~ The Seven Lively SENS (Strategies for Engineered Negligible Senescence): An Interview with Dr. Aubrey de Grey

By David Jay Brown

Aubrey de Grey, Ph.D. is on a search for the Holy Grail of medicine—the ability to stop and reverse the human aging process. Although this ambitious biogerontologist at the University of Cambridge in England was trained as a computer scientist, he is also a self-taught biologist with a strong interest in why organisms age. After marrying a geneticist in 1991, Dr. de Grey became so interested in biology that he began teaching himself the subject. In 1996 he had progressed far enough to make a significant contribution in molecular biology, by identifying previously unknown influences that affect the mutations that occur in mitochondria (the intracellular structures that provide cells with energy), after only reviewing the relevant literature on this for several months.

Dr. de Grey received his M.A. in computer science at the University of Cambridge and has been working there as a computer scientist in the Department of Genetics since 1992. His insights into mitochondria earned him a Ph.D. in biology from the university, although Dr. de Grey is not a laboratory researcher. He does no biology experiments. Rather, he is purely a theoretician in the realm of biology, and he prefers to see the Big Picture. By studying the literature from different scientific disciplines, he has assembled a master plan for how to "cure aging."

Although controversial, he has outlined what many experts believe are feasible engineering solutions to the seven basic consequences of prolonged metabolism that accumulate as what we call "aging."

These seven factors involved in aging and Dr. Grey's proposed solutions will be discussed in the interview, but briefly they are:

  1. The loss of cells that we need;
  2. The accumulation of cells that we don't need;
  3. DNA mutations inside the cell nucleus;
  4. DNA mutations inside the cell's mitochondria;
  5. The accumulation of "junk" inside of cells;
  6. The accumulation of "junk" outside of cells; and
  7. The formation of cross-linked proteins outside cells.

For each of these seven problems Dr. de Grey has a solution. These solutions are organized as part of a project he has masterminded, which he calls "Strategies for Engineered Negligible Senescence," or SENS. Two of these strategies are ideas of his own, while the other five came from colleagues. The strength of Dr. de Grey's ideas lies in his engineering approach — which is goal-directed to find practical solutions — and his interdisciplinary perspective. What may be most important about Dr. de Grey's work is that he has brought together many experts from different fields that normally wouldn't interact and share ideas. It is through this cross-fertilization of ideas that so much excitement and controversy has resulted from his work.

Dr. de Grey is currently the chairman and the Chief Science Officer of the Methuselah Foundation, which offers financial prizes to researchers who can break previous records of lifespan in mice. He is on the scientific advisory boards for the Maximum Life Foundation, Legendary Pharmaceuticals, Centenarian Species and Rockfish project, and the Alcor Life Extension Foundation. Dr. de Grey is also on the Board of Directors of the International Association of Biomedical Gerontology and the American Aging Association, and he is editor-in-chief of the journal Rejuvenation Research. To find out more about Dr. de Grey's work visit his Web site: www.gen.cam.ac.uk/sens

Dr. de Grey is extremely attentive, mentally energetic, and eloquent with words. We talked about the reasons for aging and his strategies for reversing the aging process.

Q: What do you think are the seven primary causes of aging?

Dr. de Grey: It's probably not really quite correct to call them "the causes of aging." What they are is the early manifestations of aging. These are intrinsic side-effects of metabolism, of being alive in the first place, and they are things that build up throughout life. Although these side-effects are not the cause of aging, they start to become harmful once they get to a certain level of abundance. Once there's enough of them around the body starts to suffer from them and eventually it suffers seriously. But the point is that initially they are completely inert. So this is really why a twenty year old, and a thirty or forty year old, are more or less equivalent in terms of functionality—in as long they've looked after themselves reasonably well. You can run as fast, you can think as fast, and so on, more or less, because the things haven't reached a pathogenic level.

So the seven areas are as follows. First of all, there is a loss of cells. There are certain tissues in which, when the cells in that tissue die, the tissue doesn't know how to replace them, not at the adequate rate anyway. For example, in the heart, or in certain areas of the brain, cells die and are not replaced.

The second one is the opposite of that. It's having too many cells of a certain type. This includes cells that really ought to have either not come into being in the first place, or they ought to have died and for whatever reason they haven't. An example would be in the fat, in the abdominal cavity, which is important for bringing on diabetes.

Number three is mutations in our chromosomes. This, of course, is very important in the cause of cancer, and, in my mind, that's almost certainly the only thing that mutations in our chromosomes actually matter for.

Number four is mutations in a special part of the cell called the mitochondrion. It's the only part of the cell that has its own DNA apart from the chromosomes, but that DNA matters as well, and mutations there don't give us cancer, but they do other stuff.

Then number five is that, in our arteries and other tissues, there are structural proteins that give them the shape and elasticity that they have, and these biomechanical, biophysical properties degrade with time, largely because of chemical reactions that cause extra chemical bonds between proteins that shouldn't be there. These bonds build up and cause hardening of the arteries, for example.

Number six is, again, in the space between cells. But here it's not changes to the structural proteins; it's just the accumulation of aggregates of protein material that the body is incapable of breaking down. In other words, the accumulation of garbage. The best known example of this is the formation of a substance called amyloid, which is the material found in the brains of people with Alzheimer's disease.

And then, finally, the seventh one is, again, the accumulation of garbage, but this time the accumulation of garbage inside cells. This is usually in a specific component of the cell called the lysosomes, although sometimes—especially in the brain—it is in other places in the cell. So these are the seven things that we need to fix.

Q: And you have ideas for how to fix each of them?

Dr. de Grey: That's right, although it would be wrong to call them all my ideas. For two of these things I have made very specific and very new and radical proposals for how we should go about this, which I think are pretty feasible, and are likely to be much more effective than anything else that's on the table at the moment. But, for the others, all I've really done is read the right literature and talk to the right people, because all the ideas that I've brought in are ideas that other people have been working on already. In general, they have not been working on them within gerontology though. This is why I was the first person to come along and actually create this grand scheme, with all these components of a unified whole. I was able to do this because most gerontologists don't know what's going on in these areas well enough to know how close they are to being successful.

It's because biology is a very big field. So just as most biologists don't know much gerontology, most gerontologists don't much of other things. It's much easier if you're a theoretician like me and you don't do experiments, because experiments, of course, are very time-consuming.

Even writing the grant applications to get money for your students for the experiments is very time-consuming. So most gerontologists, like most biologists, don't really have much time to read—and this is a major failure of biology in general, I have to say. The comparison with physics is very instructive here.

In physics you don't have this problem at all. In physics there are lots of people who do experiments, and there are also lots of people, like me, who are theoreticians—people like Stephen Hawking, just to name a famous example. They become experts in a much wider range of disciplines than you can if you're spending all your time doing experiments. They have new ideas for new experiments to do, and new things to try that result from bringing concepts together from far apart. And there's virtually nobody in biology doing that. There's certainly nobody except me in gerontology doing that, and that's a large part of why biology goes so slowly.

Q: What are some of the new anti-aging treatments that you foresee coming along in the near future?

Dr. de Grey: A lot of my colleagues are working on things on the basis that calorie restriction may actually give us maybe fifteen or twenty years of extra life.

Q: You mean working on ways to mimic caloric restriction?

Dr. de Grey: That's right — tricking the body into thinking it's on calorie restriction when it's not. I think that's marvelous, because, you see, even though I'm pessimistic given what we know already about calorie restriction, I might be wrong in my interpretation of it, and it may be that we will actually get a lot more life extension from it. So I definitely think it ought to be tried, and these products may not be very far away. We have learned a great deal in the past five or ten years about the genetic basis for the life extension phenomena of calorie restriction in rodents. We ought to be able to use pretty realistic pharmacological and genetic tricks as therapies to elicit the same sort of response in humans as they do in mice. These ideas, and the experiments to see whether this works, have been taken forward by a number of my senior colleagues. They managed to get all the venture capital that they need to support the work, so this will be tried fairly soon.

When it comes to the components of the actual SENS initiative some of the components are even further along than that. For example, there is a drug being produced by a company called Alteon in New York that actually breaks these extra chemical bonds that I was talking about that cause hardening of the arteries. And there's another company in California that has been working on immunization against Alzheimer's plaques to get rid of the garbage that accumulates between cells in the brain by causing cells to actually internalize this stuff and break it down.

Both of those drugs have been in clinical trials already. The Alzheimer's one was aborted because the vaccine had bad side-effects. But they're working really hard to produce better vaccines, and they will do so pretty quickly. The cross-link breaker one doesn't even have any side-effects, so that's going really well. But, in terms of life extension, the point is we're probably going to have to get all of these things — or at least most of them — working simultaneously in order to actually get a significant deferment of aging. So half of them working just won't cut it.

Q: Could you briefly explain what your strategies are for reversing each of the seven factors involved in aging?

Dr. de Grey: Okay. I've mentioned two of them in the last answer. We've got these new drugs that break the chemical bonds that cause hardening to occur in structural proteins, and we've also got systems for stimulating the immune system against garbage outside cells. So the other one that everyone knows about is the ways to replace cells in tissues that don't replace their own cells well enough, and that's what stem cell therapy is mainly for. So stem cell therapy is being explored very heavily in, for example, type 1 diabetes, where you lose the ability to make insulin because you lose the islet cells in the pancreas.

But it's also being used for various age-related problems, in particular the one that's got furthest is Parkinson's disease, where people have been putting neural stem cells into the brain to differentiate into the particular type of neuron that's lost in Parkinson's disease. So there's a long way to go with stem cell therapy, of course. There are many things that we certainly can't do yet with stem cell therapy, but that's an area which can be approached incrementally. It's an area which has got a lot of work going on, and little steps are discovered, little tricks, of how to treat and manipulate your cells in the laboratory so they get into a state where they will do the right thing after you put them into the body. There's a lot of things like that going on.

Then the one that's sort of in an intermediate stage of development, I suppose, is the one about getting rid of cells that we've got too many of and we wish would just keel over. So there are various systems being developed to make such cells keel over, or else to put them into state where they're not harmful after all. In the case of visceral fat — the fat of the abdominal cavity that seems to be largely responsible for diabetes — people have tried, in rats, just surgically removing the stuff, and that has had a marvelous effects on reversing diabetic complications in rats.

There are also drug therapies being looked at that will make these cells transform into benevolent cells. Some people are looking at somewhat more high-tech approaches involving some sort of gene therapy that puts new genes into cells that kill those cells, and specifically only kills the cells that are in this bad state. Again, of course, this is a situation where the immune system can be activated to engulf and destroy cells that we want to get rid of. There are various ways of doing that, and most of these things are some way along in mice at this point.

The other three are all a lot further off, and we haven't really got to the mouse stage even. We're only at the cell culture level. So one of them is, I mentioned, the mutations in the mitochondrion. It turns out that we've only got very little DNA in the mitochondrion—DNA that only encodes thirteen proteins, as opposed to tens of thousands of proteins encoded in the nucleus. It's rather interesting that we have any genes in the mitochondrion, because the mitochondrion itself is a big complicated machine made of about a thousand different proteins. All the others, apart from these thirteen, are already encoded in the nucleus, and the proteins that they encode are constructed in the cell, outside the mitochondrion. Then they're imported into the mitochondrion by a very special and really sophisticated system.

So you'd think you could do the same with the other thirteen. Then you wouldn't need mitochondrial DNA. It turns out that there are pretty good reasons why these things are encoded in the mitochondrial DNA, but these reasons are not complete show-stoppers. They have been show-stoppers for evolution, but we have different tools than evolution has, and so it's looking very good now. There has been very important progress in that area recently that indicates that we ought to be able to put copies of these genes in to the nucleus, and that would solve the problem because the nuclear DNA is enormously better protected and better maintained than the mitochondrial DNA. So if you had working copies of the mitochondrial DNA in the nucleus, then it wouldn't matter whether you had you had mitochondrial mutations any more. The proteins that had been constructed by the mitochondrion would be coming in from the outside, so it'd be okay.

Q: The mitochondria are almost like organisms unto themselves, aren’t they?

Dr. de Grey: Well, they used to be organisms. They were originally free-living bacteria. That's right. But they are very much not organisms unto themselves anymore. They're wholly integrated into their hosts now.

All of the strategies that I've discussed so far are not my own ideas. The idea that I just explained, for example, was first discussed twenty years ago, and it was first discussed as a therapy more than fifteen years ago. People have been working on it for most of that time. One of their big breakthroughs will actually be coming out in a paper in my journal Rejuvenation Research in the next issue in a month or so, with the results of a study that began in 1991. So we've been working on this for awhile, and I believe that we'll crack it.

The other two that I haven't dealt with are the ones where, basically, I have completely identified a new approach from scratch, that no one else has done before. The first one deals with the junk that accumulates inside cells. I have a really crazy idea here. I realized that this junk is energy-rich. If you go to a graveyard, for example — that's enriched in human remains — you probably won't find this stuff, because anything that energy-rich is not going to be sitting in the ground for very long if it's worth eating. If you're a bacterium, a microbe in the soil, you can eat this stuff and live off it. I didn't come up with this principle myself by any means; this is the principle behind a field that's been flourishing for fifty years called bioremediation, which is basically a part of the environmental decontamination industry.

People are interested in getting rid of contaminants in the soil to build houses on the soil, for example, and this works. If you have any chemical in the soil that you want to get rid of that's energy-rich, and it's organic, then you can find bacteria that will break it down. Even explosives like TNT are no problem. You can find bacteria than can break down TNT, dioxins, and PCBs. It's ridiculous, and it's simply because evolution is very, very clever. If you give evolution a reason to evolve the machinery to do something, it'll do it eventually.

So I reckon this ought to work for the junk that accumulates in our human bodies when we're alive that we don't know how to break down.

There will be bacteria in the soil that do know how to break it down, and this idea has gone down very well. I've discussed it extensively over the past few years, and pilot studies have already been done to demonstrate that it really works, so this is likely to be developed fairly soon. But it is difficult to say how soon as there is only early data at this point. We don't even have it actually working in cell cultures yet, so I would expect that it will be the best part of ten years before we see a serious improvement and it is functioning well in mice. Then, of course, it will be longer to get it working in humans.

The final one is mutations in chromosomes. I mentioned earlier that I think the only mutations in our chromosomes that actually matter are those that cause cancer. Other mutations just don't accumulate fast enough to do us any damage in anything like a normal life time.

So I came up with a really complicated, really ambitious therapy for cancer which I felt one needed in order to really avoid the fact that cancer is so insidious. Cancer is insidious because it has the advantage of natural selection. Cancers are a seething mass of genetic instability. They're basically doing experiments all the time to try to work out how to evade all of the things that the body throws at them to kill them, and the things that the doctors throw at them to kill them for that matter. That's why we've made so little progress over the past thirty years, since Nixon announced the war on cancer. Cancer is by far the hardest aspect of aging to fix.

So I came up with an idea than involved essentially removing — from the whole body, not just the cancer — the ability to extend the telomeres, the ends of the chromosomes, which one has to extend in order for the cells to divide indefinitely, which, of course, is what cancers do. It would take me another half hour to explain the whole thing. It's a complicated therapy, but, again, I have discussed this extensively with people who are expert in the various components of the therapy. We had a whole meeting to discuss it.

Q: I recently interviewed Michael Fossel, who went into great detail describing how telomeres influence cell devision and the possibility of telomerase theraphy in the future.

Dr. de Grey: Oh that's interesting. Michael Fossel and I are good friends, but he thinks that the main key to actually fixing aging is to reinvigorate the ability of cells to maintain their telomeres, and I think that's crazy. I think that what we want to do is actually eliminate the ability of cells to do that so that we won't die of cancer. This is actually an area in which I am in the gerontological mainstream, and Michael isn't.
David Jay Brown is the author of four volumes of interviews with leading-edge thinkers, Mavericks of the Mind, Voices from the Edge, Conversations on the Edge of the Apocalypse, and Mavericks of Medicine. (Mavericks of Medicine will be published by Smart Publications as a book in late 2006.) He is also the author of two science fiction novels, Brainchild and Virus. David holds a master’s degree in psychobiology from New York University, and was responsible for the California-based research in two of British biologist Rupert Sheldrake’s bestselling books on unexplained phenomena in science: Dogs That Know When Their Owners Are Coming Home and The Sense of Being Stared At. To find out more about David’s work visit his award-winning web site: www.mavericksofthemind.com.

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