How A Tiny Worm Helped Unlock The Biology Of Aging
Source: Time, Dominique Mosbergen
Photo: Logan Weaver @LGNWVR
In the 1990s, molecular biologist Cynthia Kenyon made a discovery in a tiny roundworm that transformed our understanding of aging.
She found that a single gene mutation could double the worm’s lifespan, proving that the aging process, previously considered unchangeable, could be modified—at least in some creatures. That opened the door to the notion that drugs and other interventions could potentially slow aging and improve health span, the amount of time spent in good health, in people.
“Back then, people thought that if you studied aging, it was because you probably weren’t a very good scientist,” says Kenyon, who now heads aging research at Calico Life Sciences, the secretive longevity biotech backed by Google’s parent company Alphabet. “People thought I was wasting my time.”
Today, some 30 years since her groundbreaking research was published, many companies including Calico are working to develop treatments that could boost health span. Researchers have been able to extend the health and lifespans of more complex animals like mice, and many scientists think that helping people live healthier for longer is within reach, too.
“Since the days of Ponce de León and the fountain of youth and even before that, it’s always been a dream of people to live forever or at least age in a healthy way,” says Kenyon, a former professor at the University of California, San Francisco. “But now we can actually start from science and not just wishful thinking.”
As part of TIME’s series interviewing longevity leaders and influencers, we spoke to Kenyon about her seminal discovery and her excitement for the future of longevity research and treatments.
This interview has been condensed and edited for clarity.
When did your interest in aging science first take root?
When I was little, I liked animals and nature. I explored the woods and had a lot of pets, and I was interested in what you might call “truth”—understanding myself and the world. I realized that science was a good way to address the truth.
As my career as a scientist progressed, I began to get really interested in aging biology, which wasn’t well understood at the time. All animals appear to age, yet they age at really different rates. Among mammals, whales can live to be hundreds of years old, but other mammals live only a few years. But how does that happen?
My thinking was: the reason different species age at different rates is because they have different genes, and evolution changed those genes from an early precursor. For example, dogs have much shorter lives than we do, and they age much more quickly than we do, but humans and dogs evolved from a common precursor that gave rise to all mammals. What happened that led to these different lifespans? It occurred to me that there had to be genes that control the aging process, and I wanted to understand what those genes were.
Was there a specific project that sparked these questions about aging?
I was working in my laboratory on a type of roundworm called C. elegans. It’s very tiny, about the size of a comma in a sentence, and it ages really quickly and dies within a few weeks. But it’s a complex animal: it has different tissues and muscles, a gut, and a little brain that can do lots of things.
At the time, there were a couple of researchers who were looking for gene changes that affected lifespan in C. elegans. They found a gene change that made worms live longer, but the problem was that it also decreased the worms’ fertility. I thought, “My gosh, I just want to look for these genes myself.” I became really, really, really obsessed with the idea of trying to find gene changes that allowed the worms to live longer.
I also had this idea that maybe there were universal genes that control the rate of aging in all animals—like a thermostat for temperature, except this would be a thermostat for lifespan. Turning it up or down could make animals age faster or slower. I thought that maybe every animal had a little dial like that, but evolution set this dial differently in different species. It was just a hypothesis, and we still don’t know if it’s true or not, but I think aspects of it might be true.
That idea motivated me. It made me think that there could be a great discovery to be made, and I had the tools to do it—I had this little animal, a little worm with a three-week lifespan. So, I could do an experiment, and at the end of three weeks, I could just do another one. I was really, really excited about it.
Were other scientists as enthusiastic as you were?
Nobody would work on it, actually, because they thought this just couldn’t be done. People assumed that there would be all these different genes, so you’d get all these tiny little effects. Everybody had an idea of why it wouldn’t work.
But I was lucky. It turned out to be right that you could find a mechanism [for aging] and get a big change.
We started by looking for long-lived mutant worms and we found one that had a mutation in the gene DAF-2. This gene had previously been identified, and it was known that it played a role in the development of the worm before puberty. It controlled a switch that allowed the animal to grow to an adult or, under stressful conditions, to pause for a while and wait until conditions improved in the environment before growing to become an adult.
What we discovered was that partially disabling DAF-2 caused the worms to live twice as long as normal. They were completely fertile, active, and healthy. They aged more slowly. It was really amazing. It wasn’t a miracle because it was science, but it was like a miracle.
We also found that these long-lived worms needed another gene called DAF-16. Without a functional DAF-16 gene, they aged more quickly. So right away, not only did we find a gene change that could double the worm’s lifespan, but we had a little circuit: this one gene was somehow talking to this other gene, and there was a kind of a program, in a way, for aging.
I always tell young scientists: if you have a good idea and you think it’s possible that it’ll work after thinking really critically about it, always do it—even if everybody else says no.
How did the DAF-2 discovery transform the field of aging research?
This whole area of science had been like a cesspool. Really, no one wanted to work on it. People thought it was a waste of time. But, my God, it then became hot, it became interesting. That was 30 years ago now, but since that time, it’s just become more and more interesting.
There are now all these different ways of extending lifespan and health span in mice. We’ve seen that a version of these genes can make mice live longer and look younger. There are also labs that have shown that clearing senescent cells [damaged cells that stop dividing but don’t die] can improve health span in mice and others that have apparently been able to turn back the clock by using [special proteins known as] Yamanaka factors that can make mice much healthier and youthful. We don’t know yet if that will ever be possible in humans, but people are trying.
Is that what you and your colleagues are working on at Calico?
I won’t go into specifics, but Calico and many other companies are trying to slow down aging in people. Calico is taking more than one approach, which I think is a smart thing to do.
Aging is very tightly linked to age-related diseases, so the idea is, if you could slow down aging, it would give us new ways of treating diseases like Alzheimer’s, heart disease, cancer, and osteoarthritis. It would also be a way of learning more about these pathways in humans.
I’m really excited about the possibility that we could be healthier. I’m not talking about living longer while being sick. Can you imagine going into the nursing home and just staying there twice as long? No one wants that. But my goal in life is to help people to just be healthier when they’re older. And that’s what Calico lets me do. As an academic, I couldn’t be as close to the translational aspect of this—bringing this science to people. That’s why I’m so in heaven right now with my job.
I’m just super excited about the whole field. We’re on the brink of something unbelievable. Or maybe not. We won’t know until we know—and really proving it in humans won’t be easy, but I still think we are part of something that’s really big.
I remember giving a talk about the DAF-2 mutation in the early 1990s at one of these big scientific conferences. It was this huge room, and it was so empty. There were only like 30 people in there, and most of them were people I knew and people who were also working on C. elegans. And I remember standing there and spreading my arms and saying, “This room should be full!” I was so passionate about it.
And now, when I give talks or when other researchers give talks about aging, the room is full—even overflowing sometimes. Just thinking about it, tears are welling up in my eyes. It’s like a dream come true.
Is there anything you’ve changed in your life in the hopes of extending your own health span?
As a matter of fact, yes. At some point, I decided to try giving the long-lived C. elegans some sugar, because other researchers had found that sugar made other animals live shorter lives. And it happened with the worms too. They didn’t live as long—and interestingly, they lived shorter because the same genes that made them live longer were having the opposite effect.
When I got this result, I thought, “Oh no.” At the time, I ate tons of sugar. I was a sugar addict. I remember going to Costco one time and buying a bag of sugar that was so big, it came up almost to my waist.
I decided to follow a low-glycemic diet, and I’ve basically been doing that for 23 years. I do that and I exercise—aerobics and weight-lifting. I don’t take any pills or anything to live longer. The reason I don’t is, I would like a Phase III clinical trial to be done first before I try anything. But the problem here is, those trials cost a ton of money to do. What I would love to see is a kind of World Health Span Organization—like the World Health Organization, but for health span—where lots of governments chip in and we could do clinical trials for a lot of these substances.
I know other people are taking their chances. They are taking things like metformin or rapamycin, but I don’t know—I would say, buyer beware. Until the proper trials are done, I think exercise and the diet that I’m eating right now is about the best I can do for myself. I don’t actually know that they are going to extend my lifespan, but I feel great.