipulations in particular. Rapamycin extends lifespan like 10, 15%, depending on males or females. Metformin, I believe it’s less than that.
We have many ways of extending lifespan with pharmacological approaches, but effects are smaller than what you see with,for example, genetic manipulations. There’s lots of interest in longevity biotechnology.
This is a plot from our DrugAge database of aging-related drugs. As you can see, there’s an exponential increase in the number of drugs associated with longevity. There’s lots of interest in it, because if we’re going to translate findings from model systems to humans, we cannot, at least not yet, do genetic manipulations; we have to do pharmacological approaches; it’s the low-hanging fruit that Aubrey alluded to earlier on.
There are some difficulties. I’m very excited personally about longevity drugs. There’s challenges. Peter made the point that humans are not mice, or worms, or flies, or yeast for that matter.
There is a gap of translating discoveries between animal models and humans, not just in aging, but I would say in biomedical research in general and for many diseases, so that’s a challenge that we are aware of. Not everything we discover in animal models is going to pan out in humans, but possibly something will.
I’m relatively optimistic in that sense. I know not everything is going to work in humans, but some things are going to work in humans. If they do, and they retard aging in humans, then that’s going to be a tremendous benefit. Of course, there’s tremendous financial benefits as well, and that’s why we have this fast growth in longevity biotech, in the longevity industry.
There’s a lot of companies now focusing on it; we’ve heard from Jacob from Calico already. There is rapid growth in the longevity industry, because investors, a lot of even bigger companies, they think that they’re going to make money out of the longevity field.
I think it’s probably right; a lot of companies are going to fail, but some of them will succeed, and they will make a lot of money. I do think that longevity biotech, in general, has a bright future ahead, we’ll be able to retard aging. Having said that, there is a problem at least going back to that child; that’s a photo of me when I was a child doing my homework on top of the dinner table.
It’s that longevity drugs are not really a cure. They will extend lifespan, and if we could extend lifespan in humans like 5% by retarding aging, we would already have tremendous benefits, medical, health, social, and economic benefits, but there’s not really a cure for aging. Even if we develop longevity drugs, we’re still facing death and eternal oblivion.
In my book, at least, that counts as a failure; that means I’m still going to die. We need to figure out other ways of intervening. That’s why, in addition to looking at retarding aging and longevity drugs, there’s also this emerging field of rejuvenation.
What about rejuvenation therapies and approaches? It’s not so new. People have been talking about rejuvenation for quite a long time. Here’s a photo of me when I was at university, and back when I was at university, I bought this book from Michael Fossel called Reversing Human Aging that promised that science perhaps discovered the true fountain of youth that would make you younger and keep you that way, halt cancer, heart disease, Alzheimer’s, and stroke, change life as we know it. The book was published, I checked, in 1997. I’m not entirely sure that’s when I bought it, but that’ll tell you a little bit about my age as well.
The book focuses on one discovery that happened in the late 90s, and that’s the discovery of telomerase, the enzyme that repairs, elongates the telomeres and allows cells to evade cellular replicative senescence; we can immortalize cells. I did actually do my PhD in cell senescence. It’s interesting for a variety of reasons, but I’ll just focus on a couple of them.
First of all is the complex process. These are photos of young fibroblasts and senescent fibroblasts, and there’s a lot of changes between young fibroblasts to senescent fibroblasts. People used to think that there was a stochastic process behind that. It turns out that no, actually, in human fibroblasts, in essence, it’s a very clear timekeeper, which is telomeres. Telomeres shorten with cell division, and that triggers replicative senescence. It’s a very simple driver to a complex process, a complex phenotype.
Of course, telomerase elongates the telomeres, and prevents replicative senescence, and immortalizes human fibroblasts, human cells. That’s a quite remarkable discovery in itself, and it received a Nobel Prize.
What about aging of organisms? The point is that, of course, immortalizing cells is very different from immortalizing organisms. Although we can immortalize human cells, we cannot really do it; as I mentioned, changing genes in humans is not really that practical at the moment.
We can do these experiments in mice, we can activate, we can have mice with lots of telomerase. Without digging into a long literature, this doesn’t really immortalize animals. In fact, it doesn’t really even extend their longevity.
There’s one paper by Maria Blasco and colleagues suggesting that gene therapy of telomerase extends lifespan in mice, but to my knowledge, that’ss never been replicated, so I take it with a grain of salt. The point is, and this is a paper review I published several years ago, but I stand by its conclusions, is that telomeres and telomerase are not really a fountain of youth.
By and large, this really has not panned out the way Michael Fossel’s book in 1997 promised. That’s what happened in the past. There’s a couple of other caveats, a side note I would like to mention: improved function is not necessarily rejuvenation. You can be healthier, you can have better functional outcomes, and not necessarily be rejuvenated.
I’ll show you actually one example of people who underwent, I wouldn’t say therapies, but they underwent changes that reduces their chances of diseases, it retards all kinds of diseases, it increases their life expectancy, it increases their function, and yet did not rejuvenate.
These are people that went on exercise. Particularly overweight men and women that went on exercise regimens, which is healthy, of course; for them, that’s great. If you’re overweight, you should exercise. That’s not going to make you younger, that’s not going to rejuvenate you, but it’s going to make you healthier, and by chance, it’s going to allow you to live longer, it’s going to reduce your chance of developing diseases, but it’s not rejuvenation.
The reason I mention this is that we do see a lot of hype around rejuvenation. Around longevity as well, which is something I believe Aubrey touched upon as well. It’s a bit of a gray area; there’s a fine line between it, but there’s a lot of studies that they do something to mice, and the mice show some functional improvements, and they say, “We rejuvenated the animal.”
That’s not necessarily true. You’ve just made the animal healthier or improved its function, but that’s not necessarily rejuvenation. Extraordinary claims require extraordinary evidence. If you’re claiming rejuvenation, you need to really show that that’s what you are achieving.
The other caveat in this context is that there are differences between short- and long-term effects. I’ll show you one example from historical biogerontology, which is growth hormone. We’ve known for quite a long time, from the past century, that the levels of growth hormone decline in human beings.
This is levels of growth hormone with age in humans, and they decline. Therefore, there were therapies with growth hormone. Growth hormone can have benefits, it can improve your function, it can have short-term benefits, it can increase muscle mass, immune function, it can increase libido, so we can have short-term health benefits.
Again, it doesn’t mean that it is rejuvenating. In fact, it’s probably not even good for longevity. We know, for example, from many studies in mice, that mice with low levels of growth hormone signaling, they actually live longer. What you see here are actually two mice of the same age. The small mouse is a dwarf mouse, which has low levels of growth hormone signaling, and it’s actually going to be long-lived, it’s going to live significantly longer than its counterpart that’s wild type and has normal growth hormone signaling.
There’s some data from Andrew Bardikay suggesting that growth hormone can even accelerate mouse aging, so if you have high, very high levels of growth hormone, these may even accelerate mouse aging. The details are not important. The point is that you can have short-term health and functional benefits from an intervention that, in the long term, becomes detrimental.
Again, it’s important to consider that from the perspective of extraordinary claims require extraordinary evidence. That’s why I have some skepticism about a lot of advances that are touted as rejuvenation.
There is one intervention has been talked about, which is cell reprogramming. Yamanaka factors induce pluripotency as a way of rejuvenating cells. At the cell level, that does appear to rejuvenate cells. I think that there’s abundant evidence for that. This is a slide or two from a paper from the Ocampo lab in Switzerland. Daniel before me talked a lot about this; Jacob from Calico as well, so we’ve heard quite a lot.
Cell reprogramming can rejuvenate cells, I do think there’s quite abundant evidence for that; it resets the epigenetic clock from Steve Horvath, and so on. It does rejuvenate cells. The question is, what happens in cells is not necessarily what happens in organisms. They’re quite different. Rejuvenating cells and rejuvenating an organism, they’re different things; just like for telomerase, we had immortalized cells in a petri dish, that doesn’t mean that we have immortalized organisms; quite different.
The jury’s still out. We heard previous speakers talk about the experiments from Alejandro Campo in progeroid mice, which seemed promising, but it’s a progerized, it’s accelerated, very short-lived mouse model. I would take it with a with a grain of salt.
It is still an open question whether cell reprogramming could rejuvenate organisms in the same way you rejuvenate cells. I think it’s still an open question; maybe it will, that would be fantastic. Maybe it will be like telomerase that works at the cell level but doesn’t quite work the same way on an organismal level.
Even other methods for rejuvenation are very interesting. The talk by Jacob on how we’ve known for decades, it’s the work of Gurdon, that you can go back in biological time, for example, with cloning. That, from a conceptual perspective, opens the door to developing artificial methods of of rejuvenation.
In theory, it is possible, but there’s still a lot of way to go. From a practical perspective, it may turn out not to be possible. We don’t know, but we still need to do those experiments, of course.
There’s been a lot of advances in longevity, in particular at the genetic, dietary, and pharmacological levels, there’s been a lot of advances in retarding age-related diseases, and retarding the process of aging. We’ve known for decades about that, and there’s been a lot of advances.
That’s great. I don’t think longevity and rejuvenation are mutually exclusive, I think we need both of them in the field, but in order to prevent us from dying, we need much more than longevity interventions, we need rejuvenation interventions.
There’s a couple of problems in moving in that direction. The first problem is that we have a poor mechanistic understanding of aging. In my talk in well, in New York, in the last Ending Age-Related Diseases conference, I mentioned a slide on how I was quite skeptical about the hallmarks of aging.
In the past two years, and in cooperation with David Gems in London, we expanded on that. We’ve just published a perspective in Ageing Research Reviews a critique of the Hallmarks of Aging as a paradigm.
Our argument is that the Hallmarks of Aging are excellent as a review, I think they’re excellent as an introduction to aging, but they do not necessarily explain aging. They are not the Holy Grail or the commandments of aging that some people assume they are, they are a hypothesis and they could be completely wrong.
We have the example of telomerase. If you look at the older literature, people used to argue that there was a lot of mechanisms in cellular senescence, lots of things going on; the mitochondria will change, this will change, lots of mechanisms. It’s not that, actually; it’s just one thing, which is telomerase, telomere shortening, and that is the driver of cellular senescence in human fibroblasts. There’s nothing else to it. There may be in another cell perhaps, but in human fibroblasts, that’s it.
The point is that what we think we know about mechanisms of aging could be completely wrong, and that includes the Hallmarks of Aging. That includes from a mechanistic understanding of aging, that implies having an open mind to it but also be skeptical about what we think we know.
That is a problem if we want to intervene in aging, in particular if we want to rejuvenate ourselves. The other problem or another problem that already picked up as well is that science funding is quite conservative.
Investors in the private sector, they’re looking for a return of investments. They’re looking to make money out of an investment. Therefore, they’re going to look for a low-hanging fruit. Which is not necessarily from a rejuvenation perspective what we want; we want to have more long-term thinking.
Likewise, I’m mostly in academicals, although I’m also working for a company at the moment, as I’ll mention in a minute or two. Academia’s also quite conservative, in the sense that grant funding bodies tend to be very risk adverse.
I have a couple minutes; I’ll tell you a quick story. More than a year ago, I applied for a grant for UK government funding. The grant was about applying machine learning to predict drug combinations in the context of longevity, to predict if you combine two drugs that extend lifespan, whether they’re going to have synergistic, antagonistic, or neutral effects, which I think is quite interesting.
We know a lot of longevity drugs, but we don’t know how they work together. If we can find combinations, they’re going to be synergistic. That got funded. That’s great. The project was supposed to start already, but there’s been some delays because of COVID. We’re now actually recruiting someone to work on that project. We should begin as soon as we can recruit someone to work on it.
That’s great, but at about the same time, we applied for another grant looking at cell reprogramming. The idea was, can we identify factors that allow us to rejuvenate cells without the differentiation? That was rejected because they thought it was too risky. Ambitious, but too risky to do that.
I don’t have a track record of working on cell reprogramming, so it was rejected. The money between the two was pretty much the same or similar. If I had a choice, I would prefer to do the cell reprogramming project. It’s riskier, but I think it’s much more ambitious. That’s what I would like to do.
Unfortunately, as an academic, I’m limited to what I can get funding for my lab, and even though I’ve been pretty successful in getting grant funding, it’s not necessarily to what I think are the most exciting projects. Most projects I tend to be more excited about tend to be rejected by grant funding bodies, because they’re much more conservative and they’re risk adverse.
That is a problem in academia. Even if I would like to do more ambitious, more risky research in my lab, I’m still restricted by what I can get funding for. Anyway, that’s one of the limitations I think we have in academia. The point is that science funding is conservative, and that prevents the more risky approaches.
Having said that, I am also now working for a company, Centaura. I’m the CSO of Centaura since last year, it’s going to be one year very soon, actually, which focuses on reversing aging. I can tell you, it’s in the public domain, that one of the technologies we’re developing is human artificial chromosomes, which is actually something I was thinking about when I was a student as a way of reversing aging.
I think that’s quite exciting. Of course, it may fail completely, but if it works, it would give us a tool in which we could much more powerfully intervene in aging. That’s what attracted me to take on this role, really this prospect of having a powerful technology to not just slow down aging but potentially reverse aging. You can find more information on our website.
The last point I will make is that in terms of hype, how much do we want? I mean, from a PR perspective, how should we place the field, which is something I’ve been trying to, to raise awareness about longevity and aging for for over 20 years now, actually. I do think we do need a narrative, we need some sort of storytelling that is ambitious, and if you look at other fields, they do so as well.
Alzheimer’s, cancer, all the institutions, charities, or, foundations, or even government initiatives working on diseases, they want to find a cure. They don’t just want to slow down Alzheimer’s, the ultimate goal is to find a cure. I think that’s fine. I think saying that we want to cure aging is fine. I know aging is somewhat more controversial, but that’s something we have to address.
It is fine to say in the long term, we want to find a cure, and I don’t see that there’s any problems with it. Sure, in terms of what we’re discovering so far, we’re quite far from that point, but having that long term ambition, it’s something that the field needs.
In summary, I’ve told you from a longevity perspective, there’s very fast growth, we can retard aging in animals in many different ways. Dietary, we’ve known for decades, pharmacological approaches, genetic approaches, there’s many different ways of retarding aging, and that’s very exciting.
I think the longevity field is really expanding a lot since I started a little over 20 years ago. Many more scientists, bigger companies focusing, many more startups and longevity companies. I think that’s fantastic.
Rejuvenation, however, I think it’s much harder. Longevity or retarding aging, we can only do so much in terms of animal models. Rejuvenation is much harder for a variety of reasons, including, I think, a lack of mechanistic understanding of aging. At the moment, I would argue that we do have one way that can rejuvenate cells, which is cell reprogramming, but whether that’s going to work in organisms remains to be seen.
I told you about our ambitions in reversing aging, particularly developing cell and gene therapies based on developing technologies for human artificial chromosomes. Lastly, I told you that we do need to take some risks in the approaches we take, or we will die.
I don’t assume, I don’t argue, that everyone should want to prevent their death. I think that’s a personal decision, but if our goal is really to cure aging, then we need to take some risks. We need to take the risks of having more ambitious research. It might fail, might not get us papers or products for our companies, but we need to take those risks if we want to really develop these rejuvenation technologies.
With that, I think I’m out of time. This is the lab in Liverpool and our funders. If you want more information about either lab or the company, please check out our website and feel free to get in touch. Thank you very much for your time and attention.