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The Biologist Who Extends Life Spans
‘The idea that aging is something that’s not a given is a new paradigm’
By David Ewing Duncan
DISCOVER Vol. 25 No. 03 | March 2004 | Biology & Medicine
Cynthia Kenyon is a structural biologist who trained at MIT and at Cambridge University under the legendary Sydney Brenner, winner of the 2002 Nobel Prize in Medicine. In 1993 she stunned the world by announcing that her lab had suppressed a single gene in Caenorhabditis elegans worms—nematodes only a millimeter long favored by geneticists as model organisms—and doubled their normal life span. Recently, with a few more changes, she has extended their life span sixfold. Usually the worms live about 20 days. Her worms lived more than 125 days. More startling, the worms remained robust almost until they died. Kenyon is the Herbert Boyer Distinguished Professor of Biochemistry and Biophysics at the University of California at San Francisco. She is also the cofounder of Elixir Pharmaceuticals, a company that plans to apply her findings and those of other researchers to create a human antiaging pill.
I understand you wanted to be a writer when you entered the University of Georgia.
K: Yes, I was one of those kids who was always seeking the truth, and I first looked for truth by reading novels. It took quite a long time for me to realize there are better ways. My mother worked in the physics department as an admin, and one day she brought home a copy of James Watson’s Molecular Biology of the Gene. I looked at it, and I thought: This is really cool, you know, genes getting switched on and off. And I thought: I’ll study that. I loved the idea that biology was logical. A big tree seemed even more beautiful to me when I imagined thousands of tiny photosynthesis machines inside every leaf. So I went to MIT and worked on bacteria because that’s where people knew the most about these switches, how to control the genetics.
 Photograph by John Clark At the ripe old age of 13 days, one of Kenyon’s mutant nematodes squirms like a younger worm. Kenyon favors nematodes for longevity research subjects, partly because they reproduce quickly, have short life spans, and use mechanisms similar to those in humans to control their growth and development. |
K: The gene we changed, called daf-2, encodes a hormone receptor. Changing daf-2 produces large increases in life span because daf-2 protein controls the activities of many other genes, each of which contributes in its own way to longevity. You can think of daf-2 as the orchestra conductor leading the flutes and the violins and the cellos, each doing a little bit. So they play in concert.
How many genes are we talking about?
K: Probably about a hundred. I don’t know the exact number. But what’s neat is what they do. Some of the genes function as antioxidants—they stop the damage done to cells by free radicals. Some of the genes make proteins that are called chaperones; they help other proteins, damaged proteins, refold correctly. Other genes have an antimicrobial function; they prevent the worms from getting infections. Still others affect metabolism; they affect fat transport and food utilization and things like that.
How could there be one regulator for so much?
K: Maybe because that way you can make big changes in life span all at once. I believe this was a part of early evolution, that the first organism, which gave rise to all life, probably had a very short life span. It turns out that the daf-2 circuitry also allows the animal to withstand environmental stress, like high temperature and ultraviolet light, which also damage proteins. It probably evolved for that reason, but once it existed it could also drive extensions of life span during evolution. This could happen by mutations that change the regulatory genes, like daf-2. Now, the conductor makes the whole orchestra play forte instead of pianissimo. You see? Having everything under one system made this relatively easy to do.
What about extending the life span of humans by using these regulator genes?
K: We might be able to, we don’t know; but it’s possible that we could change a human gene and double our life span. I don’t know if that’s true, but we can’t rule that out. I think that the difference between the life spans of different species may boil down to the activity of master regulator genes, like the daf-2 receptor. We also discovered that downstream from daf-2, the hormone receptor, is another important gene, a master transcription factor called daf-16, which binds the many downstream genes and turns them on and off.
The cellos and violins?
K: Yes. I doubt that humans have special genes for longevity that the worms don’t have.
What about the IGF gene—insulin growth factor? What does it have to do with longevity?
K: In the worm, the daf-2 hormone receptor is equal or similar to three different receptors that humans have. One is the receptor for insulin, and one is the receptor for a hormone called insulinlike growth factor, or IGF-1. The third is called the insulin-related receptor. No one really knows what that third one does. Insulin, of course, controls food utilization, and the IGF-1 receptors have been known to control growth. So the question that was raised by our studies in C. elegans was whether this same hormone system also regulates the way in which different organisms age. So far, from what we know, it’s all looking good because now we know that if you change the same genes in fruit flies, Drosophila, they live longer. And they’re not worms. They’re very different from worms, though they are not humans either.
What kinds of genes do you change in Drosophila to extend life span?
K: People changed the fly’s daf-2 gene, the insulin and IGF-1 receptor homologue—the gene in flies that corresponds to the genes in the worms. There’s only one insulin hormone receptor in worms and only one in flies. If you change that, they live longer. Or you can change other genes in the pathway downstream.
Where are these genes actually located in the worm? Humans have 23 chromosomes. How many are in a C.elegans worm?
K: These worms have six pairs of chromosomes. The daf-2 gene is on chromosome 3. But the genes for longevity aren’t all on the same chromosome. The transcription factor is on chromosome 1. And these downstream genes are scattered around. They’re being called up when they’re needed.
It’s all very well to extend the life of worms and fruit flies in the laboratory, but these organisms are quite different from humans.
K: That’s why it’s so exciting that these experiments are working in mice, in mammals. In mice, two different research groups have shown that the homologues of daf-2 control mouse life span. Normal mice have two copies of the gene for the IGF-1 receptor, just as humans do: One copy they got from their mother and one from their father. So what one research group did was to knock out one copy. Now they have mice that have half as many receptors as normal, and they found that the mice live longer. The other group took mice and completely removed the receptor for insulin in just one tissue. Not IGF-1 but the insulin receptor from the fat tissue, which is known to be an active hormone-producing tissue. They removed the insulin receptor from this tissue and extended life.
Were there any side effects?
K: Not for those mice; they were lucky mice. They lived longer, and they didn’t get fat. That’s great. That’s the kind of thing we’re trying to do.
Do you think there will ever be a pill to increase human life span?
K: Maybe. That would be nice. The real value of all this is not just increasing life span. We’re also interested in the relationship between normal aging and the diseases of aging. There are lots of these diseases—cancer, osteoporosis, diabetes—that are much more prevalent among people as they get older. And it turns out that these long-lived animals that stay young, like the daf-2 mutant worms, don’t get these diseases until they’re older. Another lab made worms get Huntington’s disease by putting the Huntington’s disease gene into the worm. Then as the worms aged, they got the disease. They found that the long-lived mutants didn’t get the disease until they were older, which is great. We went on to show that the reason is that the same chaperones that extend life span, that are controlled by daf-2, also prevent the Huntington’s protein from clumping together. So we found the molecular basis of this linkage, the linkage between normal aging and this age-related disease, at least in part.
What you’re talking about is a whole new approach to disease, to health care.
K: That’s exactly right. Age is the single largest risk factor for an enormous number of diseases. So if you can essentially postpone aging, then you can have beneficial effects on a whole wide range of disease. It’s radical. The whole idea that aging is plastic, and it’s something that’s not a given, it’s another variable, is a whole new paradigm.
But this seems too easy. Is there a catch?
K: We’re so used to thinking that you can’t get something for nothing. But why would that be true? Humans live a lot longer than dogs, and we don’t suffer any penalty that I can see. We’re superior in almost every way—they can smell better. But really, they can’t drive cars, they can’t do half the things we can. I don’t understand why you can’t live longer and be really fit. Like our long-lived worms.
Can you make a worm immortal?
K: I think that it might be possible. I’ll tell you why. You can think about the life span of a cell being the integral of two vectors in a sense: the force of destruction and the force of prevention, maintenance, and repair. In most animals the force of destruction has still got the edge. But why not bump up the genes just a little bit, the maintenance genes? All you have to do is set the maintenance level a little higher. It doesn’t have to be much higher. It just has to be a little higher, so that it counterbalances the force of destruction. And don’t forget, the germ lineage is immortal. So it’s possible at least in principle.
Is anyone trying to make an organism immortal, say, a short-lived organism such as a bacterium?
K: One could try. I wouldn’t stake my life on it—though it is staked on it, in a way.
Many biologists don’t believe long life is possible in humans, much less immortality. Leonard Hayflick, the scientist who discovered that cells have a programmed moment of death, says that there is a natural age limit for organisms, that things wear out and die.
K: When he heard about the worms, he apparently said that worms are just different, that it’s only true of worms but not mammals. But the fact is, it’s true of mammals now.
Would you want to live forever?
K: Of course, if I’m young and healthy. Wouldn’t everyone? Here’s one answer to your question: How many high school kids really believe that they’re going to die? They think they’re immortal. They’re not disturbed that they think they’re immortal.
But that’s partly an evolutionary imperative. They need to go out and hunt, and be brave, and confront the world to provide food and a safe place to have children. If we were 80 but had the bodies of 20-year-olds, wouldn’t we be more cautious?
K: I don’t know. You might be more cautious, or you might not be. I don’t know. That’s a really interesting question.
Wouldn’t you get tired of what you’re doing by the time you get to be 150?
K: I might want to change jobs. In fact, wouldn’t that be fun? My hobby is finance, and I’d love to go into that world, or economics.
Is your company conducting mouse trials of an antiaging drug?
K: We have animal data in the company, but it’s still in the early stages. We’re trying to make small molecules right now. We’re hopeful. We just got some preliminary information that looks great.
How would such a drug work in humans?
K: Chances are, if it works, it works in incremental steps. At first, we are more interested in various diseases and making people feel better.
How would it be delivered?
K: Our company right now is focused on a pill form. We’re working with compounds in mice, and they seem to have efficacy in mice, but we don’t know. It’s early. But it’s looking good.
At what age would one take this pill?
K: We have studies in C. elegans showing that the daf-2 gene functions exclusively in the adult to control aging. So if you turn down this hormone system during development, and then you turn it back up in adulthood, there is no effect on aging. But at the beginning of adulthood, if you turn it down, you would live as long as you would if the gene were turned down your whole life. So it’s only the adult that matters, which is great. We don’t know yet whether you continue to get large effects if you turn down daf-2 late in adulthood.
So if you trick the body into thinking it’s young and it’s constantly replenishing everything, every cell. . . .
K: It’s like building a ship where you could replace all the parts and keep it going forever. The catch, the big catch, is that there might be things you couldn’t do, you couldn’t replace. Who knows?
There are people out there who object to the whole idea of extending life, such as Leon Kass, chairman of the President’s Council on Bioethics. He says we shouldn’t fool with these things.
K: But we’re already fooling with it by treating disease. We’re extending life in many ways.
What about overpopulation?
K: If everyone ages twice as slowly, you’ll still have the same percentage of old and young. So we’re not talking about filling the world up with elderly, infirm people. Overpopulation is a problem, but it’s already a problem. The best way to control population is to slow down the birthrate; in other words, to decrease the number of children and also raise the age at which parents have kids. My grandparents had many children when they were very young. If people have fewer children and they have them later, the birthrate will go down. This is already happening; it has to happen to sustain Earth. With a life-span-extending pill, the birthrate would have to come down just a little more.
