 on the aging process on longevity. And I'm wondering, in your mutagenesis screens, originally when you selected DAF2 to do a lot of your work, did you discover a number of other genes that have almost as profound an effect? And if they didn't, then that makes more sense to me. If they did, it's surprising that several discrete genes, although they may all regulate transcription of many different proteins, would have such a large effect on longevity, perhaps two-fold or three-fold or so. Is this a bit of a master gene or not really? We've done this experiment. We've now, what we've done is we've tested many of the genes in the DNA for their effects on lifespan one by one using RNAi. We did what's called, in scientific terms, an RNAi genomic screen. And what we found was that a large fraction of the genes that we found that affected lifespan work with DAF2 in that hormone system to control lifespan. Another large number of genes seem to affect lifespan in a completely different way by affecting the mitochondria. And this is kind of a surprising result. We found that if you inhibit the process of respiration, the process by which the mitochondria make energy for the body, the worms live longer. This system, so the mitochondrial effect on lifespan, it turns out that you have to turn down respiration during childhood to get an effect on lifespan. It's not the same as the hormone system, which only matters in the adult. Also, we know that many of the genes that are involved or that are required for the long life of the DAF2 mutant are not required for the long life of the mitochondrally challenged animals. So that seems to be another major but separate system. In addition, if you, in many animals, live longer if you don't feed them as much. That's the process, something called caloric restriction. If you, I don't know how true it is in humans, but for rats and many animals, including worms, if you restrict the calories, they live long. But turns out that's also true in these little worms. But that process does happen in the adult, so it seems to be different from the, in other words, if you food restrict in the adult, the worms live long. So it doesn't seem to be the same as this mitochondrial system. And genes that are required for the hormone mutants to live long are not required for calorically restricted animals to live long. So that seems to be a third system. So in our big screen, a lot of the genes fell into the hormone class. A few of them fell into the caloric restriction path. And some fell into the mitochondrial path. And then there were just a few others. So I think that we're not just seeing the tip of the iceberg. I think we know a lot of, we're seeing the chunk, the major chunk of the iceberg. So basically, there are a few very important genes that control lifespan. I think there are a few systems. Each individual system, like the mitochondria, many genes act together for respiration. But there seem to be a limited number of major control systems that are upstream of all those genes. There are just a few that are upstream. I think so. Yeah, I think that's right. I don't think there are 50 such systems. But there could be another one that we missed. We didn't get every single, we didn't, we know that we didn't test every single gene. So we could have missed some, but not very many. I doubt it. It would be very unlikely. Laura? Great. Wonderful talk. Just wonderful. I was wondering about environmental triggers on gene expression. And I guess it was your guppy story that really made me think about that. So if you're in a harsh environment, you see one effect and you see something very different in a safe environment. So are there for humans environments that might trigger these genes? Well, I'll tell you something that is so surprising and curious that we know about the worms, and we don't know how true it would be for humans. But it's really surprising. It turns out that this hormone system in the worm is subject to control by the environment. And it turns out that the things that matter to the worm are things that they smell or taste. If you take a laser and you kill the sensory neurons, like the neurons for the nose and the mouth that allow the worm to taste and smell things, they live longer. And if you or you can take, you can use another technique and you can just simply knock out a gene that allows you to smell one particular thing, an olfactory receptor gene. And those worms live longer. So it turns out that in order for them to live longer, they need to have an active, well, I shouldn't say that. But the reason that they're living long is because when you kill, sorry, when you damage the sensory apparatus, this hormone system then is inhibited, which then allows the worms to live longer. So somehow the worms are sensitive to things they smell and taste. So you wonder, could this, it's so strange to begin with, but could it, it would be even stranger to think that human lifespan could ever be influenced by something we smell or taste. But I'll just tell you, if you're eating a meal, your insulin level goes up. But if you also smell the food, it goes up even more. So it's not completely out of the question, but we really are in the very early stages. Now, we don't even know if any other organism, if the lifespan of any other organism changes depending on what it smells or tastes. So this could be something that's specific only to the worm, we don't know. Thank you. First off, send away her driver because we're gonna keep her here. We're not gonna let you go. So, it was a wonderfully elegant talk. Absolutely. I mean, I learn more every time I listen to you. I really enjoyed this. That's very sweet. Thank you. And I think this is a real important illustration of the importance of language. And in this particular case, throughout at least the first half of your talk, you were using the phrase, aging is regulated. Aging is controlled. As if there is a gene that's there or a set of genes designed specifically for the purpose of influencing how long we live. And I think, and when you started out, you were talking about obvious genes that are associated with growth and development, reproduction, menopause. And it seems as though there's a metronome or a clock that's influencing these processes. And then, of course, there can't be any question that there is a metronome for growth, development, reproduction. And I think that was classically illustrated. And I think, frankly, what it looks like to me is you have provided an elegant demonstration of why it is that we see differences in lifespan across species. Now, the real question is, is the aging process itself regulated? Now, there's a foundational principle in evolution biology suggesting that you cannot give rise to genes that are there specifically for the purpose of causing either aging or death expressed in the post reproductive region of the lifespan because natural selection does not operate in that region of the lifespan. So that genes that would influence duration of life, and that's the phrase I would have preferred to have heard, genes that would be influencing duration of life influence something else and aging is an inadvertent consequence of genes doing something else early in life. That's just one of many questions. Is that a question? Yes. The question is, how do you deal with the foundational principle in evolution biology suggesting there can't be aging or longevity genes? Well, there are two ways I think about it. First of all, I'm a molecular biologist. So the things I told you about are completely independent actually of evolutionary theory. These are laboratory observations, but it is fun and interesting to try to reconcile it with evolutionary theory. But as I say, it stands alone because we change a gene, the animals live long. The gene controls the hormone, therefore hormones control aging. They act in the adult. Therefore, whether you want to say the hormones are controlling aging or whether you don't want to use those terminologies, the fact is the activities of the hormone in the adult are determining how long the worm lives and how rapidly it declines. So it's not really a semantic issue. It's reality. It's truth. It's what we see in the laboratory when we make these changes. Wait, I'm not finished though. And, where was I? Okay, so however, it is interesting to think about how this module that does control lifespan in the adult or does influence lifespan clearly in the adult, how it could have come about. And I think I tried to explain why I think it could have arisen during evolution, not in any way to control aging necessarily, but instead to allow the worm to survive as a dower in harsh environmental conditions. That's a sufficient reason to explain why the system should have evolved. Once it's up and running, the animal can use it to do anything. And actually these guffies, which I love this study, these guffies were able to evolve very rapidly from one form to another. If you put predators in a pool in just four years, they had, let's see, they aged, they had fewer, let's see, they reproduced, they didn't have progeny so early. They then adopted the characteristics of guffies that had already been under these conditions. So in other words, they could evolve back and forth very, very rapidly. So if you have a regulatory system, or a control system like this up and running, suppose there are two sets of guffies, one has a control system, one doesn't. The ones that do could potentially evolve faster because you could make big changes with small genetic changes, big changes in lifespan with small changes in genes. So that's one way I think about it. The other thing is, there is something else here. This hormone system does act in the adult after it acts to influence reproduction, which is a little earlier. That's when it acts in the adult to control aging. So it is acting after it, not after reproduction takes place, but after it acted to influence reproduction. So why, why does it act then? Well, one possibility is that it, what happens is that maybe it's good for the population for the animals not to have, the post reproductive animals not to live too long because if they do, they'll compete with the young ones for resources. And even if they wouldn't, if an individual wouldn't compete very much, if it has any effect at all over time, that will be amplified. So it is possible that there is a selective advantage for the group or the species to have a shorter lifespan. So these worms reproduce their hermaphrodites. So each individual makes both sperm and oocytes in its own body. And that means that the progeny have exactly the same genes as the parent, exactly. So anything that's good for, anything that the parent can do to help the offspring will help the passage of the genes for that animal because the offspring are identical. So that is actually a possible reason why there might be actually some benefit to having a shorter lifespan. Dr. Hayflick, a question. Yes, in your presentation, you use the terms aging and longevity. And I'm interested to try to understand whether you use those terms synonymously or whether these are two separate phenomena. And regardless of the answer, I'd like your views on why they are identical or different. Yes, I use them in a kind of informal fashion. I think of longevity as our lifespan is how long the animal lives. The way I think of aging is the decline in the integrity of the tissues and in the behavior of the animal with age. There's another way of defining aging which is the chance of death at any particular time. Have you ever? I'm not using it in that particular way. Have you ever or your colleagues in this field done an experiment in which whatever biomarkers you have chosen that identify the aging process, which in my view I think are questionable, but I'll grant that it's possible. Have you under those circumstances intervened in a physiological system in these animals that stopped or reversed the process that you identify by whatever means and therefore showed intervention in an indisputable phenomenon of aging that you have are free to identify however you wish? Okay, here's what we've done. That's a great question. So we did an experiment in which we looked at the tissues of the animal using a high-power microscope and in young animals the tissues are spelt, they're beautiful and as the animals age they begin to deteriorate. So what we did was we took pictures of animals and also there's another thing. As you get older, people get older, you get what are called age spots and they contain a chemical called lipofusion and these older worms also, in fact not just worms but I think maybe all or many species as they age they produce this pigment. So in older worms this goes up, this pigment goes up. All right, so what we did is we took pictures of worms that were either normal worms or long-lived worms every few days and we took the names off the pictures, we put the names, we hid them on the back of the pictures and then we scramble them up and we gave them to people like four or five people in the lab who'd never seen them and asked them to give them a score so if they had really nice, perfect, young looking tissues then they got a score of one and if the tissues looked terrible if we couldn't even believe the animal would still be alive they got a score of five and then we had scores in between. Sort of like if you're grading a multiple-question essay test, you know? So we can't say that two is twice as bad as one but it was along the line toward five and then what we did is we asked, okay, do the long-lived worms, when they're, let's say, I don't know, three weeks old, do their tissues look most like a young worm or an old worm or so forth? And what we found was that the decline in the integrity of the tissues and the increase in the deterioration of the tissues happened at a slower pace in the long-lived worms than in the normal worms and this was statistically significant. We did the same thing, very statistically significant as you could imagine from the movie I showed you and we also found the same kind of thing when we, let's see, I just realized I'm gonna miss my airplane. Hold on a minute, sorry. I can't think here, let's see, oh no, no, no. So yes, so yes, so they aged more slowly. Okay, they aged more slowly. Now, we have never found any mutant, any mutation or any treatment that stops aging, that makes them immortal or it's certainly not anything that reverses it, which is really interesting, you might imagine that you could, that for example, if you turn up a bunch of repair genes, you might take all the damaged proteins and get rid of them and make brand new ones and the worm could even look younger. We've never seen that and not only our lab but no other lab that I know of has ever seen anything like that. So we're not talking about immortality here. Well, I didn't know that it was possible to quantitate spelt cells or beautiful looking cells or even deterioration to the extent that you can distinguish it from another possibility and that is pathology. Is it at all possible in your view that what you are saying in respect to the alleged biomarkers of aging are in fact pathological process and not the aging process at all? Oh gosh, that's a very interesting question. It's a normal process. It happens in our worms that are under our laboratory conditions. That's what you see. Is it pathology? Are these worms? Is aging itself a disease? I don't know that's... Well, you yourself said that it wasn't earlier or later. Well, I don't consider it to be but you can these questions then start to blur together. If you look at these old animals, they look like they have a systemic degeneration phenomenon that's affected all the tissues. Well, the only thing that I'd like to say is I admire your enthusiasm but I have a great reluctance to accept your interpretation of good data. You know what? I have to say, I shouldn't say this because it's not, I don't mean this in a bad way but the fact that people like you say the things you do make me know I'm doing something important. Because if everyone already accepts everything you say, if they accept it all, then what's the point? Well, I think you misunderstand me. I'm flattered that you made the statement that you did. But I really would like you to consider the possibility if you can widen your view of the world and I would like you to consider the possibility if you can widen your view to the extent that that's possible to look at the possibility that you are dealing that all of your beautiful data about which there is no argument can be interpreted in light of the fact that you have manipulated very nicely maintenance processes and the longevity determining processes and not the aging processes which are indirectly affected by those interventions. I will try. Dr. Whitehouse has some closing notes in particular, and I do that. I just wanted to express my appreciation of your enthusiasm, particularly for a 90-year-old as you identified your age. You also have to realize that we were having some guy talk yesterday about cars. So when you started off saying that aging is not like a car that just falls apart, that took on something close to our heart's cars, I wanna know, I've had three old Volvos in my family and they've lasted a long time. I think it has something to do with their sweetest genes, but I'm not sure. At this point, I think we'd better get Dr. Canyon underway. Thank you so much.