Scientist Stories: Cynthia Kenyon, Staying Ahead of the Curve

So we will move on to our next speaker, which is, who, as we have heard, is Barbara's best friend. So that's really nice to have 2 friends speaking one after another. So that's Cynthia Kenyon. So Cynthia did her PhD with Graham Walker at the MIT, and then after that, she joined Sydney Brenner's lab here at the LMB. For her postdoc. And as we have heard, her time here overlapped to some extent with Barbara. And then she joined UCSF where she is the Herbert Boyer Distinguished Professor. The awards that Cynthia has won are, you know, too many to mention here. But one very interesting thing that I believe she will talk about is that she discovered that a single gene mutation could actually double a lifespan time in the healthy fertile C. elegans. So I'm not going to do a spoiler alert and tell you what the gene is. I believe she will talk about that.

Hi, everybody. Yes, I'm going to talk about, sorry, my time at the LMB and a little bit of research I did since then. I was a postdoc with Sydney Brenner, like Barbara was. I was a graduate student at MIT where I studied the bacterial SOS response, which is a bacterial response to DNA damage that kind of causes the bacteria almost to differentiate. I found specifically that in response to DNA damage, all sorts of genes get switched on in bacteria, including genes that protect it from various insults and repair its DNA. But next to me was Bob Horvitz. He had just come to MIT. And he worked on C. elegans. So I got to learn about C. elegans long before much of it had been published. I was— I loved it because it was this kind of like the crystal structure of an animal in a way. This is a cell lineage. And John Sulston, with help from a few others, had figured out where every cell in the lineage comes from. And you could also look right into the animal. It was transparent, like one of those watches where you can see the gears. And you could just watch cells. So you could follow cell lineages. And every animal developed pretty much the same way. So I thought it was fabulous. And it was a way to kind of go back into an animal and find out where the gene switches were. That's how I looked at it. So off I went to the MRC. And I was, you know, Sydney was my mentor. But these guys here, Jonathan, John White, and John Sulston, were right around me every day. And they were just spectacularly wonderful. And I also want to mention women. There were, you know, I didn't really think of myself as a woman scientist. It was, we were all just scientists, I thought. But turns out there were some really great scientists in the making at the MRC when I was there. Here's my buddy Barbara. But I remember singing in the stairwell with Marion Biens and Tabby Doniak. And Maria Lipton and I had a 2-member journal club. I was studying developmental biology, but I didn't know anything about, I didn't even know what a nucleus really was. And she was coming from immunology, so we just devoured developmental biology literature together in a 2-member journal club. And then Barbara and I hung out a lot and went to the Green Man practically every night and had Kahlua and coffee or whiskey, depending on if it was me or Barbara. Anyway, so worms. I decided— so the thing about worms is you could take a mutant, an animal that was defective in some gene, and you could follow cell lineages in it. And often you could discover a deep underlying truth about developmental biology. That had been done in Bob's lab and elsewhere. And I wanted to do the same thing. So off I went to study cell lineages. I became interested in a mutation called— a mutant called MAV5, which was told to me— Marty Chalfie told me about it. Jonathan Hodgkin had isolated it. And it was an interesting mutant because— well, I'll tell you in just a minute. It was— well, I'll tell you now. So it was an interesting mutant because cells that would migrate in one direction instead would turn around and migrate the other way. And some structures were missing, but others were present. So it seemed like an informational defect of some sort, but it was really not clear what kind of underlying message there might be. Meanwhile, so I went into this dark little room where I stayed for about 4 years. I even had taxi drivers bring me food. It was like Uber, but many, many years ago. And they would do that, and they would deliver it to my dark room where I was doing cell lineages. Meanwhile, a lot of people actually thought I was kind of crazy and made not very nice comments about being in a dark room all the time. Anyway, Peter Lawrence worked right across the hall from us, and they were studying developmental biology. And in the field, Antennapedia, one of the Hox genes, had just been cloned. And Peter would tell me, Cynthia, why don't you stop studying the worm and study something interesting like Antennapedia? And I thought, well, no, I'm just going to stay in this dark room and maybe learn something. And so I finally published a paper about this gene, which it turns out affected lots of different cell fate decisions, but they were all in the posterior body region. And that was interesting because unlike in flies where cells kind of stay put from the very beginning, the cells that end up in this region didn't come from that region during development. They migrated there, were shifted around. So it seemed like it was something besides just, you know, it was some kind of positional signal, but it seemed like it was going to be different from the fly signal. However, when I got to UCSF and cloned the gene, I found out that it was antennapedia. So all the time that Peter had been harassing me to study antennapedia. I had been studying it actually. And so I was actually kind of disappointed because it wasn't brand new. But at the same time, it was really fun to try to understand how a Hox gene could act in the worm to make worm patterns and to do it in a way that didn't start out— actually had a lineal component to it. So it was very interesting. I won't say any more about it because I don't have that much time. But this made me interested in aging. The fact that these two animals, worms and flies, could look so different and mice which had this complex, et cetera, could look also different from one another, but be generated by this kind of common program, got me really, really interested in aging. And I'll tell you why. It's a universal process, but the rate can vary a lot. And so that means that gene changes during evolution had to change— had to have changed the rate of aging. So there have to be genes that set the rate of aging. And not only that, maybe aging was evolvable. Like, if you look at this little beautiful little diagram I found on the internet, you can see here in orange, there are short and long-lived insects. In kind of brown, there are short and long-lived mammals. In green, there are short and long-lived birds. So evolution must have extended lifespan or shortened it many different times. So maybe it's not that hard to do. So even though we knew there had to be genes for aging based on evolution, many people thought it would be really hard to find them. First of all, they thought, well, there would be one gene or maybe a whole bunch of genes for the skin and other genes for the intestine. And also that changes would be just tiny and incremental in evolution. So, you know, you couldn't really decipher it. And also evolutionary biologists thought there couldn't be really genes devoted to aging because they would act after reproduction when it was too late to pass them on. To the progeny. However, branded into my brain from all my time at the LMB was the fact that small changes in genes can make big changes in body pattern—legs where there should be antennae, extra wings, even eyes in the wrong place, all sorts of cool butterfly patterns. So it seemed to me that maybe, maybe, maybe, maybe there was some kind of regulatory circuit for aging that was kind of like this program, the Hox program. But it would be more like a dial that you could turn up and down so that you could change the rate of aging, make it faster or slower. Fortunately, we worked on worms, which have a very short lifespan. And so we got really interested, I got really interested in studying aging. Now, I wasn't the very first person in the worm field to study aging. Michael Klass in 1983 found the first long-lived mutants, but interestingly, none of them ate very well. He never outcrossed them and none of them ate very well. So he concluded that there really weren't genes for aging, that genes would affect the ability to eat, which affected lifespan through caloric restriction, which could extend lifespan. Then Tom Johnson, several years later, outcrossed these mutants for the first time, and he found one called H1 that could eat well and still live long. However, it didn't reproduce very well, and there were other evolutionary theories suggesting that there might be a trade-off between reproduction and aging, and maybe that was why it didn't reproduce. So or maybe it aged, sorry, lived long because it didn't reproduce very well. So it was kind of fuzzy. But anyway, so off we went and it was really hard at UCSF to get this project started. Everybody had a reason why you couldn't get long-lived mutants. Some people said, well, the worm has a fixed lineage. And so in order to live longer, it would have to grow, but it can't grow because it has a fixed lineage. Really quite wrong, but very dogmatically and actually kind of in a mean way expressed to me. And there were all sorts of other reasons. And so nobody wanted to work on it in my lab. And so I tried to ask rotation students if they wanted to study, and I had to ask them before the lab members got to it. So everybody that studied this was a rotation student for quite a long time. So there's actually a moral to the story because it turned out to be kind of interesting, and that is, if everyone hates it but you can't see what's about— why it's a bad idea, you think really hard, why is this a bad idea, and you can't think of a bad idea, then just go for it because sometimes it's not a bad idea. So first thing A rotation student, Ramon Tapchian, removed the gonad by laser ablating precursor cells, and the animals didn't live any longer. So there wasn't, wasn't this kind of simple reproductive trade-off, which was good news. And then we set out to do a screen for long-lived mutants and amazingly found a mutant that lived twice as long as normal, which you heard about in the introduction. It was called DAF2. Here's the paper, and every single person on this paper— I was first author because I did half the experiments and wrote the paper— everybody else was a rotation student, and none of them joined the lab. None. So anyway, DAF2 was known, it was isolated by Sydney Brenner first, because it affected a developmental switch that'll determine whether the animal would grow up or would enter a kind of diapause state. In order for— so strong DAF2 mutants would go into this diapause state, and they needed this gene called DAF16 to do it. I knew that. So I asked, did the worms need DAF16 to live long. So the mutants that we were working with that live long, they were kind of weaker alleles or grown under different conditions, so they didn't go into this hibernation state. So anyway, it turns out, yes, it was amazing. They actually needed this DAF-16 gene to live longer. So that was really interesting because these were known to be regulatory genes. So even before we knew anything about the molecular biology, we knew that aging was regulated. Then Gary Ruvkin's lab cloned the gene, found out that it was a worm homologue of an insulin and IGF-1 receptor. And both of our labs cloned DAF-16, which we found was a transcription factor that regulated— so these mutants were stress resistant, and their stress resistance depended on DAF-16. And actually, it turns out other transcription factors that were isolated subsequently. So these guys, these transcription factors, turn on all sorts of protective genes. You can just read some of the things they do here, autophagy, other things. That were required or contributed to the long lifespan of the animal. So there's a deep truth here, which is that worms have a hidden life extension potential. They can live a lot longer than they normally do, way longer. And all we did is change it. We had no idea what we were doing, just changed a base and out this, out it came. And the reason was that it was wired to do this under favorable environmental conditions. These hormones promote growth and food storage, but low insulin or IGF-1 signaling, which was mimicked by the partial loss-of-function mutations in these receptors. Total loss is lethal, but partial isn't. It's informational. It signals, I think, danger, and that activates a very deliberate protective cellular response that can extend life. And interestingly, these mutants are resistant to all sorts of stresses, even before reproduction. So that provides an explanation partial explanation, at least for evolutionary biologists, for why these genes could be selected. You have this regulatory circuit that can shift the whole physiology to a state of resilience and protection, and it's easy to get it out. And you can get it out by probably changes in the environment or these mutations before reproduction, so it could be inherited. So I think we wouldn't have invented airplanes if we hadn't seen birds fly. And so these long-lived mutants became— they're just worms, but they became our role models for healthy life extension. And they stimulated really an intensive study of the molecular biology of aging. We still don't know what aging is. Just last week, a couple of weeks ago at a Gordon conference, nobody could agree on what it is, even now. But whatever it is, it's controlled by familiar regulatory genes and you could study it. So that was a big deal. And it was really fun to be part of that. So just a few little interesting things about DAF2. It's a receptor, but we did mosaic analysis of it, which you can do with this fixed lineage and other ways. And we found that it actually— there are downstream signals that affect aging, because if you take it away from this part of the lineage, which is the outside of the animal, the worms live long. And this part of the lineage, essentially the inside of the animal, the worms live long. So mutants that lack cells that will be programmed by their genotype to die could stay alive if other cells had the daf-2 mutation. So it's very systemic. Also, but we found that there are cells that can actually control the whole lifespan of the worm. For example, worms have sensory neurons, and mutations that, that affect the ability of these sensory neurons to function pretty much all extend lifespan, and they do it through this pathway. It turns out— so we kept killing germline cells, and it turns out if you take away the whole gonad, nothing happens. But if you take away just the germ cell precursors, shown here with a laser, Then you have an empty gonad, and the somatic reproductive tissues cause the animal to live really long. So again, here we have just a few cells controlling the lifespan of the whole animal. And cool, very cool, look at these worms, how they're moving. These worms were filmed at this time. So these animals have daf-2 mutation, and they also have this change in the reproductive system, this empty gonad. And here's wild type. At this time, they're all dead.. But look, many, many times that, like 6 times that, they're still alive. And these worms were photographed here where the wild-type worms are like molding in their grave. They're gone. And these guys are still moving around looking young. So it's really, really plastic. Just unbelievable. And it's very fun. And it's not just a worm thing, which is really good. If you work on worms, you always want what you study to be relevant to something else. But flies and mice live long. If you change these genes with mice, you can change many, many different genes in the pathway and get long life. In fact, these are some of the longest-lived mice that there are. And it may actually, coming full circle to why we got into this, influence aging in nature. Small dogs are IGF-1 mutants, and they live longer than large dogs. You don't have to be small to live long. You can change, you can take away this DAF2 IGF-1 system in adulthood only in mice and worms and flies, and they live long. Bats, some of them live a very long time, have been reported to have defective growth hormone receptor and IGF-1 receptors. Queen ants, just published really recently, which live much longer than workers, like many, many times longer, they actually produce an inhibitor of insulin IGF-1 signaling. Very interesting. So it seems to play a role in evolution, probably not the only role, but a role. We don't know about humans. There aren't humans that live to be 200, so we We have to just take what we have. But if you look for DNA variants in this pathway, you find that they're enriched in centenarians. In particular, DAF16 alleles are enriched in centenarians very broadly. So we don't know, but I'll come back to that. So there are other pathways known to affect aging. Killing senescent cells has been shown, not by our lab, by other labs, which are inflammatory, can extend at least healthspan of the animal. Altering NF-kappaB signaling, inflammatory signaling in the brain, can extend the lifespan of the whole animal, kind of reminiscent of these sensory neurons. Giving old fish a young microbiome can extend lifespan. If you partially inhibit respiration or translation, that can extend lifespan. Increasing telomerase activity in old mice can extend lifespan. And giving old mice young blood or young serum can also extend at least healthspan. So it's really cool. I think aging is very plastic. I mean, it's pretty clear it is in animals, and I really want to slow it down in people, not necessarily to live longer, but because they're more resilient and they could be maybe more, more healthy in old age. So because of that, I went to Calico, which is a Google company that studies aging, and we're trying to slow it down in people, and I really hope we can do it. So I want to thank the LMB who are at all all this started, where I was shaped in such a great way by Sidney, for example, and his desire to go into new areas and be a real pioneer, and by all the people I mentioned, my other mentors, the women I mentioned, everybody that was there, to other mentors I had. And these are the people in my lab whose work I mentioned during this field. And I want to thank the entire aging field also. So thanks a lot. And I'll stop sharing. But you're going to see a giant version of me, so I'm going to move back. Okay, so I won't be quite so giant.

Thank you, Cynthia, for a wonderful talk. Do we have any questions?

Thank you so much for an excellent talk. I'm really interested in this IGF-1 and relationship to lifespan. And dogs are a particular interest of mine. Large breed dogs are more predisposed to cancer. And I wondered as well if you had any thoughts on IGF-1 and its importance in the rate of growth, and the rate of growth being important for lifespan as opposed to just the IGF-1 expression. That's a great question. So, in nature, there's a very beautiful correlation between the length of time it takes you to reach adulthood and your subsequent lifespan. So there may be something programmed. I think there is something programmed into you at a young age that once you become an adult, like even a young adult, your mortality rate is fixed. Your chance of dying doubles every 8 years if you're a human, and it doubles, you know, in a similar way but faster if you're an animal, depending on the species. However, DAF2 mutants and H1 mutants, for example, which turned out to be in the DAF2 pathway, Anyway, they grow to adulthood at about the same rate, although remember you can stop them in adulthood, the DAF2 mutants. But importantly, to answer your question, if you intervene in an adult—Andy Dillon showed this in my lab as a postdoc—if you turn down DAF2 just in the adult, now of course they've grown already at the normal rate to adulthood, but then if you turn it down, they live long. And the same is true in mice. If you alter this pathway in adults only, then the animals can live long. So it's coupled. There may be something early that sets it off, but it can be— you need these genes to maintain the rate of aging, I think, which is good, I think, in terms of translation in the clinic and giving older people a better life, maybe, because it shouldn't be too— and rapamycin, for example, is also a— it's a drug that affects TOR, which is part of this network, and TOR inhibition also extends lifespan. And you can give rapamycin to mice even when they're very, very old, and they still live long. So, yeah.

Okay, thank you. Yes, one more question.

Yes, one online question. Mary Wei asks whether any IGF inhibitors have been developed as drugs to extend lifespan? There were, as you heard in the last question, I didn't mention this, but there's a really big relationship between diseases and these genes that control aging. In these long-lived worms and mice, etc., a lot of diseases are postponed. It turns out that IGF-1, as you heard, influences cancer. I'll just tell you, by the way, worms don't get cancer. But if you cross the mutation, the DAF2 mutation, into a cancer mutant, now the cancer is very small and no longer kills the worm. Anyway, they were developed for cancer in humans, but they didn't work. And they also caused insulin resistance because of a feedback loop that takes place in mammals. So they might extend lifespan, but no one's really really tested them. And I think other groups are at work now to see, to check this in other ways in humans. But that's— nothing's been done yet.

I hope it works, but I don't know. Okay, thank you very much, Cynthia. I think we better move on.