9UNP0153SD_Aubrey De Grey_WordPress

- I want to introduce Dr. Aubrey De Grey from the Methuselah Foundation. 
(applause)
 
- Thank you very much Justin. Now I'm very pleased that so many of you turned up. I hope I can entertain you a little bit for the next hour and tell you a little bit about what we do and why and about in particular the science. I have the impression that there's quite a variety of expertise in the audience here that some of you are scientists some of you know quite a bit of this sort of biology. A lot of you don't know anything about it. So I'm going to try to accommodate that in the range of things I talk about and we'll see whether I manage. I'm going to put this on. 

I also should emphasize before I start that I'm going to be here for the rest of the evening. I have to fly out to New York tomorrow morning but I'm perfectly happy to spend as long as anyone carries on buying me beers talking about everything that I'll be speaking about in the next hour. And indeed anything that I don't have time to speak about. So you're all very welcome to give me a hard time for the rest of the evening. I should probably mention that there's plenty that I won't have time to speak about. And for that reason I published a book about six months ago that is a pretty detailed account of the science behind the way that I think aging will be defeated. I wrote it jointly with my research assistant Michael Ray who has a real gift for putting really tricky scientific concepts into a form that holds the imagination. He's really good at imagery. So I have been told that it's a pretty good read. Though I say it myself having written some of it myself. 

And I encourage you certainly to try to get a hold of a copy it's not very expensive as you can see. Now a lot of people when you talk about defeating aging entirely they say well, hang on this is obviously impossible. But let's face it, it's certainly not obviously impossible. Because we have an abundance of evidence of actual, you know, examples out there. Of pretty remarkable phenomena with regard to aging. First of all, we have a variety of simple animals that don't age at all. And when I say don't age at all I really mean this. The have been studied -- some of them anyway -- have been studied very carefully in this respect. Hydra is probably the one that's been studied most thoroughly. And there is abundant confidence in the gerontology community that these animals just don't age at all. 

There's the existence proof there is a way to avoid aging. Now these as I did say are simple organisms. They don't have, for example, a central nervous system and you know, I'm quite of my central nervous system and I would not relinquish it even in favor of immortality. But that's not the whole story. Some vertebrates which have of course have a central nervous system very much like our own. very slow aging at least and maybe truly non-aging and a lot of them do it because they grow throughout adulthood. This turns out to be quite useful because it means that they retain the ability to lay down new cells in all of their tissues. A lot of the problems that we have with aging, in fact, the hardest problems that we have in respect to our biology is that since we don't grow throughout adulthood, several of our tissues, in particular the brain -- and the heart and a bunch of others, but the brain is the most important -- have lost the ability to do adequate replacement of cells when cells die. And the evolution has pushed us in a different direction instead in the direction of simply being pretty good at keeping those individual cells alive for a very long time without replacement but a very long time is not forever. So that's a big part of the problem that we have with aging. 

However, there are some pretty damn good examples, even within organisms that do not have indeterminate growth during adulthood, that seem to be better at aging than we are. Whales -- well certainly some species of whales -- live considerably longer, perhaps twice as long as we do, maybe even longer than that. These organisms I mention here, parrots and naked mole rats, live a very long time given their size. You probably know that larger species, especially larger warm blooded species, tend to live a longer time than smaller warm blooded species and that's for plenty of good biochemical and metabolic reasons that we think we understand. These animals seem to do better than us that way. Taking that into account. So that's again, you know, interesting. Then if we come back into the laboratory, we've actually been able to intervene again with relatively simple organisms. But, you know, not ridiculously simple. The ones we're talking about here do have a central nervous system for example. 

You know we can multiply the life span of simple organisms in the laboratory by a large factor. This is pretty good news. Now today I'm going to talk about a whole bunch of things that I think are going to work in humans. And, therefore, I want to emphasize that I put this list up really as a sort of series of strong man. On the one hand to say, listen we do have plenty of superficially relevant -- superficially impressive examples of the ability that we might have to control aging. But when we try to get beyond the superficial and we say what actually matters, what actually is likely to be promising for be doing something about aging, it turns out that none of these are particularly promising. What's really promising is the fact that regenerative capacity exists in some pretty complicated organisms, vertebrates, that can do amazing things. Now the regeneration that we see in lower vertebrates like Amphibia especially and salamanders are the most high profile example. That regeneration is not what I'm going to talk about today but it's a -- if you like it's a spectacular example of the same sorts of cellular molecular processes that exist naturally that we have a respectable chance of introducing biomedically in the foreseeable future. So this is how the rest of the talk is going to run. 

I'm going to introduce you first of all to the general philosophy, the top level description of how I think we're going to be able to go about combating aging seriously in the foreseeable future and why it's foreseeable. Then I'm going to drill down a little bit to describing it in more detail. I'm going to describe the structure of this plan. Now even at that point I'm going to have to be pretty superficial because there's a lot of detail here. It's a really pretty complicated business. That's why I had to write a whole book about it. And for that reason I want to make sure that you don't think I'm bull --. I want to go down to proper detail in one example, in one component of this grand plan just so you can see the lower substance there. Then towards the end of the talk what I'm going to do is talk about the more distant future. And when I say more distant I do not mean less relevant to people who have the misfortune to already be alive. 

I mean only slightly more distant. And you'll see what I mean. I will be introducing you to the reasons why I think that the relatively imperfect technology that I think we have respectable chance of developing in the next few decades will lead to, in fact, much much more impressive results than that technology can itself directly provide. That's the concept of longevity escape philosophy which I'll introduce towards the end of the tour. And then I'll just close with a couple of minutes about the foundation about what we're doing, how we're doing it, how we're progressing and what we're going to do next. All right, the SENS philosophy. Well, I'm going to start by describing the problem. Before you describe the solution to a hard problem, you have to describe the problem in ways that should be instructive. And the problem of course here is aging. What is aging from a biological point of view? 

Even a lot of biologist have pretty profound misconceptions about this question. So I'm going to be fairly elementary here. The first thing that we have to understand about aging is that we don't have genes for it. Aging is -- well this particular description of the nature of aging is actually due to a colleague and a very well known gerontologist, Len Hayflick. And what this says is simply we don't have data for aging. Aging has not been developed because evolution found it to be selectively advantageous for organisms to age rather than not age. Rather it was a case of it's disadvantageous but it's not sufficiently disadvantageous for evolution to have taken the trouble to get rid of it. In evolution you have, obviously, from one generation to the next, a mutational process. Every sperm, every egg has a certain number of mutations in it. And those mutations have to be purified out again at the same rate they're occurring or else they'll take over. 

That purification can only happen if the mutation is bad for the organism in terms of the number of offspring that that organism can have and the number of subsequent descendants. Aging just isn't bad enough from the point of view of evolution. You and I care about aging. But evolution only cared about organisms that are still alive. And if we were in the wild a thousand years ago then a very small proportion of the people in this room would still be alive at the age that we are because of -- and hypothermia and starvation and all those things. So evolution just doesn't care very much about aging organisms. That's actually bad news. So I want to explain why this is such bad news. Supposing there were genes for aging. Bingo we just turn them off and I'm not saying that turning them off is easy but it's fairly easy, it's just you know, a bit of gene therapy or genetic manipulation or pharmacological manipulation even. 

And certainly we live longer. Unfortunately there aren't any genes for aging so it's much harder than that. Right then. So what is aging? Well that's why we have aging because evolution couldn't be bothered to get rid of it. What is aging? The best way to describe aging at the top level is described on the next two lines. Aging is a side effect of being alive in the first place. There's no question about that. We, you know, our metabolism is this extraordinary complex network of biochemical and metabolic and cellular processes that keep us alive, keep us intact from one day to the next and those processes have side effects. 

Those side effects are initially harmless. They just accumulate in the body throughout life, even starting from before we're born and of course I'm going to be talking shortly about what exactly those side effects are in proper concrete terms but for the moment just stick with the abstract. Those types of side effects accumulate and eventually they accumulate to a level of abundance that is bad for it. They get in the way of metabolism's ability to keep us going from one day to the next. That impairs physiological function. And that of course is what I mean by the word pathology here. Age related decline of function including age related diseases but not restricted to age related diseases. So this is what aging is. It's the ongoing accumulation of changes to the molecular and cellular structure of the body that are eventually prejudicial to the continued functioning of the body. And of course as soon as this starts to emerge, things start to go down hill at an accelerating rate that's the point I'm making at the bottom line here. 

The worse you get, the faster you get worse still. Right then. So what does that mean in terms of intervention? Well, classically this is what it means. There are two games in town as far as most people have historically thought. One game is the geriatrician's approach. In other words, when pathology starts to emerge, you attack it. You try to hold back the sands of time and you try to slow down the accumulation of diabetic problems or the growth of arthrosclerotic plaque or the growth of cancer or whatever. And that's definitely better than nothing, don't get me wrong. But it's only a little bit better than nothing. 

And it always will be only a little bit better than nothing because, by definition, it's a short-termist's problem attacking a downward spiral. Because the precursors of the pathology are continuing to accumulate. These are, as I said, ongoing accumulating side effects of metabolism and therefore the geriatrician's problem is going to carry on getting more and more difficult as the patient gets older. This is definitely better than nothing but only slightly better and that's how it will always be. Now gerontologists have known this since forever. Gerontologists have known that they have to take the view that if they really want to do anything about aging in the long term then prevention is better than care. Simple as that. Prevention is better than care. So they say right let's not wait until pathology's emerging, let's clean up metabolism in the first place. Let's get in here and actually stop metabolism from laying down these various types of damage, these various cellular and molecular changes, at the rate that they would naturally be laid down. 

If you can do that, then bingo you've achieved the same objective, you've delayed the age at which the damage reaches the level of abundance that is pathogenic but you don't have the vicious cycle problem, the downward spiral of the geriatrician. So this is a great idea, in principle. But there are some problems. So I explained that the problem with the geriatrician's approach is that it's a downward spiral. It's attacking the problem too late in the game. I just thought I would emphasize that by pointing out how complex it is. And you don't need to be a biologist to know what's on this slide of course these are just a small subset of the things that go wrong with us during aging. And, as I mentioned, the more seriously wrong they go, the faster they go wronger still. So that's bad news. What's wrong with the gerontology approach? 

This is what's wrong. Metabolism is rather complicated. In fact, it's incredibly complicated. This here is a depiction of a small subset of what we know about the way the metabolism works. That's not the problem. The problem is that this is a depiction of a small subset of what we know about how metabolism works. The big problem is, as any biologist will tell you, what we don't know. Any biologist -- the more you know about biology, the more you appreciate that we have hardly scratched the surface of how cells work let alone how organisms work. We have an unbelievable amount to find out. And that's just the stuff that we know that we don't know. 

I'm ignoring the stuff that we don't know that we don't know. So it's just not -- the time for the gerontologist's approach to postponing aging has not come. In order to intervene and clean up and minimize the side effects of a system that's really complicated, you have to understand the system pretty well. Otherwise you'll dive in and, you know, 90% of the time metabolism would just get on, do what it was doing anyway and laugh at you. And the rest of the time if you do have some effect that you wanted to have it's guaranteed that you will have a whole bunch of effects that you didn't want to have. The serious consequences will outweigh the benefits that you may achieve. So gerontologists are more or less -- well I will go as far to say they are virtually unanimous that cleaning up metabolism is not something we're going to be able to do systematically and comprehensively anytime soon. So why am I standing here today? Well, basically it's because I realize that the two options that I described for intervention so far are not the only options. This is a picture that appeared on the front of "Scientific American" a number of years ago, a few ago. 

It was advertising an article in that issue written by my good friend and a couple of his colleagues. And essentially it was making fun of the idea that we could ever do anything about aging. It was a sort of tongue and cheek description of how the human body would have to be built if we were going to live any longer. And they called it -- this is what they called it. "If Humans Were Built to Last. " And there were a whole bunch of things here about building the spine better so that we could carry heavy weights and building the eye in such a way that the light doesn't have to go through a whole system of blood vessels in order to reach the retina and all those sorts of things. And that was all very humorous accept that some journalists actually took it seriously. But the thing is, you know, it was basically a tongue in cheek description by these people who were trying to make fun of the idea that you could ever do anything about aging. Saying well, you couldn't. Now, the human body is a machine. 

It's a very, very complicated machine. And we have the misfortune that we don't have the plans. But it's still a machine. So maybe we ought to be able to learn something about the extension of the life span of the human body and the extension in particular of the fully functioning healthy life span by examining other machines. For example, simple manmade machines like cars. Now, here is a car that was built to last. It -- you know, corrosion resistant metal, that sort of stuff. And sure enough it has lasted. This particular car is probably 50 years old. It might be worthwhile if someone could actually dim the lights a little bit. 

I mean, it's okay I guess I don't have any particularly dark slides but if there is possibility to dim the lights a bit that would be great. Anyway, so this car is doing fine. It's more than 50 years old. But it was built that way at the beginning. The question is, is there any other way to keep a car going? No. My title of course is treading carefully. I didn't say, you know, if your average car was built to last. Here is a car that is the same age as the car on the previous slide. And it's just as functional. 

It's working just as well as it did when it was first -- yeah, yeah whatever. What's going on? Fantastic. Thank you so much. It's working just as well as it did when it rolled off the production line. Why? Not because it was built to last but rather because it's got style and so its owners fell in love with it and have been doing an exceptional amount of maintenance on it ever since so that it's still working. Maintenance is another way to get machines to work properly for a longer time than they otherwise would. And that can now come back to look at the aging problem. There is a third way. 

It's a maintenance approach. I like to call it the engineering approach. Maybe the maintenance is even a better word. I'm not really sure. I claim -- as you can see at the bottom here -- that the engineering approach is a much more attractable and therefore a much more foreseeable approach to postponing the -- or extending the healthy life span of human beings. It has the best of both worlds of the other two approaches. On the one hand, it's intervening sufficiently early in the game that it doesn't have this problem of the downward spiral. There isn't by definition -- damage is the immediate ongoing side effects. Side product of metabolism and, therefore, intervening on to target damage itself does not have the problem of some precursor of damage that's accumulating. I should explain perhaps a little bit more clearly what I mean by the engineering approach. 

What I mean is you don't interfere in the process whereby damage translates into pathology. These flat-headed arrows, by the way, are a notation taken from the genetic literature. They just mean inhibit. So that's what the geriatrician's approach does. It inhibits the process whereby damage becomes pathology. The engineering approach doesn't do that. It also doesn't intervene in the process whereby metabolism translates into damage. And that's really important because if you're letting metabolism do what it naturally does, in other words, if you're letting it lay down the various types of damage at the rate that it naturally lays them down, then you don't have to understand it. You're not interfering with it. The engineering approach says let's let that happen, let's let the metabolism lay down these various types of damage but let's then get stuck in and repair the damage and restore the structure of the body to a biological younger state. 

Thereby, of course, having the same affect stopping the damage from getting to the point where it's got -- where there's so much of it that it's pathogenic. So in other words the engineering approach uncouples metabolism from pathology. That's the theory. And because it's intervening earlier in the game than the geriatrician but later in the game than the gerontologist it has the best of both worlds and I think it's got a respectable chance of achieving a healthy, human life extension pretty soon. That's one reason why I think the engineering approach is good. That it targets the right point in the chain of events, but there's more. The big reason why I think that the engineering approach is so promising and why I talk about foreseeable life extension for people who are already alive today is that damage isn't nearly so complicated. I've shown you a couple of slides already emphasizing how complicated pathology is and how complicated metabolism is. Here's your damage. The big breakthrough -- the big conceptual breakthrough that I made that really got my research agenda going back in 2000 was to appreciate to begin to realize that all of the various molecular and cellular phenomena that qualify as damage by the definition I'm using this evening, in other words, ongoing consequences of metabolism. 

They're eventually pathogenic when they accumulate to sufficient abundance. All of those things fit into this very straightforward simple categorization. Stuff, you know, indigestible molecules that are accidentally made inside cells sometimes. And if they're made at a high rate, than that has been a problem for evolution because it kills organisms when they are young, when they're still alive and reproducing and so on. So evolution has done something about it. But lots of different types of molecules accumulate at slower rates and evolution has said well who cares. So we care and that's one aspect of aging. Junk accumulates outside cells. Amyloid plaques in Alzheimer's disease are probably the best examples of this. Cells die and sometimes they're not naturally replaced by the division of other cells and that causes problems eventually. 

That's essentially what stem cell therapy is for. I'll come on to intervention in a second actually. But you get the idea. Now, this is a pretty outrageous statement that you can actually classify all of the things that go wrong with this ongoingly during life into just certain categories. But the more I thought about it, the more I thought well it's actually pretty good evidence in favor of this. First of all, you can take -- you can start from the simple tenet that damage can only accumulate in long lived structures. In other words, say you've got a cell and it makes a protein and the protein does some job and then it gets damaged in some way, it gets oxidized or whatever. It gets broken down. The damage then is gone. So that's not damage by the definition I'm doing because it's not accumulating. 

So you can just look at long lived structures. You can look at DNA. You can look at molecules that are sequestered in the cell rather than destroyed or excreted and so on. And that's how you can get this sort of list. There's another way you can get this sort of list. Which is more circumstantial but still quite compelling. It's been the same list for a quarter of a century. All of these things have been major topics of conversation and discussion within gerontology since at least the early 1980s and in many cases the '50s or '60s and we've come a long way since 1982 in terms of our ability to analyze biological systems and figure out what's wrong with them. And this list should have got longer if there were much to add to it. So there's pretty good reason to think that we're really right about this. 

But of course the really good news is that we know how to fix it. And when I say we know how what I mean is we know how in enough detail that the respectable just basis for confidence that we can actually implement these fixes within the next few decades. So I've written up here just in one liners the sort of approach to fixing these various problems. And this is actually the reason why this particular classification on the left is a useful classification. It's because within each of these seven categories you can ask well there are lots of examples within one or another tissue that are affected the general approach to fixing the problem is essentially the same for each of those various examples within the category. Only the details are different. Like stem cell therapy, for example. Okay it's a big field and the reason it's a big field is because cell loss has different problems associated with it in different tissues and different fixes but lots of things in stem cell therapy are the same across all tissues. For example nuclear transfer or dedifferentiation of adult cells. So you get the idea. 

And it's the same across the whole thing. Now as I say the reason why I'm confident about the time frames here is because of the detail. If you get my book then you'll find that each one of these things has an entire chapter describing the detail. Obviously I don't have time today to go into all of that. I'm just going to spend a little while talking about one example which happens to be a rather glamorous one so that you can get some idea of the sort of novelty that's involved here. But also the fact that this is really based on very solid science just science that hasn't necessarily been applied to this problem before. Stuff that accumulates inside cells is a big problem in some of the most important aspects of aging. In Alzheimer's disease you get, as I mentioned a moment ago, stuff accumulated in the spaces between cells but you also get serious problems inside cells. This is a cross section, in the electron microscope, a cross section through the long part of a neuron. The axon. 

And as you can see it's a bit of the mess. It's not very pretty at all. There's a lot of stuff in here that should be getting broken down isn't getting broken down. There's a lot of evidence here of failure of degradation. In arthrosclerosis, in cardiovascular disease, you have the same sort of phenomenon, here we are. Where the Fbam cell This is a cell that used to be a perfectly functioning immune cell. White blood cell. Migrated into the artery wall and did what it was suppose to do which was to engulf bits of cholesterol in the related molecules that was stuck in the artery wall. And it was able to process that stuff pretty well at first. But unfortunately a small proportion of the stuff that it was suppose to metabolize was recalcitrant, resistant to metabolism and accumulated inside the macrophage and turned that macrophage into sort of an undead macrophage called a phone cell. 

This is a phone cell. Where it can't really do the things that it was able to do before let alone the things can couldn't do. And this is the beginning of an arthrosclerotic plaque. You get the idea it's not very nice. What are we going to do about it? Well I had this crazy idea. It was a bit of lateral thinking. This is back in 1999. I happen to have a colleague in my department in Cambridge who worked in environmental decontamination. And specifically he worked in an area in that field called bioremediation. 

Bioremediation arose about -- well it arose from a hypothesis that was put forward may be 50 years ago called -- the wonderful name -- microbial infallibility hypothesis. And here is the hypothesis -- the guy who thought it, Ed Gale, said to himself well, hang on now, some microbes grow faster than others. So growing fast is a fine way to out compete your competitors in some environment. So if you can grow fast, you ought to be the only -- if you can grow faster than anyone else in the environment, you ought to win. You ought to dominate the environment. And if you look at a given chunk of soil, for example, you'll see one or two species of bacteria that can grow really fast and that's all you'll see. But in practice that's no what you see. If you get any sample of soil you find the most immense degree of microbial diversity. So Gale thought about this and he said to himself well maybe there is an explanation which is there's another way to carve out your ecological niche if you're a bacteria. Rather than growing faster than your other competitor, there may be something in the environment that you can metabolize and grow on -- extract energy from -- and they can't. 

And in particular, what Gale thought to himself was that well if there is something in the environment that is really pretty hard to metabolize but if you can then you can grow off it because its energy rate, then that's going to really impose serious selective pressure on the microbial ecology to develop such ability -- the ability to break this stuff down. So he said well let's suppose we go to some environment that's got let's say a just used air field that's got TNT in the soil, which is a common thing. And let's suppose we want to get rid of that TNT in order to let's say build a housing estate onto the airfield. You're not going to be able to do it at the moment because TNT is toxic. How do you get rid of the TNT? He said, well, maybe you can just go and have a look at the soil and we'll find that there are bacteria in the soil that can eat TNT. And you know what? He was right. The only reason that there's TNT in that soil is because there was not enough of those bacteria. So he said you can just get those bacteria out, expand them in the laboratory, put them back in the soil in greater numbers and your TNT goes away. 

And he was right. And it's not just TNT, plastics, dioxins, rubber, you can go to the side of the highway and you'll always find bacteria that can eat rubber because pulverized rubber is coming off tires all the time. All right, what the hell has this got to do with aging? This is my idea. I realize that there are environments that are enriched in human remains. And those environments, therefore, will be enriched in precisely the energy rich compounds that we can't break down when we're alive. But mysteriously those environments, those graveyards do not accumulate these things. They do accumulate some parts of human remains, bones and teeth. But hey, brilliant -- that's consistent with the hypothesis because of course bones and teeth are not energy rich. You can't live off bones and teeth. 

So it seemed very probable to me that in fact graveyards would be a fine source of microbes that would be able to break these things down. Now what use is that biomedically. We're not going to inject bacteria into our bodies are we. Let's face it. But that wasn't my idea. My idea was that we could figure out what the genetic basis for that capacity was. Why -- how these bacteria were able to break these things down. We can find the genes that were encoding the enzymes that were doing the jobs. And then we could use those genes with straightforward -- well, relatively straightforward molecular biology gene therapy and so on to actually have a therapeutic affect. This is the idea put graphically. 

You've got this process in the human body that turned young people into old people and eventually into dead people and then you've got this other process that's completely outside the human body and it's encoded -- and that turns dead people into decomposed people and the idea is to take that and do standard molecular biological work basically and translate that capacity into human cells -- this is my pitiful picture of a neuron. And thereby slow down -- you see this flat-headed arrow again -- slow down the process that turned young people into old people in the first place. All right, so that's all very well in theory. Does it work? Well the answer is yes. We've actually -- the Methuselah Foundation that I'm going to be at, that I run that I'm going to be talking a little bit about later on. We have been funding some work in this general area for a little while now. For a couple of years. Especially in two laboratories -- one in Arizona and one in Texas. And these laboratories are getting good results. 

We have actually publications now on this stuff. The first target that we looked at most intensely was this thing called -- cholesterol which is a particular variant of cholesterol that appears to be the public enemy number one when it comes to arthrosclerosis and possibly Alzheimer's as well. And here you can see the sort of experiment that gets done. Over ten days, you've got a whole bunch of different bacteria being exposed to this stuff and being given this to grow on and not being given anything else to grow on. And most of them don't know what to do. They haven't got the genes to break this stuff down so the stuff just sits there. The amount of the cholesterol that's in the culture. And it stays constant. But I'm sorry about the lighting here, it's my fault for the colors on this thing but there's a couple of trajectories here, a pale blue one and a yellow one, in which the stuff completely goes away after ten days. Okay. 

So this really says these bacteria are able to break the stuff down and you don't need a microscope to see this. Here's a petri dish with the stuff, before and after and it's pretty glamorous really. So that's pretty good news. Now I'm not saying this is easy, you understand. This is an extremely ambitious approach to the cure and prevention of cardiovascular disease and arthrosclerosis and so on. But it is going to be so much more effective when it works than anything that we have today or indeed anything that is coming down the pike that it's worth it. We have to go through all these steps obviously identify the enzyme, put then into mammalian cells, make them work. There are a whole bunch of tricks that we may have to play in order to make sure they're not toxic and don't break down things that we want to protect but we have a lot of tricks for that. We have to do the same thing in life before we go to human trial, the usual deal. It's going to be a long project but it's worth it. 

All right, now that's all I'm going to talk about tonight with regards to the detailed science that of course as I've said here I'm absolutely abundantly happy to answer as many questions as anybody has later on. What I'm going to talk about now is I'm going to switch from science to technology. And in particular to the history of technology. Because those of you who have come across me in the media and so on will know that the thing that I tend to be most famous for is that I discuss not simply the postponement of aging by a little bit but by a lot, an awful lot. And being reasonably, you know, realistic about biology I know perfectly well that the sorts of technology that I've written about in my book and that I've given you a taste of just now will not do that. They're going to have an impact on each of the various types of damage that accumulate with age. But they're not going to solve them completely. Because within each of these categories there are things that are relatively easy to fix and there are things that are relatively harder to fix. We have a respectable chance, it seems to me, of perhaps halving the severity of each of these problems in the next few decades but we won't solve the problems completely. And if we only halve them, then I reckon we're problem going to get may be 30 extra years of healthy life. 

We're going to be able take people who are middle age, let's say 60 years old when we start, and we might be able to rejuvenate them for a while but eventually the things that the therapy just doesn't work on well enough will catch up with those people. So what's the catch? How do I get out of this? How do I say that people are actually going to live indefinitely? Well, the fundamental four-word answer to that question is here. It's the third reason why the engineering approach is such a good idea relative to the other approaches. Repairing damage buys time. Here I'm giving you a very, very schematic description of what I'm talking about. So don't read too much into the, you know, quantitation into this. This is really just to give you the conceptual idea I'm putting forward. 

But, you know, it's an important thing to get across and it's not always easy for a lot of people here. This word reserve that I'm using on the Y axis is not a new concept I'm introducing. It's the inverse of damage. You can think of reserve as the amount of additional damage that someone can afford to accumulate before pathology starts to hit. So you've got on the red line a very schematic just sort of representation of what normal aging consists of. You start off at age zero with not much damage, lots of reserve. Damage accumulates -- damage in all these various sorts that I've been talking about -- in other words, reserve goes down and eventually you hit this thing I'm calling the frailty threshold, this dotted line and at that point pathology begins to emerge and it's all, you know, you're going to have in a hand basket. Now supposing you had a therapy that halved the rate of accumulation of damage. I told you earlier that cleaning up metabolism is basically impractical. But let's forget that it's impractical for a moment. 

Let's just think hypothetically supposing we had a therapy that could slow down the accumulation of damage by a factor of two for the sake of argument. And let's pretend we start applying it to someone when they're here. Let's say middle age. Let's say 55-60 years old. So that's the blue line. Eventually you hit the frailty threshold. And at that point I'm drawing the line as revealing it's previous gradient, and the reason I'm doing that is because the frailty threshold is a bad thing to get to. Once it gets to that point you've got this downward spiral, you've got this auto catalytic accumulation of damage and so the therapies are basically not going to have much effect anymore. Right now. What's going to happen if we now consider a comparably effect reversal therapy. 

I said that here we are halving the rate of damage. In other words, we're having a 50% effect on the accumulation of damage starting from the point that we apply the therapies. Now, if we start reversing the damage and again we reverse half the damage, what's the result? Well, this is the result. You're going to be able to take someone up to here to rejuvenate them effectively. So I'm calling the damage the therapy works on the easy damage and the damage the therapy doesn't work on is the hard damage. Now because we're not intervening at the rate at which the damage is laid down the rate of aging as determined by damage as determined by a lot of reserve is the same after the therapy has been applied as it would be in the absence of the therapy, the red line. But then of course we can reapply the therapy and again and again and so you get a lot more efficacy than you do if you only retard the damage. But you do have only a finite amount of improvement. And this is the sort of trajectory that I call robust human rejuvenation. 

The addition of maybe 30 extra years of healthy life to people when you start the therapies at middle age. The reason you have diminishing returns is of course because the hard damage, the damage that the therapies don't work on is continuing to accumulate unabated and eventually on its own irrespective of the thoroughness and frequency with which you apply the therapy, it's going to be enough to tip the person over the frailty threshold. So that's what I call robust human rejuvenation. And it's a lot better than retardation but it ain't immortality. It isn't even indefinite life span. Addition of 30 extra years of healthy life and total life to the lives of people who are already in middle age when the therapy's begun. So I still haven't answered the question. How can I talk about four digit life spans? How can I talk about the total elimination defeat of aging? If we were mice, I would not be able to. 

If you and I were mice, then I would have reached the end of my story because on the X axis here where I've carefully put no numbers we will be talking about in like in a year, two years, three years. Okay? But we're not. We're humans. So the X axis is maybe 25-30 times as long. In particular the interval between the first two applications of this therapy, this punitive therapy. Here and here. May be as much as let's say 20 years. Now, what's so special about that? Well the answer is 20 years is one hell of a long time in technology. 

It is enough time, in particular, in biotechnology for these therapies to be considerably improved. Not just in the cost and the convenience but in their comprehensiveness. So it means that we can be very confident that the second time that someone who was here when the therapies first arrived goes back for his re-rejuvenation, he will not be receiving the same therapies that would only give this amount of rejuvenation. He'll be receiving therapies that will fix not only the type of damage that could be fixed the first time 20 years previously. But also let's say for sake of argument half the damage that could not be fixed previously. That's why I'm dividing the hard damage now into hard and very hard. So this brown line, this orange line is the depiction of that. Now, most of you can probably see where I'm going with this. The orange line -- the thing about it is not only the person is rejuvenated to a greater level than they would have been if they'd been using the 20-year-old therapies, they're also rejuvenated to a greater level than they were 20 years previously when they were chronologically 20 years younger and that, of course, iterates. It means that the diminishing returns problem does not occur. 

All you need to do is continue to improve the therapies at a sufficient rate to keep one step ahead of the problem to make the therapies sufficiently comprehensive to keep the overall level of damage of all the various types down to a tolerable level, a sub-pathogenic level, And you never hit that frailty threshold. You don't have to apply the therapies increasingly more frequently. You don't need the therapies to become -- you don't have the therapies becoming increasingly ineffective. That's what I call longevity escape velocity. It's the rate at which these rejuvenation therapies need to be improved following that initial breakthrough where we could fix roughly half the damage. And we get this thing I'm calling reversed human rejuvenation. The rate at which the therapies must be improved thereafter in order to outpace the accumulation of the various types of damage that they can't yet fix. Is it's a bit of a mess and it took me five lines to write it down but conceptually it's a very simple idea. Longevity escape velocity. Now, I said earlier that if we were mice this would not be realistic because we need to double the efficacy of the therapies every year or something. 

But every 20 years or 30 years sound all together more realistic. Is it realistic enough? Well I thought it might be useful to try to ramify that. To try to get more data on that. To try to get more of a solid argument that it really was a realistic scenario. So I work with an excellent computer programmer from New York called Chris Phoenix and we published a paper last year which gave a summary of our results. Essentially we wrote a pretty faithful simulation of all of this. Since this is the nature of aging, metabolism ongoing recording these various types of intermediate that eventually cause pathology, we should be able to simulate that. We should be able to write a computer program that essentially, you know, just recapitulates that process. And that's what we did. 

We wrote a simulation in which there were various types of damage each of which could individually kill us, that's a very important component. However, within each of which there are additive subtypes, contributions from things are easy to fix and things that are hard to fix. We built in this concept of the downward spiral. We built in the concept of different people aging at somewhat different rates. Which is, of course, actually true. And we also built in the fact that you don't just die of aging, you die of the combination of aging and your external environment. If you're unlucky and you get the flu when you're a 30 year old then you might die sooner than you otherwise would and so on. And this is the simulation I won't be talking about that. This is the validation of the simulation first of all we want to see whether we could actually describe the distribution of ages at death that is seen in the real world using this program. And the answer is yes we certainly could. 

The orange line here, which you can hardly see, is the distribution of ages at death. Although I think it was U. S. mailed in 1999 just happened it the first data I could get my hands on. The yellow line which you see fits the orange line fairly well is the best that a typical demographic analysis would achieve. Demographers like to use something called the Gompertz curve -- the Gompertz relationship. Which is essentially saying that the mortality rate is an exponential function of age and this is a pretty good fit in most populations. In fact pretty much all populations not just human ones and it worked pretty well here too. But the green line is what we got for our simulation. And as you can see it fits it like a glove. 

It's even better than the Gompertz curve. So this was nice good news. It showed that we were representing reality here. This was also useful. The fact that the damage seemed to accumulate in a reassuringly realistic manner. Here we have simply a vessel -- a plot of how each individual's rate of accumulation of damage goes throughout life. And you can see a couple of important things here. First of all, the degree of variability in the population looks about right. People who are aging nice and slowly and healthily reach a level of damage at the age of let's say 85 that's about the same as rapid agers reach at the age of 70. That seems about the right degree of variability. 

Another thing that's good about this is that the rate of accumulation of damage seems to follow the right sort of trajectory. The rate is perhaps twice as fast at old age as it is at young adulthood. If it was 30 times as fast, we'd know there was something wrong. If it was 1. 01 times as fast, we'd know there was something wrong. We didn't get that. So that's good news. So then the question is having reassured ourselves that we're talking about a simulation that's pretty realistic, what do we see when we look at interventions? Well, first of all, let's look at the damage. So here we have a bunch of curves, each of which documents a cohort. 

That's to say a group of people of the same age. Now, these cohorts are ten years apart. Each is ten years apart in age. And in particular the top curve, the top blue one, is people who are already 80, 8-0 years old, at the point where the first therapies start to arrive. Start to knock down half the damage of various types. And you can see it's up and down a bit for a little while because the thing is not very comprehensive. But eventually since we're above longevity escape velocity, the people start getting biologically younger as they're getting chronologically older and eventually they end up being biologically very useful. Now, there's one thing I want to emphasize before you miss it which is that we're looking very conservatively here. We're talking about therapies being improved in terms of the doubling of efficacy on at half as fast as the schematic description I was giving a few slides ago. Every 40 odd years. 

Really slow. And yet we're still way ahead of longevity escape velocity. The second curve is people, as I said, are ten years younger. These little circles document the point at which the therapies arrive. So this is the people 80 years old when their first therapies arrive. These people are 70 years old when their therapies arrive. Before the therapies arrived you've got the exponential accumulation of damage and after that you have the gradual bringing the thing under control. I suppose you'd like to know it what it means for life span. Well, unless on the next slide I don't have anything about life span limitations due to things other than aging. These curves are going to be just probabilities of death caused by aging. 

But they're quite good news. The black curve is what happens in the real world as we know it today when we don't have anything that can do about aging. The blue curve as on the previous slide is therapies -- is what happens to the group of people who were already 80 years old roughly here. Half of them, pretty much half of them were dead before we begin when the therapies arrive. And as you can see not a lot of good. It's, you know, it's going to give a few people the longest survivors, a few people perhaps, you know, ten or 20 years. That's all. But if you're just ten years younger than that, 70 years old when the therapies arrive. Which would be about here. Then again you only pull gradually away from the line -- from the non-therapy line. 

But you pull further and further and further away and eventually you get down to here and your chance of dying of aging is getting rather low. And as you can see eventually once some of these people get out to the age of maybe 200 at which point they are biologically so young that their chance of dying of aging is basically nil. And 10% of them do that. 10% of people who are 70 years old at the time that the therapies arrive. And if you are ten years younger than that. That's the brown line -- these are people who are 60 years old when the therapies begin to arrive. Nearly half of them make it. Pretty damn good news. So that's life extension escape velocity in practice. And as you can see -- and I'll repeat again -- I'm talking about a very conservative estimate for the rate at which these therapies arrive. 

Why am I saying it's so conservative? Would you like to me justify that? Well, let me justify it. Let's look at other technologies. These are just for illustration, I can certainly make the same argument using cars or using computers or using, you know, combating infectious diseases or anything you like. You know, when the Wright brothers got off the ground in 1903 they probably didn't think it would be terribly likely that anyone would be flying across the Atlantic any time soon but it only took 24 years for Lindbergh to get to Paris. From there, you know, Lindbergh probably wasn't thinking in terms of commercial jetliners. This is 22 years between Lindbergh and the first commercial jetliner. Only 20 years from there until concord. Now you may say, well, okay, yes it got that far, didn't it? 

But where are our flying cars? The answer is not flying cars are really hard. The answer is we can't be bothered. Just in the same way that you know we could have obviously got to mars by now if there had been the same degree of national pride attached to it that there was with regard to the moon in the '60s. We know that. We couldn't be bothered. Public pressure, enthusiasm for this is not going to be in short supply in respect of fixing aging. So we should look at this sort of trajectory in order to judge whether the scenario, the rate of progress that I'm talking about fought incremental improvements after we make the initial breakthroughs is going to be fast enough. It's even better than that. This is my last point about longevity escape velocity. 

You may think well yeah, okay, so we might -- it looks pretty, pretty easy that we're going to be able to double the level of efficacy of these therapies, half the amount of damage that we can't fix. Every 20 years or every 40 years. That looks pretty reasonable. But it's going to go up and down isn't it? There's going to be some times when progress is fast and sometimes not and maybe sometime in the future we're going to have a really bad century and everybody's going to die because we make no progress. Right? Now, I mean, that would be bad, yes but hey we got that far so that's good enough in and of itself. But also it turns out that argument doesn't even work because it turns out that we can slow down. Here's a scenario in which we fix half the damage in order to get to robust human rejuvenation in the first place. But the second time around 20 years later we're not fixing half of the remaining damage in this scenario we're only fixing a third of it and the third time around another 20 years later we're only fixing a quarter of what we couldn't fix previously and so on. 

And as you can see that's still good enough. The people are still staying nice and healthily above the frailty threshold. So it gets easier, it actually gets easier with time. And that means that it's really extraordinarily difficult to argue against the conclusion that -- rejuvenation therapy is giving a few decades of extra life will, in fact, give an indefinite degree of extra life as a result of the rate of subsequent progress. And you want to believe that just again go back to cars. Now here's a vintage car. It's not 50 years old it's well over a hundred years old taking part in a London rally which is an annual car rally. It happens in England every year. And this car, of course, is getting a lot of maintenance, no question. But the critical point is it's getting no more maintenance, no more sophisticated maintenance than it was, let's say 30 or 40 years ago when it was only 3 or 4 times old as it was designed to be. 

In other words, longevity escape velocity for cars is already negligible. We're not having to, you know, to get more sophisticated. So I'm just going to complete with a couple of minutes on the Methuselah Foundation. This is the foundation that I run. I used to be at the University of Cambridge but I quit because I was able to get paid to do this stuff full time. And basically what we are -- we're a 501 charity based and registered in Virginia. And we promote and fund, sponsor the hastening of just what I'm talking about. When we began back in 2002-2003 we had no money whatsoever. And that didn't stop us. We decided that we would get stuck in and get public enthusiasm going raise the profile of life extension research in a legitimate, you know, respectable way that didn't in any way demean it and so we launched the prize called the Methuselah Mass Prize, as we called it back then. 

We call it the M prize now. It's simply -- we offer you money if you can get, if you can make mice that lived longer than any mouse had lived before. Very simple idea. Gets the message across to people who go to sleep when you talk about science to them for more than 10 seconds. And, you know, it really worked. It got the word out there. And we didn't have to spend very much money. We only put $5,000 in it in the beginning. And now as you can see it's got quite a lot. And that's just because of people like Justin, for example. 

And people around the world who have put money in and you can still do it. And anyone with a credit card or a PayPal account can add to that part. The research part is the other thing we do. When we got the M prize really going properly we a couple of years ago started funding research directly in just the same way that any standard funding agency would do accept because we're very small -- well still fairly small -- we don't have standard grant solicitation procedure. We just fund stuff that I think is cool. Which is fun because I know what's cool. And we are spending that money as fast as we fill it. The project that I told you about a moment ago, the introduction of microbial genes into cells to get rid of stuff that we can't naturally break down is something that we're funding at three universities now around the U. S. in Arizona state, at Rice University in Houston and also Columbia in New York. 

Going very nicely. Funding's going up all the time. The group is fantastic. They're really committed to all of this. They're the best graduate students you could possibly imagine and the PIs that we're funding are also really committed to it so it's a glorious situation from point of view of the grant administrator, so to speak. Also over the past year or two we've been funding one of the other major really challenging components of the sense program. The obviation, rather than reversal, of the accumulation of mitochondria mutations. And again a comparable amount of funding which again is going up all the time. We're funding that not in the U. S. 

this time but in Paris. Because we are a very much a global enterprise. We expect to be funding at least three probably more like five projects in the next few months. Again at the same sort of level one or two people. Where are we getting all this money from? Well our number one donor at the moment is a guy you may have heard of Peter Thiel who was the cofounder of PayPal and is now the spearhead of probably the most successful hedge fund in the world, in terms of its rate of growth, clarity and capital. He's very good at making money and he's got a lot of it. But he's got slightly less than he would otherwise have had because he gave some of it to me. To fund some of this stuff. And a lot of what he gave was not straightforward unconditional but rather as a challenge pledge, in other words we have to get money from other people in order to extract his money from him. 

And we're doing our damnedest to get that money. Eventually we want to be quite a lot bigger than what we are now. I've told we we're funding maybe half a dozen people at the moment plus we've got maybe a half dozen or a few more in the foundation itself. We'd like to be up around 500. Both employed by the foundation and funded by the foundation. This is the sort of structure we expect to have. It will include work like this around universities around the world and it will also include a stand alone facility in which especially the integration of multiple different interventions into the same mice will be pursued. We hope to be there as soon as possible. We're not there yet. But we're working on it. 

A year ago we were at this sort of 6-digit level of budget. We're now very much at the 7-digit level. And we're moving through that as fast as we can. Next step will be along the order of magnitude bigger than that. We will set up a standard grant solicitation and administration and application procedure. So that we can find out about and fund work that I haven't come across myself already. And eventually we'll get to the point that I described a moment ago where we have a stand alone facility as well as funding extramural work. So we're talking about a pretty pitiful amount of money really given the scale of the problem that we'd like to solve. We're talking about really a drop in the ocean of biomedical research. The reason we're talking about such a small amount of money is because all the work I've described to you here is work that we want to do in the next several years up to a maximum of ten years on mice. 

It's after we break through to what I like to call robust mass rejuvenation where we can take middle aged mice and seriously postpone their aging, that the serious money will be needed in order to translate that technology to humans. But that's the easy part. Because after we get sufficient proof of concept that the gerontological community in general are saying yes, it's only a matter of time before we do it for humans, then Oprah will be up there saying let's do it. And then -- 
[LAUGHTER]
 Money will be no object. It will be impossible to get elected except on a manifested commitment to fund this. So we are focusing on the shortest but the relatively short term, relatively cheap order of nine digit funding to get to that proof of concept in the laboratory in mice. And I'll stop there. Thank you. 

(applause)
 I imagine there's a few minutes for questions if anyone's got any. 
- What will the benefit to society be of extending life? 
- Aging is really bad for people. It doesn't just kill people. It kills people really horribly. It causes suffering. We generally agree among ourselves that suffering is bad, right? God said so. You know, most people feel this. 

Ageism is also generally considered to be a bad thing. You know, we are actually suppose to regard old people as people too. So, you know, putting two and two together we have a moral obligation to do this. And yes, there will be a degree of restructuring of society that will be required after results. Just as there was with the industrial revolution. I don't know many people who would like to go back to the pre-industrial world and the world before we had hygiene and vaccines and so on when 40% of infants died before the age of one. Progress does cause upheavals but get over it. Progress is progress. And progress that alleviates suffering is unfailingly good progress. 
- I have two questions for you. 

One is do you practice caloric restriction? If not, why not? 
- I don't. I don't and there are two reasons. First of all I already look as though I do and that's not a frivolous point. I have a feeling that the people who might find calorie restriction easiest to do are precisely the people who will get the least benefit from it. However, that's a detailed point we can go into it more later if you want. The other reason I don't do it is because I don't think it's going to do anyone much good. I published something on this a few years ago. But essentially my reasoning is that the -- even though we -- all organisms seem to have genetic pathways in them that respond to nutrient deprivation by hunkering down to one degree or another. 

The shorter lived you are the more impressive the metabolic acrobatics is that occurs in response to nutrient deprivation. For example, worms and flies can live several times as long as they normally would if they're starved at the right time of their development. Whereas, mice can quite only live 40 or 50% as long. Now there is good evolutionary reasoning to suggest that this is actually not surprising. That actually the only reason we have these pathways is to the extent that they're useful. And long famine much longer than a year just don't happen often enough to apply enough selective pressure to retain the ability to survive them. 
- Second question then is of the beliefs and attitudes that people have that are posing the greatest resistance or barrier to you, what are they that are really preventing them or blocking them from buying into your vision? And by buying into, I mean literally by giving more money. 
- So, first of all, let's get the wealthy people out of way because the problem the wealthy people don't deserve all the blame for not getting me money. Because they're just members of the general public. 

And they, too, have the misfortune to have televisions on which they don't receive the right message and so on. So, you know, it's a social problem. It's not a problem just of wealthy people not being sufficiently visionary. Basically, it's the same problem like when I just gave a fairly scathing answer to the previous question. Nobody clapped. You've all got this problem, right? It's what I call the pro-aging trance. People have made their peace with aging. Aging is something that we've had to live with all our lives. All civilization's life, so to speak. 

And the reason we rationalize it away is because until now, that's been our only option. It's been this grim thing that's going to happen to you and it's not going to happen to you for quite a long time, okay, but there's nothing you can do about it. Then what's your choice? You can spend your life, you know, obsessing about it and not having much of a good time or you can put it out of your mind and get on with your miserably short life, you know, and make the best of it. And obviously that's the thing to do, right? And given that that's the thing to do, it doesn't matter how irrational your rationalization is. Okay, so the people are very good at and coming up with and believing and swallowing irrational rationalizations about aging and, you know, worrying about things if they applied the faintest sense of proportion to the problem they would not dream of considering to be arguments against this. So what I spend my time doing is essentially, well, to varying degrees of aggressiveness, ridiculing that and getting people to grow up and take this problem as seriously as they would take any other problem. 
- I have two questions, as well. My first question is do you think your anti-aging technology will be able to keep stride with ecological solutions to basically deal with the fact that humanity is beginning to reach -- well, it will eventually reach carrying capacity. 

- It's whether the ecological -- societal, you know, whether we as society will keep pace with the anti-aging stuff. So the anti-aging stuff will happen and the question is how soon will it happen and we will be able to cope. A large part of why I'm fairly strident about these things is because I need -- I feel a need, not only in order to hasten the technology but also to hasten the anticipation of the technology so that there's a certain amount of forward planning that goes on and we don't just get -- get surprised when suddenly people announce that they've made these mice. It seems to me that it's probably going to be okay. But I don't say that it's going to be okay immediately. I think that the transition to a post-aging world is going to be pretty damn turbulent just as the transition to a industrialized world was pretty turbulent. But that's not the question we have to ask ourselves. The question we have to ask ourselves is it worth it? 
- And my second question is given the complexity of the metabolic processes and the fact that, you know, they're going to basically inflict various kinds of damage on the body, how do you account for, you know, how you're going to target that very damage and especially -- my main interest is in the brain. How are you going to, for example, target a decreased cognitive abilities into old age? 

- So first question is why do we have decreased cognitive abilities with old age in the first place? And the biggest reason I think pretty clearly is the sort of things that I put up on the screen, the fact that the brain accumulates crap. Inside cells and outside cells get in the way and stop neurons from communicating so well with each other and from working so well. And a more advanced rate they'll die at an accelerating rate and they, therefore, can't do much when they're dead. So we're fixing those -- we're going to fix those things. Now that's almost certainly not the whole story with regard to cognitive decline. There are two other things. Number one is -- and the biggest one -- is we don't learn so well because there are too many distractions. It's often -- you know, people have done quite interesting psychological studies on what people can remember in their lives. And they found that there is a phenomenon which they've given the wonderful name to the reminiscence bump. 

Basically what this says is that however how old, whether you are 40, 50, 60, 70, 80, that the time of your life that you're going to remember best is your adolescence. And everything else is more of an equilibrium. And if you think about it, that's not surprising. Even people, you know, at middle age are probably forgetting things as fast as they are learning new things because the process of recalling a recollection -- a memory -- reinforces it. So you basically remember the interesting things -- a lot of which happened during adolescence -- rather well, more or less indefinitely. Whereas, the things that were not so interesting tend to be the ones that are forgotten. That's fine. If it's fine between 40 and 80 then it continues to be fine. In the blue T-shirt. 
- The process which you are working on, is it going to be a completely experimental stimulus to the -- 

- I can't hear. 
- What kind of a treatment are you working on would it be just external stimulus to the body or would it require conscious effort for people to do? 
- Certainly it's clear that having a good frame of mind, you know, especially being able to cope well with stress, is good for longevity. Lots of people have determined that. However, these therapies will certainly be straightforward biomedical therapies. If, for whatever reason, you're aging faster than average, either because you haven't got the right attitude or because you smoke or because you really like Big Macs, or whatever, you know, that's going to be fine. But the thing about rejuvenation therapies is that the only difference between someone who's aging a bit faster or a bit slower is the frequency at which the therapies need to be applied. The same therapy should work on anybody. I think that answers your question. 
(inaudible)

 
- So what? 
- A conscious effort on the part of the human. 
- You got to go to the hospital or whatever, you know, it's not going to happen in your sleep. We're not going to chain people down and rejuvenate them by force, if that's what you mean. 
- How would you solve the problem of space? 
- Clearly the birth rate and the death rate have to more or less match. That's clear. So if we're lowering the death rate by using these therapies very widely then we will end up lowering the birth rate as well. How will we do it? 

Who can say? I have no idea. But I do know that first of all it's not for us to ask. We have the duty, a moral duty -- a very clear moral obligation to develop these therapies as soon as possible so that humanity in the future has the choice between the high death rate that we have today and the low birth rate. And that may be a dilemma but a dilemma that they are entitled to choose between for themselves rather than have us impose these values on them by saying, you know, you got to have the high death rate. That's the first thing. Second thing is if we look, you know, pragmatically at the what the problem really is and how bad it is -- well, first of all, let's remember that the population, the fertility rate is already plummeting across the whole developed world and indeed the pre-developed world. China and India are fine examples as well. And that's going to continue. Furthermore, there's a good reason to believe that it may accelerate. 

In the west, we see that not only are women having fewer children but they are having them later. And that's very interesting because we have to ask why are they having them later? And of course there are different reasons for different individuals but the point is they are, for whatever reason, choosing to do other stuff with their lives until the mid '30s or whatever. Then why are they having the children then? Answer of course, it's then or never. Right? It won't be that way anymore. That's one thing we're going to fix. So if you know you're going to be perfectly capable of having a child safely, you know, at the age of 70 then maybe you will choose to postpone your birth for a bit longer if you're enjoying yourself at age 30 and 40 and 50. And that won't happen really early on in the process before the resulting from the death rate being low, right? 

So if you look at the actual math of that the demographic trajectory is a really powerful influence. Red T-shirt. 
- Hearing all these examples of how this would adversely effect society and how these changes come about, isn't this theory kind of vague as seeing how the effects improves your life or effects one person but adversely effects many or could? 
- Who is the one person you're thinking about? 
(inaudible)
 
- But everyone is yourself. It's going to benefit everybody. The question is are the benefits to health more important than the social dangers? 
- What about people that have to change their life and don't want to? 

- They don't have to. Okay, consider the Amish. The Amish are a perfectly respectable, stable community that reject a bunch of existing modern technology. Now, that's fine. We don't resent them for it, they don't resent us for it. We get along. It may very well be in the future that some sections of society choose to stay where they are and not to go this way and others sections choose to go this way. And that's fine too. What's not fine is to say today overpopulation or whatever let's not go there let's impose our values and make everyone Amish in the future. That's not fair. 

Go on. 
- The first you showed for the therapies where you have this kind of like you mentioned about like you have to apply the therapy to like reach half of the one third and like that. But I'm kind of curious what I could see is that like you're more or less having the same amount of -- same amount of like recovery rate need to do each time because the pink curve is exponentially decreasing so it becomes almost flat and so each time you have applied a therapy there person you're actually not decreasing -- 
- If you think it through that's what you would expect. This is the limit. This is the slowest that you could get and still stay above the frailty threshold. Because what's happening here is that each time you're knocking off the a certain chuck of the amount of damage that you're not repairing, right? So the rate at which the overall amount of damage is increasing is slower than it was previously because there are less types of damage that are increasing. So each of these lines has -- is increasingly closer to horizontal and so you expect to have to do less each 20 years. It's what you would except. 

- So the damage is not the orange line but the blue line? 
- Yes, that's right. The blue line. The reserve, the Y axis, is the amount of damage that you can afford to accumulate before frailty happens. So, yes, each of the blue lines is the trajectory of how much damage you have or equivalently how much reserve you have left. And the orange line is the individual, you know, what's happening. So the orange line is, for a particular individual, how much damage they actually have. And the blue lines are the trajectory of the damage that the therapy doesn't yet repair. So back here, for example, okay, this chunk of damage here could be repaired but none of this could. And so these blue lines are just notional at that point. 

But down here they become less notional because -- yep? 
- Like have you taken has something new if like you can? 
(inaudible)
 
- I think that-- Okay, so this is actually something that I used to, I guess, misjudge in terms of people's reception of the whole thing. It's perfectly clear to me that the hardest part of all of this is going those first 40 years. Going to this point. That's really tough. And I think we got a 50/50 chance of going there within maybe 30 years. But I think we've got at least a 10% chance of not going there in a hundred years if we just hit a lot of problems. 

What I'm much, much more certain about is that once we get to here this is going to happen. We're going to have no trouble staying ahead of the longevity escape velocity. I think that answered your question. In the back. 
- I was just wondering how you would assess fixing or engineering the damage that occurs -- the quote-unquote damage that occurs with every replication. 
(inaudible)
 
- yeah, okay. So this is something that I've published on but it's pretty controversial and a lot of people don't agree with me on this but I reckon my logic is pretty sound. There are a bunch of things that can happen to a cell when it accumulates mutations. 

One thing that can happen is that it can die. Okay? We've got a solution to that. Stem cell therapy. Cell loss right? Another thing is that it can get into a state where can refuses to die. Okay? So the immune system has this problem. You accumulate cells that are not doing anything. They won't proliferate when they should but they also won't die and they get in the way they inhibit the proliferation of other cells. 

The third thing that can happen is that it will die quite easily but it will also proliferate really easily. And that's, of course, cancer. Uncontrollably. Now it may surprise you to learn that I think cancer is a really good thing. It's a really good news that we get cancer. Here's why. Cancer is so bad that just one cell going wrong can kill us fairly quickly in a fairly short order like ten or 20 years later. Anything else that goes wrong in a cell has to effect a lot of cells in order to matter. Now that means that the problem, the main problem that evolution has had in getting us to live as long as we do is cancer. And if we look at the nature of aging closely, we find that a lot of the aspects of aging are side effects of making sure that we don't die of cancer even younger than we do. 

In particular, the accumulation of mutations in the genome that have nothing to do with the cell cycle, is constrained, in terms of its race, simply by the fact that DNA repair and maintenance has to be incredibly good in order to stop us from dying of cancer at the age of four. So actually cancer is an enormous help. It has forced evolution to make a DNA repairing machinery unnecessarily good for other purposes. In other words, if we can just really, really fix cancer, then we're done. The other mutations are going to accumulate but they're not going to matter in terms of pathology until we're a lot older than we can ever get at the moment. So, yes, we're going to have to fix that in order to maintain longevity escape velocity in the long run but we're talking off the curve. We're talking over here. That's my view. 
- Are there any types of damage that we'll never be able to repair and does that imply that as life span increases we're continuously dependent on synthetic or artificial technologies organs, bones and teeth. 
- I don't agree with the structure of your question, because I think that what you call synthetic or non-biological technologies sort of blend into the biological ones. 

I think that at the moment we will almost certainly reach longevity escape velocity and robust human rejuvenation in these first few decades in fact almost overwhelmingly by using straightforward biotechnology, biomedical approaches to this. But I also think that increasingly we will use non-biological approaches. We already use them for some things of course, cochlear implants, you know, things like that. I think that as a non-biological sophistication improves that more and more things, more and more problems of aging will become easier to tackle by non-biological solutions than by biological solutions. So I think there will be a continuum and eventually we'll get to the point where yes, we'll be using a lot of non-biological solutions. 
- Is the slope on this curve -- exclusive of science and exclusive of technology -- is the slope on that curve dependent on money more than anything else today to reach robust regeneration? 
- Yes, it is. I think at this point, you know, lots of research is happening that's useful. So it's not entirely that progress is zero. Certainly not. 

Lots of stuff is happening in stem cells, for example. But most of the seven -- that I'm talking about are definitely not proceeding as fast as they could if people -- if there were more appropriately directed funding. There are in each case really, you know, absolutely world class scientists who work in this general space and who have all the expertise necessary and who are interested in working on these particular things but they don't work on them because other things are easier to fund or easier to get publications for and, you know, the sort of things that scientists tend to have to prioritize. That why I started the Methuselah Foundation because with a bit of change, I can -- with a bit of money I can change that. I used to give up somewhat slip and slide that said scientists will do anything interesting for food. And that's more or less true. Certainly, I mean, I'm well integrated into I know personally all of the world leading scientists in all of these various fields. I'm constantly communicating with them and trying to control them into doing stuff when I can't pay them as well as now of course increasingly actually paying them. So really at this point I've done all the hard work other than getting enough money sent in the direction of the appropriate project. Far side. 

(inaudible)
 
- Specific treatment is going to change extremely fast. It's going only when these things come along clearly there's going to be massive pressure to engage in incremental refinements that do not simply do this sort of thing in terms of the comprehensiveness but also improve the cost. No question about that. However, even at the beginning when these things are very expensive indeed, I do not foresee any significant delay between the point where they're available to anyone and the point where they're available to everybody. That seems, you may think, to be a very unrealistic and optimistic prediction. But here's why. There's going to be this gap between the point where we get proof of concept in mice and the point where we get these therapies in humans. That gap is going to be a absolute minimum of ten years and it's very likely to be 15 or 20 years and it might be a lot longer than that. 

That's a long time for society to get its head around the whole thing. And, in particular, it's time for society to have a few general elections in which it's going to be impossible to get elected unless you have a manifesto commitment not only to put enough public money in, as well as, of course, encouraging private money, to get the research done but also to get all of training of the medical personnel and sufficient numbers and all of the building and factories and so on so that when the therapies do finally arrive, the serious decisions have been made -- the serious money's been spent. This is going to be straightforward for a bunch of reasons. First of all it's going to matter to people. You know, it's not going to be the economy stupid in the famous Clinton phrase. It's going to matter more. It's going to be a wartime mentality when people are willing to embrace a certain amount of -- of standard of living in order to end the slaughter as soon as possible once they actually see it that way. But more than that even from an economic point of view it's going to be easy to justify. Because being frail is not just risky, it doesn't just kill people, it's really expensive. I don't know if you know the statistic but the average person in the west consumes a lot more medical expenses in their last year of life than in the whole of the rest of their life put together. 

And that's irrespective of how old they are when they die. So we won't have that anymore. We won't have frail people anymore with these technologies and all that money is going to be saved. Even at the beginning when these therapies are very expensive. That expense will be absolutely dwarfed by the amount we save by not having to keep people alive in a grisly state for an extra year or two. 
- All right now this is more of an opinionated type of answer. 
- You can tell I don't like that. 
- How do you think that the whole psychological process is going to be different because, I mean, someone thinks differently when they're 25 versus 45. So 150 versus 100. I mean, how do you think that's going to differ. 

- Well I'm 44. I was 45 yesterday. Okay, so I mean I can see some changes in both myself and my -- you know, people of my age with regard to how they behave toward -- in terms of youth and so on. So I, for example, I feel that in some ways I'm absolutely as much of a child as I ever was. You know, I still enjoy the same sort of informality. I still live like a student. But on the other hand I despise most of modern music. I still listen to stuff that was from the '60s and '70s and '80s, right? So there's plenty of things that I can see even in myself, let alone in society, that are clearly aged structured. The question is will that actually be to the extent that that might be a good thing is it going to go away? 

And to the extent that it might be a bad thing, you know, the people are sort of old before their time if you like. Will that go away? And I again I feel pretty good about this. I think that the more health you have, the more vigor you have, the more options you have to change to choose to go to discos with your granddaughter if you want to. You know, things like that which people just don't have at the moment. So I think there inevitably will be a greater degree of variety among society with regards the sorts of people that people are at given ages but I think that's fine. And equally there will be more mixing between those groups. You know, age will matter less. And there's another question. Yeah, you have one. 

- Sort of an evolutionary ambivalency in terms of how there hasn't been a lot of -- 
- Evolution is a function-- Sorry, aging is a function of evolutionary neglect, yeah. 
- And so in the future as you proposed, more in terms of things that then -- 
(inaudible)
 Do you think that there could be the potential of evolutionary ambivalency in the other direction? 
- No. Basically evolution of the human race is, at this point, already overwhelmingly under our own control. We're actually, at the genetic level, we are evolving far faster now than we ever did before and we're doing so because the evolutionary pressures the selected pressures on the individual genes and genetic pathways are being altered by technology, by civilization. The immune system is a fine example. A lot of the -- it's pretty much accepted now that a lot of the reasons why people's immune systems tend to be worse now than they used to be -- and more allergies and stuff like that -- is because of the absence of selective pressure imposed by infectious diseases. 

You can get away with having a weak immune system whereas previously you would die before having any kids. So that would happen even in a accelerated rate especially when we get to the point of being able to have good and effective and safe gene therapy. We will be doing our own evolution. 
- Their own treatments in the future. Do you think that will be limited at all by own only intellectual capacity -- 
(inaudible)
 
- That's a pretty hard question. I think probably not. Simply because we're so good at enhancing our intellectual capacity at all with computers and so on. 

- What about species that have no predators. 
(inaudible)
 
- You mean why don't they age? 
(inaudible)
 
- They do of course live, in general, a lot longer than organisms that do have natural predators. That is the dominant determinant. But it's not the only determinant. Because even the organisms that have no predators they still have other causes of death that are not age related. 

Things like starvation and especially hypothermia, accidents, infections, all these things count for the same thing. Anything that's extrinsic contributes to the determination of how much evolution cares about aging. 
- Is there some sort of, you know, evolutionary sort of pressure for aging that we haven't quite comprehended yet? 
- There are still a few gerontologists who look at that. Who are interested in the possibility that that might be so. Because there's so much data out there which in some way looks a bit like, you know, an aging program. The fact that all of everything goes wrong more or less simultaneous, for example, is often brought up. But in each of these cases, one can see that actually is indeed what you expect from the absence of an aging program. But at this point, very few gerontologist take seriously the idea that there is an aging program. Essentially in order for there to be a aging program you have to have a model for how the aging program would not only evolve but also be retained. 

In other words, how it would actually be a good thing for the species. And people just haven't succeeded in finding a model for that. 
(inaudible)
 
- Speak up, speak up. 
- Are these therapies going to get rid of things like wrinkles and gray hair? 
- Yes, they are. If we can fix the inside than it's going to be pretty damned easy to fix the outside. 
- Are there categories of diseases that will be difficult to deal with like auto-immune diseases. 
- There are plenty of diseases that will be difficult to deal with but luckily they, the point in the train of events where we're targeting, in other words these ongoing types of damages, the precursors of various diseases, right. 

The cause and effect relationship is very complex and indeed not really known and, in fact, it probably won't be well known for a while. But that's fine. If we fix all the various types of damage then by definition since structure defines function, we are fixing all the consequences of the damage. So auto immune disease -- well, sure, that's important but what will they come from? They come from inadequacy of the immune system. And certainly to the extent that auto immune problems are age related. That people's allergies get worse, for example, then yes, that will be something that will be fixed by the rejuvenation of the immune system even though that rejuvenation is being done for more life threatening reasons. I've exhausted you all. Oh, no I haven't. One more. 

- If you were to fix something, you need to know what's broken. 
- That's not necessarily true. Carry on. 
- Well, how do you propose to do surveillance in realtime of entire organisms in order to be able to target different therapies? 
- All right, good question. So the question is -- it's quite a profound question so I want to make sure everybody heard it. The objection that the questioner gave is okay how do you know -- in order to fix something you got to know that it's broken. You've got to know that the thing is in some way -- you know, would be better in some other way. How are you going to know this? You mentioned surveillance of the organism in some way. 

The thing is we can sidestep all of our ignorance about that by a very simple trick. All we have to do is look at the difference between younger people and older people. And I don't mean children and really old people here. I'm talking about, let's say between 25 and 40. Now the difference is at the molecular and cellular level between someone who's 25 and someone who's 40 are pretty small. I mean, I'm 45 now and I can still run more or less as fast as I could when I was 25 and I can still think more or less as fast. I'm functionally more or less intact. But as things stand I've got a considerably shorter remaining life span and that's of course got to be a function of what I'm made of. Of my of composition at the molecular and cellular level. Now, therefore, if we look at the composition of an older person and we find differences and we know differences between that person and a younger person and we can say if we reverse those differences, that's going to be a good thing. 

We can't say that if we reverse some individual difference it's going to be a good thing because a lot of those individual differences may be adaptations, may be compensations but they'll be compensations for other differences. So if we put everything back the way it was at a younger age, we know we're going to have the result we want even though we don't know which of the things were actually bad for us and which were not. I'm all for fixing things that might not matter. All right. 
(inaudible)
 The issue of evolution and the objective of evolution. 
- Yeah. 
- So if the objective of evolution, survival of species, it seemed like that there may be some innate aging mechanism going on that hasn't been identified and still hasn't been identified. Because you've got two different possibilities to sustain the species. One is you have a higher turnover rate, right? 

Faster death rate. Or you have a very, very slow turnover rate. Either of those strategies will result in survival of species but so far it appears evolutionary from our experience we're on a high turnover rather than a slow turnover objective. 
- So that doesn't work. And the reason it doesn't work is because you're thinking about turnover in an environment that's protected. You're thinking about an environment in which most organisms die of decrepitude. Most organisms in the world do not die of decrepitude. In a typical ecological niche in the wild, most organisms -- nearly all organisms die of starvation or hypothermia or whatever. Okay. Evolution has to work within that. 

Evolution can't change that. Okay. Evolution has -- for a particular species evolution is going to work on that species to maximize the number of offspring that the species has and so on in order for the species to survive. And it's going to do so in the context of the mortality rate that's going to happen anyway. And therefore in the context in the fact that not many organisms are going to have offspring at the age of 50 because they're all going to be dead from other causes than aging. So that's why aging doesn't matter at those ages. 
- But evolution does not -- the evolutionary pressures are not restricted to just creatures in the wild. We're subject to evolutionary pressures -- 
- You're right, and I mentioned that earlier in respect to the immune system ago. But that's very recent. 

We age now simply because we always did age when we were in the wild. Which was actually not very long ago in evolutionary terms, remember. So eventually we'll fix it. But yes, at the moment, you're quite right, at the moment our environment, our protected environment is imposing evolutionary pressure to live longer. And for just the same reason that, you know, if you took a species that lived a very short life span and you put it in a protected environment the same pressure would exist. But that pressure has only been applied very recently and it hasn't done the job yet because it's a very hard job to do. I think we really ought to stop. I'm desperately thirsty so anyone who wants to ask more questions can follow me.