Aging: the foremost target of regenerative medicine

July 11th, 2008

The Methuselah Foundation is a 501c(3) non-profit organization committed to the acceleration of progress toward a cure for age-related disease.

Biogerontologist Aubrey de Grey has formulated a wide-ranging plan for the comprehensive and eventually indefinite postponement of age-related physical and mental decline, named Strategies for Engineered Negligible Senescence. He is the organizer of an ongoing series of conferences and workshops that focus on the key biomedical research relevant to SENS, the most recent of which was entitled “Aging: the disease, the cure, the implications.”

The following transcript of Aubrey de Grey’s presentation for Aging: The Cure, The Disease, The Implications has been corrected and approved by the speaker.

Aging: the foremost target of regenerative medicine

I am going to try in the first few remarks over the next ten minutes to give an overview and introduction to the first half of the evening. After the interval I am going to come back for another ten minutes and introduce the second half of the evening.

The reason I’m doing it that way is because the evening splits very cleanly between two parts, which you might think of as the “how” and the “why” of combating aging. In the first half of the session, we are going to hear from some luminaries in biology and biotechnology with regard to how aging can be challenged, especially in terms of future technology that comes under the heading of regenerative medicine.

One of the big reasons that we chose to run this conference now and in California is because I expect there is nobody in this room who is ignorant of the leadership position that California holds in regenerative medicine worldwide, with not only the scientific expertise that exists across the state but also the electoral support demonstrated very strongly with Proposition 71.

It seems to me to be most appropriate that in California we should be beginning the process of educating the public, and certainly policymakers and others, to the renewed possibilities for applying regenerative medicine to the problem of aging.

The title of my remarks that I have up here really sums it all up. Aging is bad for you. It is a degenerative condition, and thus a theoretical target of regenerative medicine. What I have come here today to tell you, and what my scientific colleagues will be telling you over the next hour or so, is that it is no longer simply a theoretical target of regenerative medicine. It is on its way to becoming a practical one.

Why is that? Really it comes down to this definition of aging that I have written down. This is something that gerontologists and people who study the biology of aging have known for a very long time, but it has not always been stated quite so explicitly.

Aging is very definitely a side effect of being alive in the first place. You accumulate various types of damage, just in the same way that a simple man-made machine like a car will accumulate damage as a side effect of its normal operation. Again, just like man-made machines, the human body can tolerate that damage with more or less no loss of function or performance for a very long time. The damage only starts to really matter when it reaches a threshold of abundance that is prejudicial to the optimal performance of metabolism.

In other words, the first half of life we are accumulating microscopic molecular and cellular changes, but those changes at that time are harmless. Yet, our remaining lifespan is becoming shorter and shorter as we see that threshold emerge and actually translate into what I’m calling pathology (the various diseases of aging, the various other degenerative aspects of aging) only in the second half of life. What this means from the point of view of intervention, of postponing the pathology of aging, is what has classically been interpreted as this: that there are essentially two alternatives.

Either we can be what I am going to call “geriatricians,” we can adopt a geriatrics approach, which is to try to slow down the progression of these pathologies. When they start to emerge in the early stage, to try to in some way hold back the sands of time so that the pathologies do not become problematic and life-threatening until a later age than they otherwise would. The second approach, which I am calling here the “gerontology” approach, is to try and intervene at an earlier stage in the chain of events and “clean up metabolism,” if you like, and prevent metabolism from laying down this damage. Or, at least, slow down the rate at which it lays it down, so that the age at which this damage reaches the level of abundance that causes pathologies will be delayed.

Now, that sounds pretty good, these two alternatives. Why aren’t they so good? You know the answer to why the geriatirican’s approach is not so good: aging is very, very messy. An awful lot of things go wrong with us at the same time, and they exacerbate each other. It is basically a downward spiral, a vicious cycle. There is essentially no way of holding that back by more than a little bit.

The geriatrician’s job is not a happy one. It is a short-term approach. Geriatricians are not completely useless–what a geriatrician can do is better than nothing. But it is not much better, and never will be. Precursors of the pathologies that are the target of the geriatrician are continuing to accumulate as side effects of normal metabolism, and so the geriatrician’s job is always going to be harder and harder as the patient gets older and older. That is not going to change.

The geriatrician’s approach is not really very promising — what about the gerontologist’s approach? Unfortunately there is a problem there as well. Metabolism is very complicated, indeed. In fact, any biologist will tell you that this is a considerable oversimplification of what we know about how cells work, let alone how organisms work. In fact, it is worse than that. This is an oversimplification of what we know about how cells work and organisms work. That, as any biologist will tell you, is completely dwarfed by the enormous amount that we do not know–even leaving out all the stuff we… don’t even know that we don’t know.

Basically, it is a situation in which we simply don’t know enough. We are not in a position to mess with this machine in a manner that does not do more harm than good. That has led most gerontologists to the rather pessimistic, fatalist view that intervention in aging to achieve any significant extension of healthy lifespan is a concept whose time has definitely not yet come. The reason I am standing here today, and the reason I have made such a nuisance of myself over the past decade or so is that I have seen a different way of looking at this problem.

This is a somewhat humorous way of putting what I just said about the gerontologist’s problem. Some of my colleagues wrote a column in Scientific American a few years ago. They suggested that the only way we could actually live longer than we do in a healthy state would be to implement what might be called “design improvements” to the human body. These design improvements were suggested distinctly tongue in cheek, although it must be said that not everyone really saw the joke. You know, things like bending the knees backwards, changing the curvature of the neck and making the ears bigger. Of course, the thing about this is it does rather strongly encapsulate the reason why this logic is incorrect.

If we go back again to simple machines, there we can see that there are two ways to make a machine last considerably longer than it normally would. One way, as depicted on this slide, is very similar to what was suggested by my colleagues in Scientific American, namely to build it really well in the first place, with corrosion resistant metal in this case. Sure enough, cars built like that do last maybe a few times longer than normal, average cars.

There is a second way. The reason I have picked out VW Bugs to mention here is of course because there are just as many 50 year-old VW Bugs driving around as there are Land Rovers. The reason is because they’ve got style. Their owners have fallen in love with them and done enough maintenance to them to keep them going.

Maintenance works. It works really well, just so long as you can do it comprehensibly enough. Most of us don’t do sufficiently comprehensive maintenance on our cars to keep them going indefinitely, but some of us do. Cars are simple enough that it is possible with current knowledge to do enough comprehensive maintenance to keep the car going indefinitely.

If we now return to the human body, we can see that the same applies, in principle. There is really a third approach to the postponement of age-related pathology. It is very much the same approach that car enthusiasts apply to their vehicles. Rather than trying to intervene too late in the game by slowing down the downward spiral of pathology, and rather than trying to intervene too early in the game by manipulating a machine that we don’t understand, we can go in in the middle of the process and directly target the initial ongoing side effects of metabolism before they reach the abundance that would cause pathologies, and thereby stop that from happening.

This is no more and no less than the application of regenerative medicine to aging. Therapies that fall under the rubric I am mentioning here of the engineering approach to postponing aging are bona fide rejuvenation therapies — that means rejuvenation therapies applied to aging. Why do I think that this is so realistic? It turns out that these intermediates between metabolism and pathology, these various things that I am grouping under the heading of damage, actually do not amount to very much in terms of complexity, compared to their precursors (metabolism) or their causes (pathology).

All of the phenomena that qualify as damage by that definition fall into these seven categories. These seven categories are rather useful. First of all, it is quite straightforward to give a pretty strong argument that these categories really are comprehensive — one being a biological argument, saying “What are we made of? Damage can only accumulate in long-lived structures — what long-lived structures do we have?”

The second argument is more circumstantial, but also quite strong. It has been the same list for a quarter of a century. Of course, we have come a long way in that time in our ability to analyze biological systems. We should have found some more if there were any to find.

That is not the really good news. The really good news–I am not going to talk about it in detail tonight, because this is a general audience–is that we have a pretty good idea of how to fix all of these things, to cut a very long story short. And if you want the longer version then I invite you to take a look at the book that I published about nine months ago. Then you will find out a lot more about this:

The topics that are mentioned here are topics in which some of the scientific members on the panel here have played enormously important roles in pioneering, and they are moving forward at an ever-accelerating rate. I feel that we have a realistic chance of achieving the goal that I listed at the top here. I believe we have a fifty/ fifty chance within maybe 25 years from now of adding thirty years of extra healthy life to the lives of people who are already in middle age before we start by the range of therapies that I am listing on the right. I’ll stop there.