Fascinating People :: Aubrey de Grey

Some years ago I happened to meet a fellow name Aubrey de Grey at a party. de Grey was fascinating then, and he remains so now -- seen by some as a harbinger of advances in medical science, but also viewed by others as a quack. de Grey's thesis is simple, and yet also incredible: He believes that medicine will, at some point in the future, be able to counteract the aging process, and quite possibly do so in our lifetimes.

Already, science has made significant strides in the study of aging. It seems that we grow old and enfeebled due, at least in part, to an ongoing process that affects our cells: With each cellular division, a part of the cell's chromosome called a telomere loses a little bit of its length. As the telomeres shorten, the aging process grows more pronounced. The eventual result is cellular breakdown, and the death of an organism at the cellular level.

But other factors are involved, also. As we age, we're exposed over time to free radicals in food; those can cause problems like cancer. Even oxygen, which is immediately necessary to human life, is likely to cause cancer over time. Then there are the mechanical aspects of aging: Joints wear out, as do teeth. The brain loses neurological capacity faster than it can regenerate lost neurons. The body's tissues get gunked up -- quite literally, as it turns out, but de Grey explains this better than I could. The point is, entropy seems poised to win the game.

On the other hand, the goal might not be immortality but rather a radical extension of life. de Grey doesn't claim that his work aims to eradicate aging so much as manage it. As far as that goes, there are already indications that this is a sound principle: By under-feeding test animals, researchers have determined they can prolong their lives; methods for artificially restoring telomeres are already being tested; and when it comes to diseases like cancer and spot problems like neurological deficiency and tissue replacement, stem cells still seem like a promising approach.

In the years since our interview, de Grey has gone on to be featured in documentaries, make appearances on talk shows like "The Colbert Report," given a TED talk, co-author a book titled "Ending Aging," assume the role of editor-in-chief at the journal Rejuvenation Research, and be written up -- with varying degrees of seriousness -- in any number of different publications, including TIME Magazine. He's also the focus of a new documentary titled "The Immortalists." His message has gained some traction.

de Grey has also attracted his share of criticism. That's to be expected; any truly visionary advance tends to be met at first with scorn and skepticism, because scientists can be a hardheaded and conservative lot. This all to better, given the nature of scientific inquiry; as Carl Sagan said, "Extraordinary claims require extraordinary evidence." Then again, as someone else noted, "In principle, anything is possible," and it's exquisite possibilities that excite scientists.

The evidence, in this case, will be in years lived, and so the jury remains out. Meantime, the best way to understand what's at stake, and what may one day be possible, is to start at the start -- and that's where we're going this week, with a re-print of the interview I did with de Grey (over a decade ago, now!) for a different, now-defunct, website.

Dear readers, the fascinating Aubrey de Grey.

EDGE: Your idea of aging is that it isn't simply something to be managed, but potentially it's something that might be cured?

Aubrey de Grey: Yes, well, I wouldn't go so far as to say that's my idea. I think everyone who thinks about aging at all accepts that, in principle, it's something we ought to be able to cure.

So, let me first define what I mean by "cure." What I mean is, to have as much control over it as we have over things like tuberculosis -- diseases that we pretty much know what we're dealing with. That means not simply stopping its progression, but reversing its progression -- taking someone from a state of advanced suffering from the thing, whether it's something like tuberculosis, or whether it's aging, to a state where they are not suffering from the thing.

EDGE: So your idea is that someone in the advanced stages of this disease -- aging -- can be made well again.

Aubrey de Grey: Well the specific point of my idea is that we might eventually reach the point of being able to do that fairly soon, because I have a reasonably detailed idea of how to go about it. Saying we can [achieve a cure for aging] in principle is not very controversial, but it's also not very useful because "in principle" [means] eventually, sometime in the next couple of centuries...

EDGE: And your idea is to bring about a cure for aging in the near future.

Aubrey de Grey: That's right, a few decades. Twenty or thirty years.

EDGE: What's the first thing that needs to happen in order to make this possible?

Aubrey de Grey: Well, a very large number of things need to happen if you go down to the level of mechanistic detail of what advances need to be made in the science -- if I try to be a little bit less detailed, then the first big thing that needs to happen is to have a big effect on aging in mice.

Now, when I say "a big effect," what I mean is not simply a significant extension of the healthy life span of mice, I mean a significant extension of the healthy life span by an intervention that is only initiated when the mouse had already got most of the way through its life span -- let's say, a middle-aged mouse. A two-year-old mouse. Until we can do things to middle aged animals, most of society isn't going to pay any attention, in the same way society didn't pay any attention... when people worked out how to double the life span of nematode worms.

We have the misfortune to be already alive, and so if we figure out how do germ-line genetic modifications, for example, to make mice which have not yet been conceived live twice as long as normal, then that's all very well, but unless it's easy to see how to translate those interventions to a somatic form, in other words, into a form that can be applied to organisms that are already alive, people cannot identify with it. And especially really cannot identify with it unless you can do it not simply to organisms that are already alive, but organisms that are already somewhat advanced in years.

EDGE: When we were talking about this earlier, it sounded as though you have been thinking of such intervention not only in terms of being a medical procedure, but as a form of engineering.

Aubrey de Grey: That's not quite how I would put it. Medical procedures are engineering. The distinction that I think I can make between how I think about fixing aging, and the way that most of my colleagues think about it, is that most of my colleagues don't really think about it as medicine at all, and therefore they don't think about it as a type of engineering. They think about it as a sort of trying to copy evolution.

[But] evolution doesn't do medicine, it does new types of organisms. And evolution is, actually, pretty good at creating long-lived organisms starting from relatively short-lived organisms. But not only does it take a long time to do it, it also has very different tools from what we have, so it can't really do what we would call engineering. It doesn't have the right sort of ways to manipulate DNA in the test tube, for example. It's only when one starts to think about how one could approach these [questions] in a medical way that one starts to be able to see the sorts of avenues that are available to us that aren't available to evolution, and of course it's only when one starts identifying the possible approaches that one can actually evaluate their feasibility and thereby get some sort of estimate of the time-frame in which we might be able to implement it.

EDGE: So when you say that this may come about in the next few decades, you've thought this through in terms of what has to happen and in what sequence.

Aubrey de Grey: That's right. The first step that I mentioned was to get serious progress in mice. Mice normally live for about three years. The numbers I usually put on this [are], we have to be able to take mice who are two years old before we do anything to them at all, we do stuff to them that makes them live, on average, five years rather than three years, trebling their remaining life expectancy at the age of two years, when they are already middle aged.

EDGE: What would that translate to in terms of human life expectancy?

Aubrey de Grey: That would translate into taking a fifty-year-old, who would normally live until eighty, and making him live until one hundred and thirty. And let's absolutely stress the point that all of this extension of life span would be healthy years. We wouldn't be keeping somebody in a state equivalent to the age of seventy-nine, akin to being a year away from death for fifty years; it would be keeping someone at, essentially, age fifty or less for those extra fifty years, and only then would they have the decline.

EDGE: So you do expect there would be some rejuvenating effect?

Aubrey de Grey: Definitely. There would have to be. You can't keep frail people alive. Being frail is risky, and always will be. Frail people will die. It's only robust people who are at low risk of dying.

To come back to your question about the reasons for my time scale, the thing is, we ought to be able to do this in mice within ten years. It's very inadvisable, and indeed unjustifiable, for a scientist to make predictions beyond, roughly, the twenty-year time scale if those predictions are indivisible. But I don't do that. I say in ten years we ought to be able to do a whole bunch of things in mice, and of course I can go through the details if necessary, and we will produce mice of the sort I've just described, whose life span is extended by that sort of amount. That will be enough to change society's attitude toward the inevitability of aging sufficiently that we will see an almost indescribable influx of money and effort into the translation of such technology from mice to humans.

Now, money isn't everything. There's only so fast that science can go, even with an infinite amount of money, but with an indefinite amount of funding, the problems that I know of that could stand in the way of translating this technology from mice to humans would be very unlikely to take more than about ten years to be fixed. So that means we might not take the trouble to fix those things in the first ten years -- the ten years starting now -- but by the time we've got the [long-lived] mice, and therefore the motivation, it shouldn't be more than another ten years to fix all the things I can think of that could stand in the way of translating that technology from mice to humans.

Now, I throw in an extra five or ten years on top of that, basically because I know there are going to be things that I haven't foreseen, that will also stand in the way -- and of course, this is an estimate. It could be that we will only take five years to get from the mice to the humans; it could equally be, I completely acknowledge, a hundred years, because we might hit problems that are much harder than anything we've thought of so far. But I think it's important for people like me who know a lot about the biology of aging to take the responsibility to science seriously in this, and to make their best guess as to how long these things are going to take.

Most my colleagues disagree with me on this. Most of them will absolutely refuse to answer a question that starts with the words, "How long is it going to be...?" Just because they say it's not scientific -- it's, in some sense, abusing their exalted status as scientists and experts in their fields. And I completely agree with that in fields that have no biomedical relevance, because, ultimately, you don't know what's going to happen, you should only say what you know. But in a field that does have biomedical relevance, in which one's best assessment of the situation affects one's life choices, I think that the general public have the right to hear the best information from the people who know best, even if the people who know best know that they still don't know very well.

EDGE: Already, people are conscious enough about the aging process to know that they need to maintain their health, to keep fit, to keep supplements and vitamins, to keep the sorts of decline that they can control, like arteriosclerosis, at bay. They undergo medical intervention, sometimes cosmetic and sometimes more profound, to avoid decrepitude; they even take hormones -- for example, androgens, to maintain lean muscle mass. How is your approach going to differ from what's already being done?

Aubrey de Grey: Eventually it's going to differ, because there are a lot of things that all the things we can do at the moment simply don't even slow down, let alone reverse at all. And those things are really -- well, they're fatal, ultimately. They turn into pathologies and into loss of function in the various tissues, and eventually they kill us. Things like, for example, the accumulation of mutations in our chromosomes -- that's how we get cancer. If you can't fix cancer, there's no point in fixing anything else.

Supposing we fixed everything else that was responsible for the increasing risk of death per unit time that we experience as we get older, but you don't fix cancer, then the net result would be an extension of life expectancy by no more than about ten or fifteen years -- and everyone would die of cancer. Cancer is not much fun to die of, so I regard this as an altogether unsatisfactory outcome. You have to fix everything.

The stuff that we can do at the moment, of the sorts that you listed, definitely have their place. They extend the time that one can live in a robust way and be active and all that sort of thing a little bit. Usually only a little bit, but a little bit is better than nothing. But it's just not good enough. You've got to do better than that.

EDGE: So are you at liberty to say, specifically, in what you your procedure differs? Are you talking about changing the cells, or doing some sort of gene therapy?

Aubrey de Grey: Certainly I'm at liberty! I take great pains to stay at liberty. I have no commercial involvement in anything whatsoever, and I find this actually to be a very important part of how I'm able to do the work I do. I can't be accused of vested interest. So, yes! All the stuff that I'm interested in is at the molecular and / or cellular level. And that's because it's the early events that are really only microscopic and that have not yet translated themselves into large-scale problems for the organism, it's at that stage that things are quite simple.

There are not many types of things that go wrong with this that accumulate gradually over time. It's only later in the process of that accumulation that things begin to spiral out of control and feed back on each other in a really complicated way. I like to give the analogy of maintaining a house in a state that is intact and inhabitable. We are very good at this -- we can keep houses intact and inhabitable more or less indefinitely, certainly for much longer than we can keep ourselves intact and inhabitable. And the way we do it is by a moderate amount of maintenance, but it's the right sort of maintenance. There's storm damage [that] happens to a roof, for example. We don't just wait and let water get in and ceilings come down and staircases collapse, and so on, and then try to fix the staircases and the ceilings, but not fix the roof; we fix the proximate problem, the actual roof. So this is a sort of analogy for why geriatric medicine is fundamentally short-term, it's a losing battle.

But conversely, we don't simply try to pre-empt the damage to the roof by, for example, planting lots of tall trees around the house as a windbreak, because that's only a partial solution, a very partial solution. First of all, storm damage is going to happen anyway; secondly, other types of storm damage that might be worse might happen, for example, bits blowing off the trees and making bigger holes in the roof. So pre-emption is no good either, really, not on its own, and that's the sort of attitude that most gerontologists take.

It turns out that this is a good analogy. I don't like to hang too much on analogies without justification, but the reason why this is a good analogy is because metabolism -- the process of the storm damage, the myriad of molecular and cellular processes that keep us alive from one day to the next -- is an incredibly complicated thing. We know a lot about our biology right now, but that's nothing [compared] to the amount that we don't know yet. We've really hardly scratched the surface, and there are good ways to explain that we really have an enormous amount to learn. So if you try to mess about with metabolism -- in other words, if you try to be truly pre-emptive about it -- then... we're just not in a state where we're likely to design interventions whose benefits will outweigh their deleterious side effects. It's not the way to go. And it's for that reason that most of my colleagues feel that we're many decades away from getting anything like as far as I say we can get in a couple of decades.

The reason they say that is because they overlook the alternative of fixing the roof -- in other words, of letting the metabolism do what it does, lay down the molecular and cellular damage like mutations and loss of cells and so on -- but simply stop that damage from ever reaching this threshold level at which it starts to really spiral. If you can do that, or even if you take someone in whom it has started to spiral, but you take away the primary problem so that the secondary problems become [simple,] like an inflammation, and they can basically be sorted out by what the body already knows how to do, if you can do that, you've basically uncoupled being alive from being dead. You've uncoupled metabolism from pathology. And it turns out that this isn't such a tall order.

Pathology is nearly as complicated as metabolism. The types of things that go wrong with people who are really getting on and really getting frail are really messy, and if you don't die of cancer or of heart disease or whatever, then you tend to die, at a slightly older age, of what you could only really call multi-organ system failure, which basically means, it's so complicated we haven't even got a name for it. Intuitively, one would think if the metabolism is so complicated that we can't get to grips with it yet, and pathology is also so complicated that we can't really even get names for it all, then we haven't a hope. But it turns out that's not the case. It turns out there's this sort of nexus, this sort of fulcrum in the middle of the causal chain of events, which is the microscopic damage, which turns out to be really simple.

I normally list only seven serious things that go wrong with us throughout our lives, seven things that, shall we say, distinguish a forty-year-old from a twenty-year-old, and explain why a forty-year-old has so much a shorter remaining life expectancy than the twenty-year-old. The seven things are, number one: We lose cells from some of our tissues, like the brain, the heart -- cells die and they aren't replaced.

Number two, as I said, we get mutations in our chromosomes, and that causes cancer.

Number three, we get mutations in a special component of the cell called the mitochondrion, which has its own DNA, and they may or may not matter, but they might matter, and so they count as a candidate mechanism [for the effects of aging].

Number four is something called cell senescence: Basically, cells can into a state as the result of, usually, DNA damage, but also as the result of excessive division, where they change what genes they express in a bunch of ways, and they cease to be able to divide, but they may be actively toxic to their environment. There aren't very many of these cells in the body, even in elderly people, but there are more [in elderly people] than there are in younger people, so that counts as a possible bad thing.

Number five is, there are cross-links. There are chemical reactions that happen between proteins and other things, and this happens especially, unfortunately, in the extra-cellular matrix, so in proteins which have been secreted out of cells and which have built structures that are important -- things like the blood vessels, for example. There are proteins in the blood vessels that hang around for many, many years, and they react with things in the circulation, especially sugars. It turns out that some of these chemical reactions can cause cross-linking, chemical bonds between proteins that are not supposed to be bonded together. And this reduces the elasticity of the artery wall, and causes hardening of the arteries, and that's another thing that happens progressively throughout life.

Number six is junk in the extra-cellular space, so basically this is important in a bunch of things, especially in Alzheimer's disease. You just get accumulations of aggregated proteins that are sitting there between the cells, and there are more of them in older people. They may actually not be bad for us, but they may be bad for us -- they may be important in Alzheimer's, for example. We shouldn't let them accumulate. It can't be bad to get rid of them.

And the seventh one is accumulation of junk again, but inside the cells rather than outside. There's a special compartment inside of cells called the lysosome, which is, if you like, the degradation machinery of last resort in the cell. There are many different types of machines that we have in the cells that degrade things; if they fail, basically the lysosome gets the hard work to do. But there are some things that even the lysosome can't degrade.

Okay, so there are these seven things. That's all very well, and if you list these things and ask any gerontologist, "Is this a complete list?" they may demure a little bit, but more or less they will say yes. I would say one can add to this list, but only by adding things that are really, really easy to fix, compared to the things I described. One of them is excess fat. Excess fat is almost certainly the major reason why we get diabetes, and particularly what's called visceral fat, as opposed to fat immediately under the skin, so the central abdominal adiposity that you have when have a beer gut is the sort of fat that matters [in terms of] diabetes. But fixing those is just taking something away, and it may not be terribly easy to take it away -- it's a bit harder than just liposuction, but it's really not very hard compared to the stuff I'm talking about.

Critical thing, though: All of the seven things I've listed, even though they may be harder to fix than that, but still, I know how to fix them, and when I say "I know," [what I mean is] I know the literature and I know the people who are doing the experimental work to develop ways to fix each of these things. Not just to slow them down, but to actually reverse the damage. Or sometimes to obviate the damage, in other words, to disable the mechanism by which the accumulation of the problem can ever be harmful, pathologically. And all of these things are some way along, and are moving rapidly enough.

So, for example, [the problem of] loss of cells is well known. Stem cell therapy is what is designed to fix this, and as you, stem cell therapy is proceeding rapidly in many, many [sorts of] tissues, and so that's why things are proceeding so [rapidly] in so many different areas of stem cell therapy. All the other things I've talked about, in general, the things that can fix them well enough to [help] us live more or less indefinitely are less high profile, but none the less, solid scientific published work is available [on these other therapies] and things are moving fast.

It's because I can see that there are now good potential ways in the foreseeable future to fix all of these things, initially in mice and then in humans, that's what gives me the confidence to say what I say about life expectancy.

EDGE: Do you think that socially, or even religiously or politically, people are ready for the idea of an significantly extended life span?

Aubrey de Grey: I do -- I know that they're ready. The way I know they're ready is this: People say to me, "Well, wouldn't it be a terribly dangerous thing to have all this overpopulation, or boredom, or tyrants living forever," and so on. But then they ask me, "How long is it going to be?" They actually do want to know how long it's going to be [before human beings might start living far longer lives], and they wouldn't want to know if they didn't want to take advantage of it.

It's perfectly clear. I mean, there are plenty of perfectly interesting, valid, ethical arguments, pro and con, as to the desirability of actually extending human healthy life span a lot. But when people are faced with the choice, these arguments are just going to vanish, because it's a visceral thing. Dying is not what we are built to like. We are built to be keen to carry on living and to help each other to carry on living. We don't like letting people die.

And it could certainly be pretty tough in many ways to re-organize society appropriately to cope with a different age structure. Certainly, there are very likely to be serious impacts on the ability to have as many children as you'd like. Children are [already] getting progressively more and more unpopular, as far as we can tell -- more and more people are choosing not to have children. But realistically, it's unlikely that the rate of [population decline due solely to] that phenomenon will be enough to stop there being, eventually, a population crisis such that one would need to impose a certain amount of birth control. I say, get over it! It's better than letting people die.

EDGE: And for yourself? You seem like a very young person to dedicate his life to the proposition of defeating, or at least delaying, death.

Aubrey de Grey: Well, I see your point. But I don't really see it that way. As far as I'm concerned, we have roughly two people die every second, worldwide, and more than half of those people die of causes that young people more or less never die of. So we're talking about [the fact that] aging kills one person a second, it kills a hundred thousand people a day, it kills thirty or fifty million people a year. This is a serious number of people. And saving lives is good.

I don't actually think of it in terms of saving my own life as much as I used to. Of course, when I first got into this, I was thinking [of my own prospects]. One thinks selfishly by default. But the more I've been working on it, the more I appreciate the value of saving other people's lives as well. So at whatever level the science is, whether I feel there's any chance of saving my own life, or whether I feel that it goes without saying that I'll save my own life and it's only older people that I need to worry about, every day that I help to bring forward the true defeat of human aging is saving a hundred thousand lives, which is like, you know, thirty World Trade Centers. It's a serious business.

EDGE: So if the answer does come clear to us, but it's too late for you -- that'll still be okay?

Aubrey de Grey: I wouldn't go so far as to say I'd be okay, but I'd certainly feel a great deal happier than I would feel if I had given up at the age of 41 on bothering with all this and just gone and become a mathematician for the rest of my life. I'll feel that I did my best for the world. Already, in the short time that I've been [working] in this area [of science], I'm quite sure that I've made a significant difference to the date at which we will actually have defeated human aging.

EDGE: And if the answer comes clear sooner and you do get to take advantage of a longer life, what do you expect you would do with that extra time?

Aubrey de Grey: It would take me most of that time just to list the things that I would do. I will not run out of ideas.