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Advancing Conversations: Aubrey de Grey

John Hunt Publishing Ltd.

Part One

The Science of Indefinite Life Extension

Douglas Lain: I thought I'd start our conversation with a joke from Louis CK. Louis says that when you're forty and you go to the doctor, they don't try to fix anything anymore. Once you get over forty they don't try to fix you, they just say, "Yeah, that starts to happen." And they don't care. He says he went to doctor because his ankle hurt and the doctor showed him an x-ray and said: "Yeah, your ankle is just worn out. They get shitty like that when you're older. They're just not good anymore." I thought I'd start by asking if this is really a general attitude that people have, if doctors have that attitude, and if there is any truth in this joke.

Aubrey de Grey: Yes. There is an enormous amount of truth in it. And I think we need to distinguish here a little bit between the medical profession – doctors and other people in the medical world – as against the rest of the world. The medical profession have the enormous problem, which we need to sympathize with, that they have a certain range of tools to work with, to help people to be healthier and to restore people to health, but those tools are very limited in their efficacy. In particular they're extremely limited with regard to what they can do for people who are getting old. Ultimately, your average doctor just has to work with what they have, and a lot of that involves management of expectations. That's really all that Louis CK is saying there. Right?

Of course, that doesn't say anything about what might happen in the future. What might be possible in terms of maintenance or restoration of youthful good health with medicines that haven't yet been developed. But, that is not what doctors are supposed to be interested in. Doctors are all about doing their best with the tools that are already available.

Now contrast that with the situation that the general public has. The general public are not providing care, they are the recipient of medical care. And they are the people who should be thinking about the potential improvement in that medical care that might arise from further advances, from progress in the laboratory. It's kind of beholden on the public and therefore on policy makers and opinion formers and so on ... to actually drive this, to actually deliver the funding and general resources that are required to allow people like SENS research foundation to move forward and create therapies that don't yet exist. Once those therapies do exist, of course they enter the universe of tools that your doctor can actually prescribe, can actually administer. But until that time, it's not the problem of the doctors. It's not their fault.

Douglas: So it's no surprise to you that doctors aren't turning to you now, you haven't developed anything that they ... any tools for them to use yet.

Aubrey: You've got it. Doctors are using tools that already exist.

Douglas: Let's start then by defining our terms and figuring out the full scope of the project that your foundation SENS is working on. That's "Strategies for Engineering Negligible Senescence." That's what SENS stands for. What is aging? This is what you're fighting. What is aging and how do you and others who are working on achieving negligible senescence define that term and how does the scientific community think about aging, perhaps in contrast to how you think about it?

Aubrey: Aging is a really simple phenomenon. A lot of people in the broader world presume that aging is still a mystery, that nobody understands really what's going on. But that's bullshit. The actual fact is that people who study the biology of aging feel that they have a pretty good understanding of what's actually going on. Sure we could always get a better understanding, there are details that are still unclear, but at the end of the day the fundamentals are really well understood.

The aging of a human being, or any living organism, is actually really similar, really very similar, to the aging of an inanimate object like a car or an airplane. It's simply the accumulation of damage as a side effect of the machine's normal operation. So, in exactly the same way that a car will progressively accumulate rust and eventually the doors will fall off, similarly the human body accumulates ... well, the equivalent of rust, various types of molecular and cellular damage, and eventually that damage accumulates to a level of abundance that is more than what the body is set up to tolerate. And that's when the overall function of the body starts to decline.

That's all that aging is. It's a really simple phenomenon. That's not controversial at all, you ask any gerontologist, any person who studies the biology of aging, what aging is, then they may use slightly different words, but essentially they'll say what I just said. Then the question is, what will we do about it? And certainly there are many different approaches that people have taken to that.

I believe the approach that SENS Research Foundation is taking, which is essentially a comprehensive damage-repair approach, is the most promising. But, some people have been working hard for a long time on the idea of simply slowing down the rate at which the body creates that damage in the first place. And that's another alternative. No question. It's another alternative. As things stand it looks to me very much as though that alternative is never going to work. It's not. It's far less practical than the damage-repair approach. But, we shall see.

Douglas: Maybe the people who are working on slowing down the damage that the body does to itself have a slightly different conception of what aging is. They tend to talk about changing the genes, almost like we have a clock that ticks through our lives, and then at a certain point the alarm goes off. Am I misunderstanding this? Is there a slight difference here in the perspective on aging?

Aubrey: Yes you are misunderstanding. There is really no difference in perspective. Everyone understands that ultimately the reason why an older body works less well than a younger body is because the older body is carrying around more damage. The damage has come to exist as a result of the body's normal operation. The things that body has to do to keep us alive. There is really no controversy about that. The only real controversy is with regards to what is plausible in terms of dealing with that damage, in terms of making that damage go away, or slowing down the accumulation of that damage. So, the language that is often used, especially when gerontologists talk to the general public and journalists, may be a little misleading sometimes. Some of my colleagues, for example, let me pick out Cynthia Kenyon who is a good friend and an excellent scientist, but she sometimes is prone to use language that journalists misunderstand as in some way implying that aging is the consequence of some kind of program. She doesn't really mean that, she is just talking about the modulation, the ability of the body to modulate the rate of aging in response to certain pressures. And she'll often, of course, speak about her own work which is in very short-lived organisms. But, ultimately there is not a fundamental difference between her view and my view of what aging actually is.

Douglas: Have previous attempts to overcome aging ... there's a long history of people working to defeat aging, going back to really pre-scientific times. Have previous attempts to overcome this process had a different conception of aging?

Aubrey: That's a great question. I really don't think they have. I think that even if you go back to Roger Bacon in the 1200s or whatever, you've still got an understanding that aging is a medical problem that should be amenable to medical intervention. And certainly if we go back to, for example, the '50s when the free-radical theory of aging was first put forward, that was the first really bona fide molecular theory of how aging actually goes on. And there, it was totally clear. Everyone understood, even back then, that the process of aging consists of the accumulation of damage.

Douglas: To me it seems like there are two different issues once you come to accept that aging is just this process where the body damages itself as it goes through its daily practices and that the damage is going to build up over time, and that when you start to think about intervening, the first thought that comes to mind is maybe not too realistic. It's about overcoming death. The other though is about extending our good health.

I can imagine that if there really was a program, there isn't, but if there was a program in the body somehow that just was set so that we all die at seventy-six years of age, that your kind of intervention, what you're talking about, would still be really worth investing in because even if you didn't extend life you would be improving people's health dramatically by undoing that damage.

Aubrey: Well you're right. Yeah.

There is an awful lot of talk around gerontologists about the idea of what they often call the compression of morbidity. In other words, essentially extending the healthy lifespan without similarly extending total lifespan. Therefore reducing the gap between the two, the amount of time that people spend at the end of life being unhealthy. That sounds terribly seductive and, of course, it's very politically correct and that's probably why so many of my colleagues have spent so much time highlighting their ideas that this might in principle be possible, but in practice it's not possible at all. Pretty much all of my colleagues accept perfectly well, that actually the only way we're ever going to extend lifespan is by extending healthspan, by extending healthy lifespan. That ultimately, being frail, being in a bad state of health, is always going to be risky. It's always going to be a state in which your likely future lifespan is short. Your likelihood of dying soon is high. Therefore, the only way we're ever going to get any kind of serious extension of lifespan is as a side effect of postponing ill health in the first place, in other words by extending healthy lifespan.

Douglas: And your organization is working on many things that will extend a healthy lifespan and that I would think people would be very excited about even if they're not truly interested in longevity. I saw a video presentation on your site about heart disease and macro-phages and undoing the damage done by oxidized cholesterol. I would think that you wouldn't have to be a gerontologist interested in longevity research but could just be a heart specialist and be very interested in what you're working on. So, how solid is the science behind that speculation and do you anticipate that this project might be able to contribute to breakthrough therapies before you get everything else in line to truly extend the lifespan?

Aubrey: You very cogently highlight the issue here – the relationship between the diseases of old age on the one hand and aging itself on the other hand. Essentially what you're really doing is highlighting the fact that there is no such thing as aging itself. In other words, that all of the aspects of the ill health of old age are intertwined. There is no real profit, no real merit, in trying to dissect them or to bifurcate that set of problems into things that are diseases on the one hand and things that are not diseases on the other hand. It's just ... it's pointless. It makes no sense, and it's counterproductive because it makes people overoptimistic about some aspects of aging and unduly pessimistic about others.

In particular, if we look at, for example, the case that you mentioned of the role of oxidized cholesterol in driving heart disease then we can say, okay, yeah, heart disease is the number-one killer in the Western world and therefore if we could develop ways to enhance the robustness of white blood cells so they would be able to continue to process cholesterol without being poisoned by oxidized cholesterol the way they are today, then great! We might be able to more or less entirely prevent heart disease. But what would that mean in terms of the extension of healthy lifespan? Not a lot.

It turns out that, because of the exponential nature of the relationship between age and the risk of these diseases, we would only actually extend healthy lifespan by a few years, three or four years, before all the other things kicked in – cancer and Alzheimer's and so on – that were also increasing exponentially with age. We've got to hit the entire spectrum.

Douglas: I want to give you an opportunity to really lay out your perspective, especially this point about how you can't escape the diseases of old age without overcoming aging. That's very significant, but I'm so much on board with what you're doing that I'm looking for ways for you to get more support. It seems to me that there are people who might be reluctant to get involved in longevity research or working on all of these different pieces, but that if you could present this approach to the people who are working on heart disease, they would be very excited just in their little niche. I'm wondering if that is the case, or what the response to what you're doing is from those people.

Aubrey: Certainly it has been noticed that the real problem here is the relationship between how aging is perceived versus how the diseases of old age are perceived. We recognize that in order to majorly postpone the ill health of old age we would need to get all of these things working, reasonably effectively. That's a very tall order that isn't going to happen any time soon. So, for sure, it makes a lot sense to think about how we could appeal to the specific disease communities with regard to the effectiveness of these therapies against individual diseases. Let's just take heart disease as an example. Atherosclerosis is the ultimate driver of heart attacks and strokes, therefore it's the number-one killer in the Western world. We have this approach that involves bringing in new genes from bacteria that encode enzymes that will be able to break down oxidized cholesterol and therefore protect white blood cells in the artery wall from being poisoned by that contaminant. It's a great idea and it would certainly have an effect on atherosclerosis. We believe that it could be a much more potent therapy against atherosclerosis than anything that exists today.

But, there are a couple of issues there. The first issue is if we asked what the impact of that would be on longevity the answer is really small. The fact that all the diseases of old age have a progression that is exponentially related to age. In other words your chance of having Alzheimer's, for example, at age seventy-five is twice that at age seventy. And your chance of having it age eighty is twice what it was at age seventy-five. That is actually a real kicker when it comes longevity, because it means even if we completely eliminated atherosclerosis from the population it would still only extend people's healthy lifespan and therefore people's total lifespan by three or four years. That's a problem. The other problem is the way that ... it's kind of related ... the way that the disease community sees these things. If you have a therapy that postpones the ill health of atherosclerosis by five years, that is tantamount to a cure by most people's standards within the disease community, because they measure the effectiveness of their therapies under the assumption that no progress has been simultaneously made in postponing ill health from other diseases like cancer or Alzheimer's or whatever. This is a completely crazy assumption, but nevertheless it's the way they measure things. So, they don't think in terms of aiming as high as we're aiming.

Douglas: There are two hurdles to overcome in the thinking that's going on right now in the medical community or in the scientific community. The first one is just ... there is a lot of resistance, for a variety of reasons, to longevity as a goal or to tackling the damage that the body does to itself or just to do something about aging or intervening in that process directly. There is a lot of resistance to that. But then, there is also seemingly a resistance to just this damage-repair model itself. To what extent is this approach, this maintenance model, in play in the medical community now? How much of this type of thinking is going on just when it comes to treating diseases rather than something big and systemic like aging?

Aubrey: Great question. Both within the medical disease-specific community and within the gerontology community the idea of damage repair is kind of a Cinderella concept. Because on the one hand people understand that in the ideal world it would be the Holy Grail, it would be the way to go. You would be able to take people who are already suffering from this or that condition, or are close to suffering from it, and you would be able to turn the clock backwards and get to the point where they were, essentially, in a youthful condition whether in relation to a specific disease or in relation to all aspects of age-related ill health, but the issue is how you do it. And the only reason I was able to come along fifteen years ago and put this idea forward is because I brought together a whole bunch of ideas that came from a wide variety of different areas of biology.

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Excerpted from Advancing Conversations: Aubrey de Grey by Douglas Lain. Copyright © 2015 Douglas Lain. Excerpted by permission of John Hunt Publishing Ltd..
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