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TEDTalks, Aubrey de Grey – Why we age and how we can avoid it (2005)

Aubrey de Grey – Why we age and how we can avoid it (2005)

18 minutes is an absolutely brutal time limit, so I'm going to dive straight in, right at the point where I get this thing to work. Here we go. I'm going to talk about five different things. I'm going to talk about why defeating aging is desirable. I'm going to talk about why we have to get our shit together, and actually talk about this a bit more than we do. I'm going to talk about feasibility as well, of course. I'm going to talk about why we are so fatalistic about doing anything about aging. And then I'm going spend perhaps the second half of the talk talking about, you know, how we might actually be able to prove that fatalism is wrong, namely, by actually doing something about it. I'm going to do that in two steps. The first one I'm going to talk about is how to get from a relatively modest amount of life extension -- which I'm going to define as 30 years, applied to people who are already in middle-age when you start -- to a point which can genuinely be called defeating aging. Namely, essentially an elimination of the relationship between how old you are, and how likely you are to die in the next year -- or indeed, to get sick in the first place. And of course, the last thing I'm going to talk about is how to reach that intermediate step, that point of maybe 30 years life extension. So I'm going to start with why we should. Now, I want to ask a question. Hands up: Anyone in the audience who is in favor of malaria? That was easy. OK. OK. Hands up, anyone in the audience who's not sure whether malaria is a good thing or a bad thing? OK. So we all think malaria is a bad thing. That's very good news, because I thought that was what the answer would be. Now the thing is, I would like to put it to you that the main reason why we think that malaria is a bad thing is because of a characteristic of malaria that it shares with aging. And here is that characteristic. The only real difference is that aging kills considerably more people than malaria does.

Now, I like in an audience, in Britain especially, to talk about the comparison with fox-hunting, which is something that was banned after a long struggle, by the government not very many months ago. I mean, I know I'm with a sympathetic audience here, but, as we know, a lot of people are not entirely persuaded by this logic. And this is actually a rather good comparison, it seems to me. You know, a lot of people said, "Well, you know, city boys have no business telling us rural types what to do with our time. It's a traditional part of the way of life, and we should be allowed to carry on doing it. It's ecologically sound; it stops the population explosion of foxes." But ultimately, the government prevailed in the end, because the majority of the British public, and certainly the majority of members of Parliament, came to the conclusion that it was really something that should not be tolerated in a civilized society.

And I think that human aging shares all of these characteristics in spades. What part of this do people not understand? It's not just about life, of course -- (Laughter) it's about healthy life, you know -- getting frail and miserable and dependent is no fun, whether or not dying may be fun. So really, this is how I would like to describe it. It's a global trance. These are the sorts of unbelievable excuses that people give for aging. And, I mean, OK, I'm not actually saying that these excuses are completely valueless. There are some good points to be made here. Things that we ought to be thinking about, forward planning so that nothing goes to hell, so that we minimize the turbulence when we actually figure out how to fix aging.

But these are completely crazy, when you actually remember your sense of proportion. You know, these are arguments, these are things that would be legitimate to be concerned about. But the question is, are they so dangerous -- these risks of doing something about aging -- that they outweigh the downside of doing the opposite, namely, leaving aging as it is? Are these so bad that they outweigh condemning 100,000 people a day to an unnecessarily early death. You know, if you haven't got an argument that's that strong, then just don't waste my time is what I say. (Laughter) Now, there is one argument that some people do think really is that strong, and here it is. People worry about overpopulation; they say, "Well, if we fix aging, no one's going to die to speak of, or at least the death toll is going to be much lower, only from crossing St. Giles carelessly. And therefore, we're not going to be able to have many kids, and kids are really important to most people." And that's true. And you know, a lot of people try to fudge this question, and give answers like this. I don't agree with those answers. I think they basically don't work. I think it's true, that we will face a dilemma in this respect. We will have to decide whether to have a low birth rate, or a high death rate. A high death rate will, of course, arise from simply rejecting these therapies, in favor of carrying on having a lot of kids.

And, I say that that's fine -- the future of humanity is entitled to make that choice. What's not fine is for us to make that choice on behalf of the future. If we vacillate, hesitate, and do not actually develop these therapies, then we are condemning a whole cohort of people -- who would have been young enough and healthy enough to benefit from those therapies but will not be, because we haven't developed them as quickly as we could -- we'll be denying those people an indefinite life span, and I consider that that is immoral. That's my answer to the overpopulation question. Right. So the next thing is, now why should we get a little bit more active on this? And the fundamental answer is that the pro-aging trance is not as dumb as it looks. It's actually a sensible way of coping with the inevitability of aging. Aging is ghastly, but it's inevitable, so, you know, we've got to find some way to put it out of our minds, and it's rational to do anything that we might want to do, to do that. Like, for example, making up these ridiculous reasons why aging is actually a good thing after all. But of course, that only works when we have both of these components. And as soon as the inevitability bit becomes a little bit unclear, and we might be in range of doing something about aging, this becomes part of the problem. This pro-aging trance is what stops us from agitating about these things. And that's why we have to really talk about this a lot -- evangelize, I will go so far as to say -- in order to get people's attention, and make people realize that they are in a trance in this regard. So that's all I'm going to say about that. I'm now going to talk about feasibility. And the fundamental reason, I think, why we feel that aging is inevitable is summed up in a definition of aging that I'm giving here. A very simple definition. Aging is a side effect of being alive in the first place, which is to say, metabolism. This is not a completely tautological statement; it's a reasonable statement. Aging is basically a process that happens to inanimate objects like cars, and it also happens to us, despite the fact that we have a lot of clever self-repair mechanisms, because those self-repair mechanisms are not perfect.

So basically, metabolism, which is defined as basically everything that keeps us alive from one day to the next, has side effects. Those side effects accumulate and eventually cause pathology. That's a fine definition. So we can put it this way: we can say that, you know, we have this chain of events. And there are really two games in town, according to most people, with regard to postponing aging. They're what I'm calling here the gerontology approach and the geriatrics approach. The geriatrician will intervene late in the day, when pathology is becoming evident, and the geriatrician will try and hold back the sands of time, and stop the accumulation of side effects from causing the pathology quite so soon. Of course, it's a very short-termist strategy, it's a losing battle, because the things that are causing the pathology are becoming more abundant as time goes on. The gerontology approach looks much more promising on the surface, because, you know, prevention is better than cure. But unfortunately the thing is that we don't understand metabolism very well. In fact, we have a pitifully poor understanding of how organisms work -- even cells we're not really too good on yet. We've discovered things like, for example, RNA interference only a few years ago, and this is a really fundamental component of how cells work. Basically, gerontology is a fine approach in the end, but it is not an approach whose time has come when we're talking about intervention. So then, what do we do about that? I mean, that's a fine logic, that sounds pretty convincing, pretty iron-clad, doesn't it? But it isn't. Before I tell you why it isn't, I'm going to go a little bit into what I'm calling step two. Just suppose, as I said, that we do acquire -- let's say we do it today for sake of argument -- the ability to confer 30 extra years of healthy life on people who are already in middle age, let's say 55. I'm going to call that robust human rejuvenation. OK. What would that actually mean for how long people of various ages today -- or equivalently, of various ages at the time that these therapies arrive -- would actually live? In order to answer that question -- you might think it's simple, but it's not simple. We can't just say, "Well, if they're young enough to benefit from these therapies, then they'll live 30 years longer." That's the wrong answer. And the reason it's the wrong answer is because of progress. There are two sorts of technological progress really, for this purpose. There are fundamental, major breakthroughs, and there are incremental refinements of those breakthroughs. Now, they differ a great deal in terms of the predictability of time frames. Fundamental breakthroughs: very hard to predict how long it's going to take to make a fundamental breakthrough. It was a very long time ago that we decided that flying would be fun, and it took us until 1903 to actually work out how to do it. But after that, things were pretty steady and pretty uniform. I think this is a reasonable sequence of events that happened in the progression of the technology of powered flight. We can think, really, that each one is sort of beyond the imagination of the inventor of the previous one, if you like. The incremental advances have owed up to something which is not incremental anymore.

This is the sort of thing you see after a fundamental breakthrough. And you see it in all sorts of technologies. Computers, you can look at a more or less parallel time line, happening of course a bit later. You can look at medical care. I mean, hygiene, vaccines, antibiotics -- you know, the same sort of time frame. So I think that actually step two, that I called a step a moment ago, isn't a step at all. That in fact, the people who are young enough to benefit from these first therapies that give this moderate amount of life extension, even though those people are already middle-aged when the therapies arrive, will be at some sort of cusp. They will mostly survive long enough to receive improved treatments that will give them a further 30 or maybe 50 years. In other words, they will be staying ahead of the game. The therapies will be improving faster than the remaining imperfections in the therapies are catching up with us.

This is a very important point for me to get across. Because, you know, most people, when they hear that I predict that a lot of people alive today are going to live to 1,000 or more, they think that I'm saying that we're going to invent therapies in the next few decades that are so thoroughly eliminating aging that those therapies will let us live to 1,000 or more. I'm not saying that at all. I'm saying that the rate of improvement of those therapies will be enough. They'll never be perfect, but we'll be able to fix the things that 200-year-olds die of, before we have any 200-year-olds. And the same for three- and 400 and so on. I decided to give this a little name, which is "longevity escape velocity." (Laughter) Well, it seems to get the point across.

So, these trajectories here are basically how we would expect people to live, in terms of remaining life expectancy, as measured by their health, for given ages that they were at the time that these therapies arrive. If you're already 100, or even if you're 80 -- and an average 80-year-old, we probably can't do a lot for you with these therapies, because you're too close to death's door for the really initial, experimental therapies to be good enough for you. You won't be able to withstand them. But if you're only 50, then there's a chance that you might be able to pull out of the dive and, you know -- (Laughter) eventually get through this. And start becoming biologically younger in a meaningful sense, in terms of your youthfulness, both physical and mental, and in terms of your risk of death from age-related causes. And of course, if you're a bit younger than that, then you're never really even going to get near to being fragile enough to die of age-related causes. So this is a genuine conclusion that I come to, that the first 150-year old -- we don't know how old that person is today, because we don't know how long it's going to take to get these first-generation therapies. But irrespective of that age, I'm claiming that the first person to live to 1,000 -- subject of course, to, you know, global catastrophes -- is actually, probably, only about 10 years younger than the first 150-year old. And that's quite a thought. All right, so finally I'm going to spend the rest of the talk, my last seven and a half minutes, on step one; namely, how do we actually get to this moderate amount of life extension that will allow us to get to escape velocity? And in order to do that, I need to talk about mice a little bit. I have a corresponding milestone to robust human rejuvenation. I'm calling it robust mouse rejuvenation, not very imaginatively. And this is what it is. I say we're going to take a long-lived strain of mouse, which basically means mice that live about three years on average. We do exactly nothing to them until they're already two years old. And then we do a whole bunch of stuff to them, and with those therapies, we get them to live, on average, to their fifth birthday. So, in other words, we add two years -- we treble their remaining lifespan, starting from the point that we started the therapies.

The question then is, what would that actually mean for the time frame until we get to the milestone I talked about earlier for humans? Which we can now, as I've explained, equivalently call either robust human rejuvenation, or longevity escape velocity. Secondly, what does it mean for the public's perception of how long it's going to take for us to get to those things, starting from the time we get the mice? And thirdly, the question is, what will it do to actually how much people want it? And it seems to me that the first question is entirely a biology question, and it's extremely hard to answer. One has to be very speculative, and many of my colleagues would say that we should not do this speculation, that we should simply keep our counsel until we know more.

I say that's nonsense. I say we absolutely are irresponsible if we stay silent on this. We need to give our best guess as to the time frame, in order to give people a sense of proportion so that they can assess their priorities. So, I say that we have a 50/50 chance of reaching this RHR milestone, robust human rejuvenation, within 15 years from the point that we get to robust mouse rejuvenation. 15 years from the robust mouse. The public's perception will probably be somewhat better than that. The public tend to underestimate how difficult scientific things are. So they'll probably think it's five years away. They'll be wrong, but that actually won't matter too much. And finally, of course, I think it's fair to say that a large part of the reason why the public is so ambivalent about aging now is the global trance I spoke about earlier, the coping strategy. That will be history at this point, because it will no longer be possible to believe that aging is inevitable in humans, since it's been postponed so very effectively in mice. So we're likely to end up with a very strong change in people's attitudes, and of course that has enormous implications. So in order to tell you now how we're going to get these mice, I'm going to add a little bit to my description of aging. I'm going to use this word "damage" to denote these intermediate things that are caused by metabolism, and that eventually cause pathology. Because the critical thing about this is that even though the damage only eventually causes pathology, the damage itself is caused ongoingly throughout life, starting before we're born. But it is not part of metabolism itself. And this turns out to be useful. Because we can re-draw our original diagram this way. We can say that, fundamentally, the difference between gerontology and geriatrics is that gerontology tries to inhibit the rate at which metabolism lays down this damage. And I'm going to explain exactly what damage is in concrete biological terms in a moment. And geriatricians try to hold back the sands of time by stopping the damage converting into pathology. And the reason it's a losing battle is because the damage is continuing to accumulate. So there's a third approach, if we look at it this way. We can call it the engineering approach, and I claim that the engineering approach is within range. The engineering approach does not intervene in any processes. It does not intervene in this process, or this one. And that's good because it means that it's not a losing battle, and it's something that we are within range of being able to do, because it doesn't involve improving on evolution. The engineering approach simply says, "Let's go and periodically repair all of these various types of damage -- not necessarily repair them completely, but repair them quite a lot, so that we keep the level of damage down below the threshold that must exist, that causes it to be pathogenic." We know that this threshold exists, because we don't get age-related diseases until we're in middle age, even though the damage has been accumulating since before we were born. Why do I say that we're in range? Well, this is basically it. The point about this slide is actually the bottom. If we try to say which bits of metabolism are important for aging, we will be here all night, because basically all of metabolism is important for aging in one way or another. This list is just for illustration, it is incomplete. The list on the right is also incomplete. It's a list of types of pathology that are age-related, and it's just an incomplete list. But I would like to claim to you that this list in the middle is actually complete, this is the list of types of thing that qualify as damage, side effects of metabolism that cause pathology in the end, or that might cause pathology. And there are only seven of them. They're categories of thing, of course, but there's only seven of them. Cell loss, mutations in chromosomes, mutations in the mitochondria and so on.

First of all, I'd like to give you an argument for why that list is complete. Of course one can make a biological argument. One can say, OK, what are we made of? We're made of cells and stuff between cells. What can damage accumulate in? The answer is, long-lived molecules, because if a short-lived molecule undergoes damage, but then the molecule is destroyed -- like by a protein being destroyed by proteolysis -- then the damage is gone, too. It's got to be long-lived molecules. So, these seven things were all under discussion in gerontology a long time ago and that is pretty good news, because it means that, you know, we've come a long way in biology in these 20 years, so the fact that we haven't extended this list is a pretty good indication that there's no extension to be done. However, it's better than that; we actually know how to fix them all in mice, in principle -- and what I mean by in principle is, we probably can actually implement these fixes within a decade. Some of them are partially implemented already, the ones at the top.

I haven't got time to go through them at all, but my conclusion is that, if we can actually get suitable funding for this, then we can probably develop robust mass rejuvenation in only 10 years, but we do need to get serious about it. We do need to really start trying. So of course, there are some biologists in the audience, and I want to give some answers to some of the questions that you may have. You may have been dissatisfied with this talk, but fundamentally you have to go and read this stuff. I've published a great deal on this; I cite the experimental work on which my optimism is based, and there's quite a lot of detail there. The detail is what makes me confident of my rather aggressive time frames that I'm predicting here. So if you think that I'm wrong, you'd better damn well go and find out why you think I'm wrong. And of course the main thing is that you shouldn't trust people who call themselves gerontologists because, as with any radical departure from previous thinking within a particular field, you know, you expect people in the mainstream to be a bit resistant and not really to take it seriously. So, you know, you've got to actually do your homework, in order to understand whether this is true. And we'll just end with a few things. One thing is, you know, you'll be hearing from a guy in the next session who said some time ago that he could sequence the human genome in no time, and everyone said, "Well, it's obviously impossible." And you know what happened. So, you know, this does happen. We have various strategies -- there's the Methuselah Mouse Prize, which is basically an incentive to innovate, and to do what you think is going to work, and you get money for it if you win. There's a proposal to actually put together an institute. This is what's going to take a bit of money. But, I mean, look -- how long does it take to spend that on the war in Iraq? Not very long. OK. (Laughter) It's got to be philanthropic, because profits distract biotech, but it's basically got a 90 percent chance, I think, of succeeding in this. And I think we know how to do it. And I'll stop there. Thank you. (Applause) Chris Anderson: OK. I don't know if there's going to be any questions but I thought I would give people the chance. Audience: Since you've been talking about aging and trying to defeat it, why is it that you make yourself appear like an old man? (Laughter) AG: Because I am an old man. I am actually 158. (Laughter) (Applause) Audience: Species on this planet have evolved with immune systems, to fight off all the diseases so that individuals live long enough to procreate. However, as far as I know, all the species have evolved to actually die, so when cells divide, the telomerase get shorter, and eventually species die. So, why does -- evolution has -- seems to have selected against immortality, when it is so advantageous, or is evolution just incomplete?

AG: Brilliant. Thank you for asking a question that I can answer with an uncontroversial answer. I'm going to tell you the genuine mainstream answer to your question, which I happen to agree with. Which is that, no, aging is not a product of selection; evolution is simply a product of evolutionary neglect. In other words, we have aging because it's hard work not to have aging; you need more genetic pathway, more sophistication in your genes in order to age more slowly, and that carries on being true the longer you push it out. So, to the extent that evolution doesn't matter, doesn't care whether genes are passed on by individuals, living a long time or by procreation, there's a certain amount of modulation of that, which is why different species have different lifespans, but that's why there are no immortal species. CA: The genes don't care but we do? AG: That's right. Audience: Hello. I read somewhere that in the last 20 years, the average lifespan of basically anyone on the planet has grown by 10 years. If I project that, that would make me think that I would live until 120 if I don't crash on my motorbike. That means that I'm one of your subjects to become a 1000 year old? AG: If you lose a bit of weight. (Laughter) Your numbers are a bit out. The standard numbers are that lifespans have been growing at between one and two years per decade. So, it's not quite as good as you might think -- you might hope. But I intend to move it up to one year per year as soon as possible.

Audience: I was told that many of the brain cells we have as adults are actually in the human embryo, and that the brain cells last 80 years or so. If that is indeed true, biologically are there implications in the world of rejuvenation? If there are cells in my body that live all 80 years, as opposed to a typical, you know, couple of months?

AG: There are technical implications certainly. Basically what we need to do is replace cells in those few areas of the brain that lose cells at a respectable rate, especially neurons, but we don't want to replace them any faster than that -- or not much faster anyway, because replacing them too fast would degrade cognitive function. What I said about there being no non-aging species earlier on was a little bit of an oversimplification. There are species that have no aging -- Hydra for example -- but they do it by not having a nervous system -- and not having any tissues in fact that rely for their function on very long-lived cells.

http://www.ted.com/talks/aubrey_de_grey_says_we_can_avoid_aging.html

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Aubrey de Grey – Why we age and how we can avoid it (2005)

18 minutes is an absolutely brutal time limit, so I'm going to dive straight in, right at the point where I get this thing to work. Here we go. I'm going to talk about five different things. I'm going to talk about why defeating aging is desirable. I'm going to talk about why we have to get our shit together, and actually talk about this a bit more than we do. I'm going to talk about feasibility as well, of course. I'm going to talk about why we are so fatalistic about doing anything about aging. And then I'm going spend perhaps the second half of the talk talking about, you know, how we might actually be able to prove that fatalism is wrong, namely, by actually doing something about it. I'm going to do that in two steps. The first one I'm going to talk about is how to get from a relatively modest amount of life extension -- which I'm going to define as 30 years, applied to people who are already in middle-age when you start -- to a point which can genuinely be called defeating aging. Namely, essentially an elimination of the relationship between how old you are, and how likely you are to die in the next year -- or indeed, to get sick in the first place. And of course, the last thing I'm going to talk about is how to reach that intermediate step, that point of maybe 30 years life extension. So I'm going to start with why we should. Now, I want to ask a question. Hands up: Anyone in the audience who is in favor of malaria? That was easy. OK. OK. Hands up, anyone in the audience who's not sure whether malaria is a good thing or a bad thing? OK. So we all think malaria is a bad thing. That's very good news, because I thought that was what the answer would be. Now the thing is, I would like to put it to you that the main reason why we think that malaria is a bad thing is because of a characteristic of malaria that it shares with aging. And here is that characteristic. The only real difference is that aging kills considerably more people than malaria does.

Now, I like in an audience, in Britain especially, to talk about the comparison with fox-hunting, which is something that was banned after a long struggle, by the government not very many months ago. I mean, I know I'm with a sympathetic audience here, but, as we know, a lot of people are not entirely persuaded by this logic. And this is actually a rather good comparison, it seems to me. You know, a lot of people said, "Well, you know, city boys have no business telling us rural types what to do with our time. It's a traditional part of the way of life, and we should be allowed to carry on doing it. It's ecologically sound; it stops the population explosion of foxes." But ultimately, the government prevailed in the end, because the majority of the British public, and certainly the majority of members of Parliament, came to the conclusion that it was really something that should not be tolerated in a civilized society.

And I think that human aging shares all of these characteristics in spades. What part of this do people not understand? It's not just about life, of course -- (Laughter) it's about healthy life, you know -- getting frail and miserable and dependent is no fun, whether or not dying may be fun. So really, this is how I would like to describe it. It's a global trance. These are the sorts of unbelievable excuses that people give for aging. And, I mean, OK, I'm not actually saying that these excuses are completely valueless. There are some good points to be made here. Things that we ought to be thinking about, forward planning so that nothing goes to hell, so that we minimize the turbulence when we actually figure out how to fix aging.

But these are completely crazy, when you actually remember your sense of proportion. You know, these are arguments, these are things that would be legitimate to be concerned about. But the question is, are they so dangerous -- these risks of doing something about aging -- that they outweigh the downside of doing the opposite, namely, leaving aging as it is? Are these so bad that they outweigh condemning 100,000 people a day to an unnecessarily early death. You know, if you haven't got an argument that's that strong, then just don't waste my time is what I say. (Laughter) Now, there is one argument that some people do think really is that strong, and here it is. People worry about overpopulation; they say, "Well, if we fix aging, no one's going to die to speak of, or at least the death toll is going to be much lower, only from crossing St. Giles carelessly. And therefore, we're not going to be able to have many kids, and kids are really important to most people." And that's true. And you know, a lot of people try to fudge this question, and give answers like this. I don't agree with those answers. I think they basically don't work. I think it's true, that we will face a dilemma in this respect. We will have to decide whether to have a low birth rate, or a high death rate. A high death rate will, of course, arise from simply rejecting these therapies, in favor of carrying on having a lot of kids.

And, I say that that's fine -- the future of humanity is entitled to make that choice. What's not fine is for us to make that choice on behalf of the future. If we vacillate, hesitate, and do not actually develop these therapies, then we are condemning a whole cohort of people -- who would have been young enough and healthy enough to benefit from those therapies but will not be, because we haven't developed them as quickly as we could -- we'll be denying those people an indefinite life span, and I consider that that is immoral. That's my answer to the overpopulation question. Right. So the next thing is, now why should we get a little bit more active on this? And the fundamental answer is that the pro-aging trance is not as dumb as it looks. It's actually a sensible way of coping with the inevitability of aging. Aging is ghastly, but it's inevitable, so, you know, we've got to find some way to put it out of our minds, and it's rational to do anything that we might want to do, to do that. Like, for example, making up these ridiculous reasons why aging is actually a good thing after all. But of course, that only works when we have both of these components. And as soon as the inevitability bit becomes a little bit unclear, and we might be in range of doing something about aging, this becomes part of the problem. This pro-aging trance is what stops us from agitating about these things. And that's why we have to really talk about this a lot -- evangelize, I will go so far as to say -- in order to get people's attention, and make people realize that they are in a trance in this regard. So that's all I'm going to say about that. I'm now going to talk about feasibility. And the fundamental reason, I think, why we feel that aging is inevitable is summed up in a definition of aging that I'm giving here. A very simple definition. Aging is a side effect of being alive in the first place, which is to say, metabolism. This is not a completely tautological statement; it's a reasonable statement. Aging is basically a process that happens to inanimate objects like cars, and it also happens to us, despite the fact that we have a lot of clever self-repair mechanisms, because those self-repair mechanisms are not perfect.

So basically, metabolism, which is defined as basically everything that keeps us alive from one day to the next, has side effects. Those side effects accumulate and eventually cause pathology. That's a fine definition. So we can put it this way: we can say that, you know, we have this chain of events. And there are really two games in town, according to most people, with regard to postponing aging. They're what I'm calling here the gerontology approach and the geriatrics approach. The geriatrician will intervene late in the day, when pathology is becoming evident, and the geriatrician will try and hold back the sands of time, and stop the accumulation of side effects from causing the pathology quite so soon. Of course, it's a very short-termist strategy, it's a losing battle, because the things that are causing the pathology are becoming more abundant as time goes on. The gerontology approach looks much more promising on the surface, because, you know, prevention is better than cure. But unfortunately the thing is that we don't understand metabolism very well. In fact, we have a pitifully poor understanding of how organisms work -- even cells we're not really too good on yet. We've discovered things like, for example, RNA interference only a few years ago, and this is a really fundamental component of how cells work. Basically, gerontology is a fine approach in the end, but it is not an approach whose time has come when we're talking about intervention. So then, what do we do about that? I mean, that's a fine logic, that sounds pretty convincing, pretty iron-clad, doesn't it? But it isn't. Before I tell you why it isn't, I'm going to go a little bit into what I'm calling step two. Just suppose, as I said, that we do acquire -- let's say we do it today for sake of argument -- the ability to confer 30 extra years of healthy life on people who are already in middle age, let's say 55. I'm going to call that robust human rejuvenation. OK. What would that actually mean for how long people of various ages today -- or equivalently, of various ages at the time that these therapies arrive -- would actually live? In order to answer that question -- you might think it's simple, but it's not simple. We can't just say, "Well, if they're young enough to benefit from these therapies, then they'll live 30 years longer." That's the wrong answer. And the reason it's the wrong answer is because of progress. There are two sorts of technological progress really, for this purpose. There are fundamental, major breakthroughs, and there are incremental refinements of those breakthroughs. Now, they differ a great deal in terms of the predictability of time frames. Fundamental breakthroughs: very hard to predict how long it's going to take to make a fundamental breakthrough. It was a very long time ago that we decided that flying would be fun, and it took us until 1903 to actually work out how to do it. But after that, things were pretty steady and pretty uniform. I think this is a reasonable sequence of events that happened in the progression of the technology of powered flight. We can think, really, that each one is sort of beyond the imagination of the inventor of the previous one, if you like. The incremental advances have owed up to something which is not incremental anymore.

This is the sort of thing you see after a fundamental breakthrough. And you see it in all sorts of technologies. Computers, you can look at a more or less parallel time line, happening of course a bit later. You can look at medical care. I mean, hygiene, vaccines, antibiotics -- you know, the same sort of time frame. So I think that actually step two, that I called a step a moment ago, isn't a step at all. That in fact, the people who are young enough to benefit from these first therapies that give this moderate amount of life extension, even though those people are already middle-aged when the therapies arrive, will be at some sort of cusp. They will mostly survive long enough to receive improved treatments that will give them a further 30 or maybe 50 years. In other words, they will be staying ahead of the game. The therapies will be improving faster than the remaining imperfections in the therapies are catching up with us.

This is a very important point for me to get across. Because, you know, most people, when they hear that I predict that a lot of people alive today are going to live to 1,000 or more, they think that I'm saying that we're going to invent therapies in the next few decades that are so thoroughly eliminating aging that those therapies will let us live to 1,000 or more. I'm not saying that at all. I'm saying that the rate of improvement of those therapies will be enough. They'll never be perfect, but we'll be able to fix the things that 200-year-olds die of, before we have any 200-year-olds. And the same for three- and 400 and so on. I decided to give this a little name, which is "longevity escape velocity." (Laughter) Well, it seems to get the point across.

So, these trajectories here are basically how we would expect people to live, in terms of remaining life expectancy, as measured by their health, for given ages that they were at the time that these therapies arrive. If you're already 100, or even if you're 80 -- and an average 80-year-old, we probably can't do a lot for you with these therapies, because you're too close to death's door for the really initial, experimental therapies to be good enough for you. You won't be able to withstand them. But if you're only 50, then there's a chance that you might be able to pull out of the dive and, you know -- (Laughter) eventually get through this. And start becoming biologically younger in a meaningful sense, in terms of your youthfulness, both physical and mental, and in terms of your risk of death from age-related causes. And of course, if you're a bit younger than that, then you're never really even going to get near to being fragile enough to die of age-related causes. So this is a genuine conclusion that I come to, that the first 150-year old -- we don't know how old that person is today, because we don't know how long it's going to take to get these first-generation therapies. But irrespective of that age, I'm claiming that the first person to live to 1,000 -- subject of course, to, you know, global catastrophes -- is actually, probably, only about 10 years younger than the first 150-year old. And that's quite a thought. All right, so finally I'm going to spend the rest of the talk, my last seven and a half minutes, on step one; namely, how do we actually get to this moderate amount of life extension that will allow us to get to escape velocity? And in order to do that, I need to talk about mice a little bit. I have a corresponding milestone to robust human rejuvenation. I'm calling it robust mouse rejuvenation, not very imaginatively. And this is what it is. I say we're going to take a long-lived strain of mouse, which basically means mice that live about three years on average. We do exactly nothing to them until they're already two years old. And then we do a whole bunch of stuff to them, and with those therapies, we get them to live, on average, to their fifth birthday. So, in other words, we add two years -- we treble their remaining lifespan, starting from the point that we started the therapies.

The question then is, what would that actually mean for the time frame until we get to the milestone I talked about earlier for humans? Which we can now, as I've explained, equivalently call either robust human rejuvenation, or longevity escape velocity. Secondly, what does it mean for the public's perception of how long it's going to take for us to get to those things, starting from the time we get the mice? And thirdly, the question is, what will it do to actually how much people want it? And it seems to me that the first question is entirely a biology question, and it's extremely hard to answer. One has to be very speculative, and many of my colleagues would say that we should not do this speculation, that we should simply keep our counsel until we know more.

I say that's nonsense. I say we absolutely are irresponsible if we stay silent on this. We need to give our best guess as to the time frame, in order to give people a sense of proportion so that they can assess their priorities. So, I say that we have a 50/50 chance of reaching this RHR milestone, robust human rejuvenation, within 15 years from the point that we get to robust mouse rejuvenation. 15 years from the robust mouse. The public's perception will probably be somewhat better than that. The public tend to underestimate how difficult scientific things are. So they'll probably think it's five years away. They'll be wrong, but that actually won't matter too much. And finally, of course, I think it's fair to say that a large part of the reason why the public is so ambivalent about aging now is the global trance I spoke about earlier, the coping strategy. That will be history at this point, because it will no longer be possible to believe that aging is inevitable in humans, since it's been postponed so very effectively in mice. So we're likely to end up with a very strong change in people's attitudes, and of course that has enormous implications. So in order to tell you now how we're going to get these mice, I'm going to add a little bit to my description of aging. I'm going to use this word "damage" to denote these intermediate things that are caused by metabolism, and that eventually cause pathology. Because the critical thing about this is that even though the damage only eventually causes pathology, the damage itself is caused ongoingly throughout life, starting before we're born. But it is not part of metabolism itself. And this turns out to be useful. Because we can re-draw our original diagram this way. We can say that, fundamentally, the difference between gerontology and geriatrics is that gerontology tries to inhibit the rate at which metabolism lays down this damage. And I'm going to explain exactly what damage is in concrete biological terms in a moment. And geriatricians try to hold back the sands of time by stopping the damage converting into pathology. And the reason it's a losing battle is because the damage is continuing to accumulate. So there's a third approach, if we look at it this way. We can call it the engineering approach, and I claim that the engineering approach is within range. The engineering approach does not intervene in any processes. It does not intervene in this process, or this one. And that's good because it means that it's not a losing battle, and it's something that we are within range of being able to do, because it doesn't involve improving on evolution. The engineering approach simply says, "Let's go and periodically repair all of these various types of damage -- not necessarily repair them completely, but repair them quite a lot, so that we keep the level of damage down below the threshold that must exist, that causes it to be pathogenic." We know that this threshold exists, because we don't get age-related diseases until we're in middle age, even though the damage has been accumulating since before we were born. Why do I say that we're in range? Well, this is basically it. The point about this slide is actually the bottom. If we try to say which bits of metabolism are important for aging, we will be here all night, because basically all of metabolism is important for aging in one way or another. This list is just for illustration, it is incomplete. The list on the right is also incomplete. It's a list of types of pathology that are age-related, and it's just an incomplete list. But I would like to claim to you that this list in the middle is actually complete, this is the list of types of thing that qualify as damage, side effects of metabolism that cause pathology in the end, or that might cause pathology. And there are only seven of them. They're categories of thing, of course, but there's only seven of them. Cell loss, mutations in chromosomes, mutations in the mitochondria and so on.

First of all, I'd like to give you an argument for why that list is complete. Of course one can make a biological argument. One can say, OK, what are we made of? We're made of cells and stuff between cells. What can damage accumulate in? The answer is, long-lived molecules, because if a short-lived molecule undergoes damage, but then the molecule is destroyed -- like by a protein being destroyed by proteolysis -- then the damage is gone, too. It's got to be long-lived molecules. So, these seven things were all under discussion in gerontology a long time ago and that is pretty good news, because it means that, you know, we've come a long way in biology in these 20 years, so the fact that we haven't extended this list is a pretty good indication that there's no extension to be done. However, it's better than that; we actually know how to fix them all in mice, in principle -- and what I mean by in principle is, we probably can actually implement these fixes within a decade. Some of them are partially implemented already, the ones at the top.

I haven't got time to go through them at all, but my conclusion is that, if we can actually get suitable funding for this, then we can probably develop robust mass rejuvenation in only 10 years, but we do need to get serious about it. We do need to really start trying. So of course, there are some biologists in the audience, and I want to give some answers to some of the questions that you may have. You may have been dissatisfied with this talk, but fundamentally you have to go and read this stuff. I've published a great deal on this; I cite the experimental work on which my optimism is based, and there's quite a lot of detail there. The detail is what makes me confident of my rather aggressive time frames that I'm predicting here. So if you think that I'm wrong, you'd better damn well go and find out why you think I'm wrong. And of course the main thing is that you shouldn't trust people who call themselves gerontologists because, as with any radical departure from previous thinking within a particular field, you know, you expect people in the mainstream to be a bit resistant and not really to take it seriously. So, you know, you've got to actually do your homework, in order to understand whether this is true. And we'll just end with a few things. One thing is, you know, you'll be hearing from a guy in the next session who said some time ago that he could sequence the human genome in no time, and everyone said, "Well, it's obviously impossible." And you know what happened. So, you know, this does happen. We have various strategies -- there's the Methuselah Mouse Prize, which is basically an incentive to innovate, and to do what you think is going to work, and you get money for it if you win. There's a proposal to actually put together an institute. This is what's going to take a bit of money. But, I mean, look -- how long does it take to spend that on the war in Iraq? Not very long. OK. (Laughter) It's got to be philanthropic, because profits distract biotech, but it's basically got a 90 percent chance, I think, of succeeding in this. And I think we know how to do it. And I'll stop there. Thank you. (Applause) Chris Anderson: OK. I don't know if there's going to be any questions but I thought I would give people the chance. Audience: Since you've been talking about aging and trying to defeat it, why is it that you make yourself appear like an old man? (Laughter) AG: Because I am an old man. I am actually 158. (Laughter) (Applause) Audience: Species on this planet have evolved with immune systems, to fight off all the diseases so that individuals live long enough to procreate. However, as far as I know, all the species have evolved to actually die, so when cells divide, the telomerase get shorter, and eventually species die. So, why does -- evolution has -- seems to have selected against immortality, when it is so advantageous, or is evolution just incomplete?

AG: Brilliant. Thank you for asking a question that I can answer with an uncontroversial answer. I'm going to tell you the genuine mainstream answer to your question, which I happen to agree with. Which is that, no, aging is not a product of selection; evolution is simply a product of evolutionary neglect. In other words, we have aging because it's hard work not to have aging; you need more genetic pathway, more sophistication in your genes in order to age more slowly, and that carries on being true the longer you push it out. So, to the extent that evolution doesn't matter, doesn't care whether genes are passed on by individuals, living a long time or by procreation, there's a certain amount of modulation of that, which is why different species have different lifespans, but that's why there are no immortal species. CA: The genes don't care but we do? AG: That's right. Audience: Hello. I read somewhere that in the last 20 years, the average lifespan of basically anyone on the planet has grown by 10 years. If I project that, that would make me think that I would live until 120 if I don't crash on my motorbike. That means that I'm one of your subjects to become a 1000 year old? AG: If you lose a bit of weight. (Laughter) Your numbers are a bit out. The standard numbers are that lifespans have been growing at between one and two years per decade. So, it's not quite as good as you might think -- you might hope. But I intend to move it up to one year per year as soon as possible.

Audience: I was told that many of the brain cells we have as adults are actually in the human embryo, and that the brain cells last 80 years or so. If that is indeed true, biologically are there implications in the world of rejuvenation? If there are cells in my body that live all 80 years, as opposed to a typical, you know, couple of months?

AG: There are technical implications certainly. Basically what we need to do is replace cells in those few areas of the brain that lose cells at a respectable rate, especially neurons, but we don't want to replace them any faster than that -- or not much faster anyway, because replacing them too fast would degrade cognitive function. What I said about there being no non-aging species earlier on was a little bit of an oversimplification. There are species that have no aging -- Hydra for example -- but they do it by not having a nervous system -- and not having any tissues in fact that rely for their function on very long-lived cells.

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