Episode 16: Coleen Murphy on Aging, Biology, and the Future

0:00:00 Sean Carroll: Hello, everyone, and welcome to the Mindscape Podcast. I'm your host, Sean Carroll, and like most of you, I am getting older. When I was your age, we didn't even have podcasts, so if we wanted to listen to This American Life, we had to turn on the radio and listen to it coming over the airwaves and that's how we liked it. As a physicist, I study the arrow of time, the fact that the past is different from the future. So of course, there is aging in the sense that we are all older now chronologically than we used to be. But in the world of biology, there's also aging in the sense that our bodies are changing as we get older in a very uniform, monotonic way. We all had certain qualities when we were babies. We'll all have certain features and characteristics when we're elderly. And in between, we move from one to the other in a more or less predictable fashion.

0:00:52 SC: But the interesting thing about aging is that it's not really inevitable. In a sense, aging is a choice. It's not a choice that we make as individual organisms; it's a choice that evolution has made for us. If we want to have evolutionary progress, then you have certain organisms giving birth to others, trying new combinations of DNA, occasional mutations. But then the old ones have to die off. They have to give way to make room for the new generations. Aging serves a purpose biologically. But now that we're able to change things a little bit, now that we're able to manipulate our bodies through medicine and biology, it's come time to ask, do we want to keep aging in the same way we always have?

0:01:37 SC: Today's guest is Dr. Coleen Murphy. She's a professor of molecular biology at Princeton University, and she studies aging both at the level of organisms and at the molecular level. A favorite organism is C. Elegans; this is one of the favorite organisms of all biologists. It's a tiny little roundworm, a nematode, C. Elegans. And it lives a fairly quick lifespan, so we can play with it. We can mutate it, we can turn on and off different genes inside the roundworm, we can see what the effects of this are on the aging process. And, interestingly, it's not that hard to make a nematode live much beyond its ordinary biological lifespan. So what are the consequences of this? What are the implications for human life?

0:02:24 SC: What we'll talk about with Dr. Murphy is some implications for what you should do to live a little bit longer in the here and now, and a little bit more fantastical, imaginative things about whether or not aging is something that can be completely cured in the very far future. In a more down to earth way, what we care about is, given that we're going to age, you and I, we don't have miracle drugs to stop that yet, can we at least have more fulfilling, energetic, aware lives when we're elderly people? Do we necessarily have to undergo the usual decay and loss of mental faculties that are associated with being very elderly? Again, the answer is, maybe not. This is a huge direction in which medicine is moving, and fundamental science is helping along the way. So let's go.

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0:03:30 SC: Okay, Coleen Murphy, welcome to the podcast.

0:03:31 Coleen Murphy: Thanks.

0:03:32 SC: We're here at a workshop at the Santa Fe Institute on time and aging also, and you're a biologist by training who specializes in aging, is that a fair assessment?

0:03:43 CM: Yeah, that's correct.

0:03:45 SC: How did you get there? How do you choose... As you were just saying, before we started recording, a lot of books written on aging are written by people who are themselves aging a little bit. So how does a young researcher decide to pick this?

0:03:58 CM: Actually, I decided when I was a graduate student. I had been doing studies on pre-steady-state kinetics of myosin, so motor proteins, and I felt like I really understood pretty well how two proteins interact with one another and how they worked, and I felt like I wanted to start asking bigger questions. And aging is one of the bigger questions you can ask; how does it work? And pretty much everyone's interested in it, 'cause it happens to all of us.

0:04:21 SC: Oh, yeah. It's the box office topic, right? Yes.

0:04:24 CM: Exactly. So even though I was fairly young when I decided to get into the field, I felt like it was an interesting question that, at that point, actually, we finally had some really good tools to start addressing those questions. And those tools were genetics. At that point, it was right when... Especially C. Elegans geneticists had figured out that there were single gene mutations that could cause doubling of lifespan. So instead of just studying how things got old, you could start asking the question, "What's the difference between something that has a normal lifespan and one that lives much longer?" And then another critical point was that was right when... Well, the C. Elegans genome had been recently sequenced.

0:05:05 SC: Tell us about C. Elegans, for those of us who are not roundworm aficionados.

0:05:07 CM: Sorry, I should have backed up. Yeah.

0:05:09 SC: C. Elegans is a model organism, so it's a great thing because biologists of all attitudes and angles will study this little beastie to death, right?

0:05:17 CM: That's right. It's one of the major model systems, and one of the great advantages is that it's very simple. It's a simple animal. It's still multicellular. So you're basically... Instead of working with a single-celled organism, like a yeast where you can do a lot of wonderful experiments, now you're working with a real animal that has many tissues and cells. And one of the advantages, just from a daily experimental perspective, is that when you look through the microscope down at a C. Elegans, you can see that it's aging.

0:05:50 SC: Right. And it's a little worm, about a millimeter, is that right?

0:05:52 CM: It's a little worm. Yeah, it's about a millimeter long. It's a small nematode. It lives in rotting fruit. That's where... Because bacteria will be causing a fruit to rot, and so C. Elegans will be attracted to that spot and it will eat bacteria.

0:06:06 SC: Okay. But you grow them in Petri dishes? Or do you just have apples lying around the lab?

0:06:09 CM: We grow 'em in Petri dishes. That would be lovely. Yeah, we just have them in Petri dishes on a standard type of bacteria, E. Coli, and so that gives us control over its environment. And so while you could criticize it by saying, "Well, that's not what it does in the natural world, it goes through all these temperature fluctuations and food fluctuations," in fact, what we're modeling, I think, in the lab is an American diet. So these animals are always well-fed and in air conditioning, basically.

0:06:41 SC: Okay. So they have a potential to lead long, happy C. Elegans lives.

0:06:45 CM: Exactly.

0:06:45 SC: But that's not an 80-year-old lifespan. These are rapidly developing creatures.

0:06:49 CM: That's right. These animals go from an egg to an adult in only two days, and then that's when we really start counting for lifespan. Once they become adults who are capable of reproduction, that's when we start the timer. And from that point, they can live an average of two to three weeks. So any one population of animals... What's remarkably consistent, actually, is the shape of this curve. You can have 100 animals, and maybe around day 10, some of the... One animal will die. But at a day 30, there'll still be one animal alive. And so that sort of model is what we see on a population where you can have individuals... So you have an average lifespan of the population, but some individuals will die at 70 and some will die at 95. And so that's the kind of thing that we're modeling there.

0:07:32 SC: I was very affected, actually, a few months ago, The New York Times had a webpage, an app or whatever it was, where you could go in and there's a standard thing where it computes your life expectancy. You type in your age and your weight and your activity level, but rather than just telling you the final number, "Okay, you will, on average, live to be 78 years old," it chose a random number from the distribution and said, "Okay, in this realization, you live to be 58 before you die." And then you do it again, "No, this time you live to be 102." And I was struck very much by the fact that, implicitly, we think, "Yeah, if my lifespan is between 70 and 80, my expected lifespan, that's how many years I have left." And the reality is, "No, I might have relatively few years as a relatively high probability, and there's another probability I live much longer than that." Is it a similar thing for our little roundworms?

0:08:27 CM: Yes, absolutely. In any one population, you have a worm that if you... Say on day five, they all look the same. It's hard to know at that day which ones are gonna be long-lived and which ones are gonna be short-lived. And so that's actually one of the questions we're trying to figure out: What are the things... There may be genetic information. In this case, they're isogenic, so they all have the same genome, but there may be, for example, a readout in the RNA that they express, and with those they make proteins, maybe all those day five animals... If you just were able to survey them, maybe there are some of those genes that get expressed that predict which ones will be long-lived and which ones will be short-lived. And that's one of the questions we're interested in, this idea of stochasticity in aging.

0:09:04 SC: Yeah. Just to visualize it a little bit, if I was a grad student in your lab, am I literally there with the traditional little Petri dish a few centimeters across, and with the eyedropper and poking things around? Is that what life is like?

0:09:18 CM: Basically, yeah, you'd have a glass pipette with a little piece of wire at the end, and you'd be moving them around. And in fact, actually, yeah, now that I'm on sabbatical, we've been doing a giant experiment with the whole lab, and so I've been in there borrowing people's scopes and moving worms as well.

0:09:35 SC: We should... For the listeners out there, not every professor who's a leader of a lab spends much time in the lab, right? This is a precious...

0:09:43 CM: Yeah, to be honest, I haven't either, since I started my lab.

0:09:47 SC: One has an army that does the things...

0:09:48 CM: Exactly.

0:09:49 SC: And you're the thought leader here, right?

0:09:50 CM: And in fact, usually when I... For example, if someone takes a picture of my lab, I don't let them take a picture of me at the microscope 'cause I find it's very misleading. This is the one exception. I've actually been doing a few experiments, but not many. Most of the time, it's the graduate students and postdocs who are really doing the hard work.

0:10:05 SC: That's right. And this has just always been funny to me, but in theoretical physics, where I do things, when people write papers together, the author list is in alphabetical order, and...

0:10:16 CM: It's a different world.

0:10:16 SC: Biologists don't understand that. So your name, as the leader of the lab, appears last in the author list, right?

0:10:21 CM: That's right.

0:10:22 SC: And so there's this weird reverse priority thing where you're kind of very important, so your name appears last.

0:10:28 CM: We're the anchor. Yeah. Or anchor pulling them down. And the first author is usually the person who's done most of the actual labor and often the writing, and hopefully, we've all done some of the intellectual work together.

0:10:42 SC: Right, right. Often, that's the grad student in charge of that experiment or the postdoc or something like that.

0:10:46 CM: Exactly. Yeah.

0:10:48 SC: And so they have the Petri dish, and then you are looking in real time in a microscope, or are you videotaping the...

0:10:55 CM: Depends on the experiment. We have these... It's sad, they're a little bit laborious, a lot of manual labor involved in some of the experiments, because you're actually looking at it and making a judgment by touching the worm, is it still alive or not? And then we write it down and then we move the live ones.

0:11:13 SC: You can't take its pulse.

0:11:14 CM: Right. Exactly. And so there are ways you can scale that up, and lots of labs have. For example, you can do something where you just take images of plates, and we've done that for certain purposes. Yeah, there's other experiments that we take videos of because we wanna know the nature of their motility or, for example, if they're swimming in liquid, there's really nice ways where you take videos of them and then you can analyze what's the shape of their behavior, actually. And that's really nice because we actually discovered recently, when we were working on a Parkinson's project, that worms that had been predicted... This is a collaboration between my lab and Olga Troyanskaya's lab. We're using these networks of genes in dopaminergic neurons in both human neurons and worms. We've got the network that was shared between them, and that we knew were expressed in neurons of C. Elegans, and then use that information with GWAS studies, genome-wide association studies, of Parkinson's disease, to try to get a list of new genes that might play a role in Parkinson's that no one has discovered before.

0:12:18 SC: Can C. Elegans get Parkinson's disease?

0:12:20 CM: That was the question. We were wondering, could we develop a new model? Instead of putting back in, for example, alpha-synuclein, which is a protein that's known to accumulate in Parkinson's disease patients, we wondered whether other genes could participate. So that's what we're looking for, because it turns out, Parkinson's is caused... Let me restate that. The known causes of Parkinson's are actually much more limited than most people realize. Only about 5%-30% percent of Parkinson's patients have Parkinson's because of a known gene.

0:12:57 SC: I see. Is Parkinson's something we've identified even in nonhuman species mammals?

0:13:01 CM: Well, not really. That's what I'm getting to now. We were trying to figure out, could we model Parkinson's disease? And so if you just take it at its most basic level, say, it's an age-related motor defect. Is there something that we could find in worms? And so that's why we started these assays where we would knock down the genes from this list that were predicted to play some role in Parkinson's disease, and then look at how that changed the worms' swimming behavior.

0:13:29 SC: So knock down, you turn off this gene.

0:13:31 CM: Yeah. And so there's a lot of details about how that is done. We just feed the worms, actually, bacteria that expresses the RNA of that gene and then knocks it down through a process called RNA interference. So we use that, and we only did it in adults, because we didn't wanna mess up the development of the neuron in the first place. We really wanted to model what happens with age if you got rid of a gene. So doing that, and then we just guess at... If we look at age-related changes in behavior that look different from what just happens when a worm gets old, which is they slow down their swimming, maybe we'll find something interesting. And that turned out to work remarkably well. So it turns out those worms, for the top set of genes... We tested 45 genes, and the top 20 or so caused this weird defect where they would curl up, and we'd never seen that before. They curl up and uncurl, and they get stuck.

0:14:30 SC: So there's a whole bunch of genes and you have a special purpose bacteria...

0:14:35 CM: Yeah.

0:14:36 SC: That are secret spies that go into the worm and turn off these genes, and each one of them individually had the effect that the worm just curled up in a little ball?

0:14:44 CM: The top ones did. It's the very...

0:14:45 SC: The top ones.

0:14:46 CM: Our top predictions. And so that was... We didn't really know what to look for except for this very generic idea that there should be some age-related motility defect. But it could have been something subtle, just like slowing down, which is what wild type, normal worms do when they age. But they had this really different behavior. And so that led us down this path that became very interesting, where we figured out that branched-chain amino acid metabolism may play a role in Parkinson's that we hadn't noticed before. And then that caused us to go back into, eventually, looking at what happens if you look at the gene expression in Parkinson's brains. And in several of the areas that are affected by Parkinson's, you see... Normally, people have high levels of this particular gene, branched-chain amino... That's BCAT1, branched-chain amino acid transferase, and it's knocked down in Parkinson's patients. So this all worked better than we had anticipated, but this idea that maybe there's something that we haven't seen yet in worms, maybe we should just look and see what happens when we take these predictions from human diseases and go into the worm.

0:15:46 SC: And is this something... Obviously, one wants to ask, are there therapies that are suggested or strategies for treating Parkinson's based on this connection with individual genes?

0:15:55 CM: That's a great question, because what we're trying to figure out now... Because this particular gene can feed into a couple of different metabolic pathways, one important thing for us to figure out is what part of that pathway, which one of these is it messing up? 'Cause if you guess wrong, you will cause more problems. So that's what we're currently running.

0:16:10 SC: You can't poke around with human beings in quite the same way that you can mess with the C. Elegans.

0:16:13 CM: Exactly. So that's what we're trying to figure out now. And what's interesting about this is it's not necessarily predicted that this would have had this weird phenotype, because when other labs had looked at this particular gene when they were doing longevity studies, it turns out knocking down that same gene that causes this weird curling defect extends lifespan.

0:16:32 SC: Oh, okay. So you curl up, but you live longer as a curled up little roundworm.

0:16:35 CM: Yeah. Exactly. So it's a note of caution. Most of us in the longevity field for a long time have done screens to look for things to live long. My lab hasn't in particular; we've always been interested in this quality of life effect. But I think that's what's really important, is to take these ideas of quality of life with age, and ask, "Is it the same as living a long time?" And so we had originally done work on cognitive aging for exactly that purpose. This was almost just a surprise, that you could knock down something in neurons and cause this phenotype that, in the rest of the body, causes a long lifespan, but it's also... I really want to get that idea out there that it's important for us to look at all these measures of quality of life and not just how long something lives. Because I think we already know that as humans. None of us wanna live a long time in a decrepit state.

0:17:29 SC: That's right. Yeah.

0:17:31 CM: We wanna be healthy, and so I think that's actually more important. And it turns out the worms, you can actually use them to study things that we really care about.

0:17:37 SC: Yeah. I definitely wanna get into this whole idea of different modes. There seem to be, from your research, not one but a set of different ways which, in principle, life could be extended, and they have different side effects, for better or for worse. And then we can start asking questions about which ones matter. But what you just said, I think, is very important about... We're trying to extrapolate lessons to higher organisms by studying these little C. Elegans. So let's just dig into why that's okay. C. Elegans, one of the things about it, as I understand, is that we have mapped out its entire nervous system, the 300-some neurons, and we know how every one of them are connected to each other, the connectome of the nematode. And so that's very interesting for people studying the brain in some sense.

0:18:23 CM: That's right.

0:18:24 SC: But there's also... The human brain has 85 billion neurons, and so it's hard to see how exactly to extrapolate. So both from the nervous system, but also the genetic code, how similar are the genes in C. Elegans to the genes in humans? How easily can we say, "Oh, yes, this thing in that DNA strand plays the same role in the worm that this gene in our DNA plays for a person"?

0:18:51 CM: That's a great question. It depends on what you're comparing. If you're at the nucleotide level, I think the estimate's around 60%...

0:18:58 SC: Similarity.

0:19:00 CM: Similarity.

0:19:00 SC: Between C. Elegans and human beings.

0:19:01 CM: That's right, and so...

0:19:02 SC: Which is amazing, right?

0:19:03 CM: It is amazing, right?

0:19:03 SC: 60% of the same nucleotides in the DNA between you and a little worm, okay.

0:19:06 CM: That's right. And there's not even that big a difference... If you just count raw gene number, that difference is not so great. It's around 19,000 for worms and the estimate's around 24,000 for humans, depending...

0:19:17 SC: The number of genes?

0:19:18 CM: Number of gene. Now, of course, that's why I'm saying it depends on what you measure. Of course, then you start looking at alternatively spliced genes, and then so you rapidly...

0:19:29 SC: And a gene, just for... Again, because I'm not a biologist, we have DNA, and there's many, many little base paired nucleotides, we're gonna take that as understood, and a gene is somehow... We, human beings, are associating a whole length of DNA, a whole segment of it, with some function, with some ability to make some kind of proteins, and we call one such part of the DNA strand a gene. Is that fair?

0:19:52 CM: That's fair.

0:19:52 SC: Okay. And so we have not that many more genes than the C. Elegans does.

0:19:57 CM: Yeah. But we have these wonderful ways of splitting up a gene into parts, and then rearranging or inserting different parts and using them or not using them. Now, I will say, it turns out worms have that same phenomenon, and we have just been doing an experiment where we take... Worms only have a couple major tissues. They have their skin, they have muscle, intestine, their nervous system, some really major tissues. So my lab figured out how to basically take adult worms apart and do RNA sequencing on those, and so we can ask, for those large tissues, what exactly is expressed there? And there's actually a list of genes that are differentially alternatively spliced in each of those tissues as well. So even though we used to think that that was an explanation for why humans were more complicated, in fact, worms do this, too.

0:20:49 SC: So in the sense that there's one gene but it plays slightly different roles depending on which organ it's talking to.

0:20:54 CM: Exactly. For example, you can have an important transcription factor that is mostly used for metabolic purposes in the major tissues, but it could be used for a different function in the neurons. And so that's the kind of thing that we're figuring out now.

0:21:08 SC: And it's amazingly clever that evolution did all this without any foresight, without any planning.

0:21:12 CM: Selection is an amazing thing. But I was gonna add to your point about the number. So this came up at a meeting recently where someone was discounting the importance of C. Elegans based on this argument that it has so few cells and humans have so many. But fundamentally, what those cells do at the cell biological level, or at the metabolic level, is very well-conserved. And so it's just a matter of... Worms actually may have a harder job. So put this out there. They only have 302 neurons, yet they survey their entire environment and make decisions about where they should go, what they should eat, what they should avoid, using only those few neurons. And only about 100 of them are sensory neurons. And so this idea, if you think about the mouse olfactory bulb, where you have a neuron where there's one receptor for every one of those neurons, worms don't do that. They have many receptors for every neuron, so they're actually trying to figure out much more complicated things within every single neuron before they can make a decision. Now, they can't obviously figure out the same level of things, but they do some pretty, I think, interesting calculations to try to stay alive.

0:22:20 SC: They have to be pretty efficient, in other words...

0:22:21 CM: Exactly.

0:22:22 SC: With the use of those neurons. And to what extent do we... Well, number one, it was amazing to me to learn that it's exactly the same number of neurons in every C. Elegans. That's very, very specific. The DNA has baked into it quite a detailed blueprint for what that nervous system is going to look like.

0:22:38 CM: Exactly. And for aging, that has some serious implications. For example, if you think about it, there's this insulin receptor mutant called DAF-2, which lives twice as long as wild type. It doesn't do that by turning over, getting rid of damaged cells and growing new ones. It has to do it by keeping those cells healthy the whole lifespan. And so it really changes how you think about what you can do in order to live a long time. And for us, there's some parallels in the sense that we have some tissues where you could turn over the cells and replace them. We have other tissues where you can't do that. And so for those latter sets of tissues, that's what a DAF-2 long-lived animal is a good model for. So what should you do to keep that cell that you may have your whole life, like a brain cell... What would you have to do to keep that cell alive?

0:23:20 SC: And what are the organs in human beings where we have the same cells from birth to death?

0:23:24 CM: Things like muscles and things where there's not a lot of turnover.

0:23:27 SC: Right. So there's no way for that cell to leave and die being in place...

0:23:30 CM: Exactly.

0:23:31 SC: It's there since we're born, or since early...

0:23:35 CM: You should ask someone who's more of a human physiologist. But, yeah, for some tissues, you just can't replace them. They're there your whole life, or at least your whole adult life. And for some... There's neural stem cells, but I believe that the rate of turnover is very low, whereas you have... There are tissues, for example, your blood, you have... It's constantly making new...

0:23:54 SC: Your blood or your skin.

0:23:55 CM: Exactly. So those, I don't think worms, at least the major tissues, they're not a good model for those kinds of tissues.

0:24:03 SC: The skin of the roundworm's there forever, in other words.

0:24:05 CM: Exactly.

0:24:06 SC: Wow. Okay.

0:24:08 CM: And that actually... What we found out recently, that's actually not just the skin, it's actually... It's called the hypodermis, it's actually a metabolic tissue. So that's one of the things that we discovered by tracking every RNA that's made in every tissue, that revealed that to us and we were able to test that and found out it's true. But anyway, worms are good models for certain types of tissues and not good models for others, and so we keep that in mind the whole time when we do these experiments.

0:24:32 SC: Let's just allow ourselves, since we brought it up, to say a little bit more about what aging is like in humans, and then go back to the C. Elegans and get lessons for how we can change it. So what do we mean when we say a human is aging? Besides the obvious muscle aches...

0:24:47 CM: Besides obvious.

0:24:48 SC: And memory loss. Is it a known list of things that everyone agrees, this is aging, or is even that up for grabs?

0:24:55 CM: That is something that the aging field has come to. There's a loss of homeostasis. Tissues that are trying to remain constant and not lose ability, that gets lost, and of course, that manifests in different ways depending on the tissue. So a rise in cardiovascular disease, a rise in things like cognitive decline. And of course, we've all seen the more superficial ways you can age, like skin wrinkling...

0:25:19 SC: Wrinkling, yeah. Gray hair.

0:25:20 CM: Yeah. And it's an important distinction, because you could have the idea, for example, if you go back to a model system, that what you're tweaking makes the animal better. But if it's the equivalent of changing hair from gray back to black, then you're not really changing the entire animal. So we have to keep those kinds of differences, the things that are fundamental to an organism, like keeping the brain functioning, keeping the heart functioning, and separate from things that are maybe not so important, like wrinkling.

0:25:48 SC: And you can't see wrinkling or gray hair in C. Elegans.

0:25:51 CM: You can see wrinkling.

0:25:52 SC: Oh, you can see wrinkling?

0:25:52 CM: Yeah.

0:25:53 SC: Alright, very good. That was my next question. What are the characteristics... When you're at the microscope, how do you say, "Oh, this is an older worm," if you didn't know its birthday?

0:26:04 CM: That's one of the questions we're asking in the lab, because everybody who's done a lifespan experiment picks up clues, so it's not just that they... They do some obvious things. They start moving more slowly, and they also lose the shape of their trajectory, basically.

0:26:22 SC: So the younger worms are better athletes.

0:26:23 CM: Yes. And actually, Monica Driscoll's lab at Rutgers, they've done studies where they show that if they make the animals exercise by forcing them to swim for a while, they actually live longer.

0:26:34 SC: Oh, good. Alright.

0:26:35 CM: Yeah, so that's really nice.

0:26:35 SC: Cardio for the worms is helpful.

0:26:36 CM: Exactly. Yeah, their skin starts to wrinkle, their muscles get weak, which is why they can't move as well. And actually, again in Monica Driscoll's lab, years ago, Laura Herndon did some nice studies where they looked at the whole body, different tissues by EM, and they see sarcopenia, the degradation of muscle tissue, just like in humans.

0:27:00 SC: Right, okay.

0:27:02 CM: The neuromuscular junction starts to degrade, and that's actually why they start to slow down first. Shawn Xu's lab showed that years ago. And what we've found is that the thing that precedes all of those is their inability to... They start losing the ability to learn, and more important, they start... Before that, they've lost their ability to do long-term memory. So there's a sort of a... I don't know if it's a cascade, but you can certainly say there's a different trajectory for different behaviors. The most complicated thing that we find that the worms do is this long-term memory, they lose that by day four of adulthood. Later, they lose the ability to learn and do short-term memory, and then they lose the ability to smell after that, which is what's required for all of those other activities. And after that, well after that, they lose the ability to move. So there's a period where they... You can imagine a middle-aged worm, they can't remember anymore, maybe can't learn. It can still smell stuff, but it might not be able to...

0:28:00 SC: Move toward it.

0:28:01 CM: Yeah, and it can move towards it...

0:28:03 SC: Slowly.

0:28:03 CM: Yeah, exactly. So, yeah, it's not like they all crash at the same time. And I think that's sort of what we see in humans, right?

0:28:10 SC: Yeah. It's certainly roughly analogous, yeah.

0:28:12 CM: Exactly. I can't run hurdles anymore like I did when I was 16. I can still do calculations. I may not be able to do certain things, and there's gonna be things in the future that I won't be able to do.

0:28:24 SC: Number one, though, C. Elegans can learn and have things in long-term memory. How do we know that?

0:28:30 CM: Learning, that was established by some other labs early on, and they can do things like negative association. So if you starve a worm and let it smell a chemical, then later on when it smells that chemical, it will avoid it. So we were interested in asking the question a little bit differently and more analogous to what we might be interested in when we learn information. So my lab started doing assays where we paired food with a neutral odor, called butanone. And the idea was that even if a... A worm, we knew they could smell the butanone, but they wouldn't like the smell, they wouldn't go towards that odor until we'd done the training where they pair food with butanone.

0:29:08 SC: Oh, okay. So Pavlov and his dog, same...

0:29:09 CM: Exactly, it's just Pavlovian training. And so that's simple learning. And then we asked the question, "How long do they remember that?" So after we did the training, we put the worms back onto plates with food but no odor, and asked, "How long do they retain that?" And within two hours, they'd forgotten that, if we've only trained that once.

0:29:25 SC: Two hours. Okay.

0:29:27 CM: Right. So everyone thinks that sounds like a short time, but a couple things. If you are a worm in the world, maybe it's not worth remembering something longer than that if that food source is not gonna be there anymore. And the other thing is, I think it might be analogous to, if I gave you a 10-digit number and then I asked you three hours later, you might not remember it.

0:29:44 SC: And two hours is a much larger chunk of the worm's lifespan than three hours is for us, yes.

0:29:47 CM: Exactly. Exactly. So then, and this was inspired by work that had been done on other organisms like Drosophila, we did space training. We would train the worms and then give them a rest and train them again. And we found that if we did that and we trained them, for example, seven times, then the next day we could come back and they would still remember. And that turns on a different set of molecules, actually. It turns on... The earlier learning I told you about is pretty instantaneous, and it can require protein translation as well, but if we wanna do long-term memory, that turns on a transcription factor. It gets the signal, "This is worth remembering," if you hit it enough times, and it turns on this transcription factor called CREB, and that turns on a whole set of genes that we later figured out by using the same technique, RNAi, knocking them down, that if we knocked those out, memory is totally wiped out.

0:30:38 SC: And are those memory stored in the 302 neurons that were there?

0:30:40 CM: Yeah. So that CREB transcription factor is only active in one pair of neurons, called... So that's basically the worm's hippocampus.

0:30:47 SC: So you get two neurons to remember things.

0:30:48 CM: Yeah, exactly. We haven't figured this out entirely, but they must send a signal back to that sensory neuron to tell the worms when they smell that butanone again, what they should do, that they should still like it.

0:31:00 SC: It's amazing, the similarities between our 85 billion-neuron brain, and we can identify structures in the 300-neuron brain of this little worm doing the same thing.

0:31:06 CM: Exactly. Yeah, so don't be fooled by the 302 neurons. They actually can do some cool stuff.

0:31:12 SC: It almost makes you believe in evolution, right?

0:31:14 CM: Yeah, exactly.

[laughter]

0:31:15 SC: We just didn't get things from scratch, we developed...

0:31:17 CM: Exactly. That core set of proteins and genes that are used by every organism to carry out these tasks.

0:31:29 SC: So we have an aging worm, and you said the signs of aging start a few days...

0:31:36 CM: Well, certainly, they lose their memory at a point when it would be difficult to tell by eye that they're aging. So that starts pretty early.

0:31:43 SC: So memory is the first thing to go in the worms.

0:31:44 CM: Yeah. And I think that coincides pretty well with the end of their reproductive time. That makes sense; Why do they need to remember anything? It's because they need to figure out where food is, and then they don't really need that.

0:31:54 SC: And where sex is.

0:31:55 CM: Yeah. Well, actually, for hermaphrodites, they're doing their best to avoid males. They actually will run away from them.

0:32:02 SC: Right, 'cause almost all C. Elegans are females, right?

0:32:05 CM: Yeah, exactly. Say, 1000 to one, hermaphrodites to males. And so they don't really need the males, until they do. The times when they would need them is times when they need some genetic diversity, so in times of stress. And they've figured that out, too. When times of stress, they start... The mothers will lay more male eggs by losing a chromosome, and then those males will mate with the hermaphrodite, and 50% of their progeny will now be males.

0:32:34 SC: 50%, wow.

0:32:35 CM: Yeah, because, basically, when they mate, the chromosomes will be either XX or XO, so 50% of them will be hermaphrodites and 50% will be males. And so you can get these bursts of males and hermaphrodites in the population.

0:32:49 SC: Of maleness.

0:32:50 CM: Exactly.

0:32:51 SC: Yeah, yeah. I said females, but it's really hermaphrodites.

0:32:54 CM: For C. Elegans, yes.

0:32:54 SC: Right. For C. Elegans, the worms that are not males can play the role of male or female, but they are only carrying their own genetic information.

0:33:02 CM: Exactly.

0:33:03 SC: And so, like you say, if you want a little bit of diversity... Is there a lot of diversity in the genome of C. Elegans?

0:33:09 CM: I am not the best person to answer that. There are a lot of people who are asking questions like that, and also asking for natural isolates of C. Elegans, what kind of level of diversity is? I want to say yes, but there's better people who can answer that.

0:33:21 SC: Okay. Alright. So you have all these hermaphrodites, the occasional dude around there. And so you don't need to work hard to find sexual partners, but you do need to work hard to find food.

0:33:31 CM: And that's pretty much all that C. Elegans cares about, is food.

0:33:33 SC: Right. Is food.

0:33:34 CM: Yeah.

0:33:34 SC: That's right. And so you're saying that it makes sense that if you have a reproductive lifespan which is, what, about half of the total lifespan?

0:33:42 CM: Or less, yeah.

0:33:43 SC: Yeah? That once you've reached that point, your faculties begin failing you for various reasons. And memory is one of the first ones to go.

0:33:51 CM: Exactly. And I think that makes sense because those animals don't need to find food anymore, the pressure's not so great if they... So there's no pressure to keep that maintained. And I think it's actually probably a lot of work, because that long-term memory machinery is very complicated. And this was a surprise to me, because earlier, when I'd done the work to identify the genes downstream of the longevity pathway, the DAF-2 insulin signaling pathway, we found that there were hundreds of genes turned on, and when I knocked down those using RNAi, each gene that we lost only had about five or maximum 10% effect on lifespan. So that's a very cumulative process. You have to do a bunch of different things.

0:34:28 SC: Many, many genes are involved in this, yeah.

0:34:29 CM: Exactly. It was different when my lab started doing the knockdown of the genes that this CREB transcription factor regulates. When we knocked down any of those, they seemed to screw up memory. So it's more of a machine where you lose a part and now it all falls apart. And so that, I think, would take a lot more energy and effort to maintain in a pristine state.

0:34:50 SC: It's not a collective effort. It's, this gizmo better be working perfectly.

0:34:52 CM: Exactly. And so I think that's why it's one of the first things to fall apart.

0:34:57 SC: Right. And it's interesting just to think that evolution does not select for longevity. Longevity is backwards.

0:35:05 CM: The byproduct.

0:35:06 SC: Because you wanna have kids, and then as far as the population is concerned, you're not only not helpful, you're in the way, in some sense. And so the fact that... And maybe this has lessons for human beings, the fact that there is a lifespan and that we're supposed to die is not a mistake. It's what the organism evolves to do.

0:35:26 CM: It might be. Now, I don't know if they're really in the way, because old worms don't eat anything and they have so many more progeny, that probably one adult being around 300 progeny is not gonna make much of a dent. So I think of it more that there's no pressure to maintain its health anymore, and so the only maintenance that it really is invested in is to be able to be reproductive long enough to get its job done, to make more progeny.

0:35:53 SC: And it is subtle, because you might imagine that if one particular individual had a genetic code that let it live a long time and had many, many more progeny than its competitors, that would be beneficial to it and its bloodline, as it were, but the population would suffer because the genetic diversity would be diminished by that one dominant individual.

0:36:18 CM: Well, I think that may be what we have as wild type, that basically, it got to the maximum number of progeny it could have and lifespan it could have and still do everything, because the long-lived mutants, none of them have as many progeny. So there's a reason there's mutant and wild type. Wild type's won all these other situations, and it has this flexibility, it can respond to differences in environment. And when we get a mutant in the lab, really what we are looking at is something that's locked into one state. And so in the wild, it wouldn't survive as well because it can't respond properly.

0:36:52 SC: Okay. So yeah, so tell us a little bit more... Let's go through the different ways that we can make our C. Elegans live longer. So there's this DAF-2, I know, plays a big role. No one knows what DAF-2 is. Help us out.

0:37:05 CM: Yeah. This is a mutant... It's called DAF-2 because it was found in the very early studies when people were looking at development. But it turns out that you can knock down this gene just in adults. You don't have to screw up development at all, and still get this effect of long, long life. And that's really important, an important distinction, because the fact that this insulin receptor was found to live a long time, I think people discounted it in the aging field longer than they should have, because it has this other role in dauer formation, and that it was easy to say, "Well, that's just a weird worm thing."

0:37:34 SC: And dauer is this weird sort of hibernation stage you can go into.

0:37:37 CM: Exactly. So C. Elegans has a lot of lovely ways to be able to avoid disappearing. And so in times of really stressful conditions, it will go into this alternative developmental state called "dauer." And that's regulated by temperature, and food, and crowding conditions. But again, if we go back to DAF-2, you don't have to do that, you don't have to go through that state in order to live a long time. And this was shown by Andy Dillin when he was in Cynthia Kenyon's lab, that if you use RNAi to knock down DAF-2 just in adults, those worms will live a long time. And it also doesn't have to be, in that case, it wasn't coupled to reproduction. But in the wild, of course, all these changes that would allow an animal to live a long time, or cause it to live a long time, like reducing the amount of food that it has, or...

0:38:26 SC: So dieting works well to extended life, then.

0:38:28 CM: Exactly.

0:38:28 SC: So both cardio and dieting work perfectly well for C. Elegans.

0:38:29 CM: Yeah, exactly. That's right. But of course, all of those will cause the animal to have fewer progeny.

0:38:36 SC: Right, okay. So you live longer, but you're less genetically useful. And so the DAF-2, that's a gene, and you knock it out, and the worm lives longer, but it also has fewer progeny. Is that...

0:38:46 CM: Yeah. So if you knock it out for its whole life, the mutant has fewer progeny. And that's also true of worms that are either calorically restricted, or you have a mutant that mimics that state, because it can't chew its food properly.

0:38:56 SC: Right, okay.

0:38:57 CM: So all of those. So those are two different ways. And actually... And then there's something called "intermittent fasting," which probably everyone has heard about. Worms will live longer as well through intermittent fasting, but that turns out to act using that same DAF-2 insulin signaling FOXO transcription factor pathway.

0:39:14 SC: So other than not reproducing as much, what is it that DAF-2 does to the worm to make it live longer?

0:39:20 CM: Oh. Well, that's what we found when we did the... So when I was a postdoc and I built microwaves to try to identify all the genes that were different between the long-lived animals and the short-lived animals, that's what we figured out. We identified the set of genes that were different. And it wasn't just oxidative stress reduction; it was a lot of things. It changed lipid metabolism. It changes... Basically, that was... We started looking at proteostasis, keeping proteins healthy. Basically, if you made a list of everything you need to do to make a cell work better or stay healthy without turning over, that's what basically DAF-2 does. It turns on all these genes involved in things like autophagy.

0:40:01 SC: But, sorry, I'm getting confused, 'cause turning off DAF-2 makes you live longer.

0:40:05 CM: Okay, sorry. So this is an entry... It's a little bit hard to explain. The insulin receptor... You can think of it as when the insulin receptor of this DAF-2 is on high, that's signal of high food.

0:40:15 SC: Okay, 'cause it thinks there's a lot of food around.

0:40:17 CM: When the animals think there's a lot of food around, the right thing to do is to have as many progeny as you can, and you don't care how long you live. Okay?

0:40:25 SC: Right. Okay.

0:40:26 CM: So when you get a signal there is not much food, that means not much insulin, that means less DAF-2 activity. And the response to that is turning on a transcription factor called DAF-16, which is in this family of transcription factors called FOXO. And that was found later in mice, and now in centenarian studies, to also be involved in longevity in males.

0:40:49 SC: So in some sense, the pace of life slows down, so you live longer but more slowly, and less enjoyably, when these conditions are...

0:40:57 CM: Less enjoyably? I don't know, DAF-2 animals look awesome. [laughter] If I had to pick what I wanted to be...

0:41:02 SC: Right. So they don't slow down? They don't...

0:41:05 CM: Well, okay, so that's interesting.

0:41:05 SC: Their motion?

0:41:07 CM: That's an interesting question. A lot of labs have looked at just how animals move on a plate. And so if you just do that, DAF-2 animals look like they're less healthy, by that definition, but they're not. They're actually super healthy, because if you touch them, they can sprint off.

0:41:22 SC: I see. So by DAF-2, we mean the ones where DAF-2 is turned off.

0:41:25 CM: Yeah. They're the mutants. Sorry, it's very... But they're the long-lived animals. So it's not that they can't move, they just choose not to. And my lab figured out why that is. Because we thought that was really weird, because people were going around saying, "Oh, DAF-2 is not healthy," when every metric we could... Every assay we threw at them, they did better. And so what we figured out was, that DAF-2 animals have a higher level of a receptor called ODR-10. And another lab had shown already that ODR-10 levels were super low in males. The reason this is important, is because it got me thinking... This is Doug Portman's lab. And he had a great paper where he showed this difference in males in this particular gene. And when he put more of this ODR-10 gene back into males, they mated less well, and that was because they weren't exploring anymore. So low levels of ODR-10 cause an animal to explore more, and high levels think it's food. And so the headline of that... The sort of pop headline was, "Males choose sex over food."

[laughter]

0:42:35 CM: And that was all through the ODR-10 gene. And so what we figured out was DAF-2 has very high levels of this, and so they're really choosing food. And so what we did was we used RNAi again to knock it down, and found out that when you do that, the DAF-2 worms are crawling and they never stop.

0:42:52 SC: Oh, they just keep running around.

0:42:54 CM: They are totally capable of moving. They just choose not to because they're sitting on food, they know there's food, they're gonna eat the food. So anyway, it's an important point in my field, because there was this mistaken notion that DAF-2 worms were unhealthy for a while.

0:43:06 SC: Right. So they live longer but less healthily, and you're saying that, in fact, they're perfectly healthy. They think there's lots of food, so they don't see the need to exert themselves.

0:43:12 CM: That's exactly right. So I would say that... So DAF-2 worms are like that. There are other longevity mutants that are not healthy. And so it is worth thinking about this idea, as we mentioned before, that not everything that lives a long time is gonna be healthy. And so we and others did some quality assays, and we found that, for example, there's long-lived mutants that have knocked down their mitochondrial function. And those are being studied for a lot of good reasons, but if you look at the mutants in C. Elegans, they are not healthy, so they're not a good model. And then also, you have to knock down the mitochondrial function. Again, this was... This was, again, Andy Dillin's work when he was a postdoc in Cynthia's lab. You have to knock it down in larval stages to get this result.

0:43:57 SC: So very young, yeah.

0:43:58 CM: Yeah. So the human equivalent of this thing, give teenagers or adolescents a drug that will stump their growth, make them non-reproductive, but they'll live a long time. So that's not a model of good longevity.

0:44:13 SC: It's not a goal, clearly. So lesser mitochondrial function, less energy is going to our tissues, our muscles, we're just gonna be sluggish, and then we'll live a long time without even being able to move, unlike the DAF-2.

0:44:26 CM: Exactly. That's why we really like the DAF-2 model, because it really mimics something that we can sort of identify with, if we're gonna anthropomorphise anything, it's that...

0:44:34 SC: We are.

0:44:34 CM: Yeah.

[laughter]

0:44:35 CM: That DAF-2 worms are kind of the model of what we'd like to do in humans. So it's worth knowing what they do, and also asking the question, can we have this effect post-reproductively? 'Cause that's a critical point. If everything you have to do, you have to modify while the animal, including us, is reproductive, then it's not gonna do us much good when we finally get interested in taking a drug for aging. So that's what we need to figure out.

0:44:58 SC: Right. So how much can we extrapolate from the ability to knock out DAF-2, and have happy longer-lived worms, to any lessons for human beings?

0:45:08 CM: I think understanding what the molecular components are that change in those long-lived animals is really instructive. And then doing the actual experiments to ask the question, how late can we do that? And my lab's not doing work in other organisms right now, but people who work with mice are starting to ask that question, how late can we have an intervention? Because if you have to do it the whole life, that's not practical. But if you can find interventions like a DAF-2 equivalent, knocking down that receptor or something equivalent late in life, then that starts to be something that's useful for asking the question, can we keep people healthier? And then, like what I was talking about with Parkinson's, there are things that we would wanna knock down... Or sorry, or affect to improve cognitive function, and we have to know, how is that gonna affect longevity, and vice versa? If we have a longevity treatment, how is that gonna affect cognitive function? So asking those questions first in a really tactical organism like C. Elegans is very helpful, so you can untangle all those things.

0:46:05 SC: And it seems, to take an optimistic lesson from it, there's nothing biologically... Certainly, there's nothing in the laws of physics, but even biologically, there's nothing wrong with really repairing our cells to keep them going. It's just, if I may extrapolate, so correct me if I'm going crazy, it's just that our biology chooses not to do that, because we've outlived our usefulness.

0:46:25 CM: I think that's basically right.

0:46:26 SC: But we could easily imagine therapies, treatments, whatever, that tell our bodies, "No, actually, keep those cells healthy for another 1000 years."

0:46:35 CM: Exactly. And some mild forms of stress... This idea of hormesis, where you have a mild stress and that turns on a stress response, and that in the end makes an animal live longer. That's a kind of thing that intermittent fasting, or caloric restriction, or some of these drugs might be doing. So telling yourselves, "There's not enough food, let's turn on the stress response," that actually could be good.

0:46:54 SC: Right. Right, yeah. And I think that this... I've heard this kind of discussion in the context of diets, that somehow making your body think that things are going bad is good for it, because that's when its self-preservation mechanisms kick in a little bit. The body gets a little bit complacent if you just feed it healthy food all the time, and that can actually have bad effects.

0:47:17 CM: That's right. So you want more of the Nietzsche kind of thing, really.

[laughter]

0:47:20 CM: Whatever doesn't kill you makes you live longer. And that's actually true for the worms. So you give them a little bit of heat stress, or a little bit of metabolic stress, or don't feed them a little while, and then they will... The trick is you don't wanna do it too long.

0:47:31 SC: Of course. Right. So none of this gives us worms that live forever.

0:47:36 CM: No, but if you add the pathways together... So there's a nice study that, again, Cynthia's lab did years ago where they took, I believe, was germline... So it's worms that have lacked their germline, 'cause that's another mechanism to extend lifespan. And then, I think it was they also knocked down the DAF-2 receptor. Anyway, they got worms that lived something like 114 days.

0:48:00 SC: Oh, wow. As opposed to 14 days.

0:48:00 CM: Yes. And at the end, the student who was doing the work actually named the worms.

0:48:05 SC: Of course. You become attached. That's a semester.

0:48:06 CM: They were down to four, where he named them the names of the Beatles, and then they started dropping dead, so... Yeah. And then there's a mutant in that same insulin signaling pathway, there's a gene just... A protein, actually, just downstream of DAF-2, the receptor, where there are mutations of that. If they can get it through... Coax them through development, then those animals live 10 times as long.

0:48:27 SC: Wow.

0:48:27 CM: So it just means that they're turning on these repair pathways on high. Now, they probably don't have very many progeny. They can't get through their developments. They have other problems, but it does suggest that if we knew the molecular tricks to do to the cells, you could do this. Of course, it becomes more complicated with humans, with way more tissues.

0:48:45 SC: No, of course. But I get the lesson seems to be that there's individual things that point us in the right direction. And interesting combinations of these individual things don't just add, that they really reinforce each other in positive ways.

0:48:57 CM: Yeah. And I'm excited about the idea of exercise, because that's, in humans, it seems like it just helps with everything. So you could argue there, you might give somebody a drug that it would extend lifespan, but it may not help their cognitive function, or vice versa. But there are some things that seem to help everything, and I think that's where we're gonna... That seems like a more logical way to go, is to try to find the things that will help the entire system.

0:49:19 SC: Right. And there's sort of short-term strategies for people alive right now. Exercise, good. Maybe intermittent fasting is helpful, probably a good diet is helpful. Mental activity, is that something that might help?

0:49:31 CM: Well, that's interesting. My colleague, Sam Wang, has done some work on this, who says that that's all baloney.

0:49:37 SC: Yeah, it could be. I'm not sure, but...

0:49:38 CM: Yeah. So these brain games type of thing, it seems the more the idea of exercise and things that help with cardiovascular activity, that actually helps more.

0:49:48 SC: So there's analogy that would make you think exercising your brain makes it a stronger muscle, but maybe that's all just nonsense.

0:49:54 CM: Right. It turns out it just makes people really good at that type of crossword puzzle, which in itself, if you really bored, might be good.

0:50:00 SC: Which is fine. Right. An actual exercise, though, might be... Cardiovascular health will help your cognitive functions a little bit.

0:50:04 CM: Exactly. And as it turns out, some of the... I was just reading about a study yesterday, where using muscles to keep, not just cardiovascular health, but actual strength, higher is good. Because then it turns out those... Because of this mitochondrial... We haven't talked about this yet, but the mitochondria actually talk to each other through signals called mytokine. And so when there is mitochondrial stress in one place, it can signal to other tissues that there's stress as well, and turn on this response. And so this idea is that, if you keep your muscles healthy, they may actually be sending out more than just this cardiovascular activity. It may be actually telling your other cells to improve their mitochondrial functioning.

0:50:43 SC: Okay, good. So there's teamwork amongst the different cells...

0:50:45 CM: Exactly.

0:50:45 SC: Telling them to live a long time. Have we missed any different mechanisms for making our C. Elegans live longer?

0:50:54 CM: Well, interrupting their reproduction helps them.

0:50:57 SC: Don't have kids, intermittent fasting, keep exercising...

0:51:01 CM: Yeah. I think those are the the main ones, but they're all things that we can kinda relate to.

0:51:05 SC: Yeah, they are things that we can relate to. And actually, it's not just we can sit around waiting for the miracle drug, these are things that we can imagine doing.

0:51:12 CM: Yeah. I think you should still have kids.

0:51:15 SC: Is there any data on human beings? Do childless people live longer?

0:51:19 CM: There's a study that gets quoted most often to this point, and there's a study about Korean eunuchs, and those men live longer than their cohort, so...

0:51:31 SC: Okay. Men and women?

0:51:34 CM: Well, this was only a study at this palace, so...

0:51:38 SC: I think it sounds like it'll be very hard to control for an enormously large other number of actors in that particular study, so I don't really buy that one.

0:51:42 CM: I think, yeah, it's that kind of thing, I don't know.

0:51:45 SC: But it wouldn't seem to be that hard to just ask demographically, do childless people tend to live longer?

0:51:51 CM: Well, I don't think it's childless. It's, does your germline not function?

0:51:55 SC: Oh, okay.

0:51:56 CM: And in that case, if a germline doesn't function, there could be other sort of diseases, or other problems that it's not... So I'm not sure that that's actually the right question to ask, but you could ask whether there are certain hormones associated with the germline that are pro-health, or anti-health.

0:52:14 SC: And so right now, there's an upper limit to how human beings live, 120 years, something like that?

0:52:21 CM: Yeah. The longest living person that we know about lived 122 years.

0:52:25 SC: 122 years. And were they with it at the end, do you know?

0:52:29 CM: Oh, I don't know. The reports make it seem like she was, but I don't actually know.

0:52:34 SC: Again the reliability of that might be... That might be a story you want to tell, that is...

0:52:39 CM: Yeah. I do know that there's some debate about what the actual upper limit is. The study that sort of addresses... The problem with that woman was she's an outlier point, and sort of changed the curve. And so she wasn't there, that would give us the impression that it continues to increase. And all the time, like right now, the oldest living human is usually around 115, 116, something like that, but it doesn't mean... There's evermore... Those are super-centenarians, and there's more and more people who live that long. So it's suggested that won't be the upper limit soon.

0:53:14 SC: And also, the different things we were talking about in terms of diet and exercise, is it safe to say that they improve the quality of life when we're in our upper years, not just the number of years?

0:53:24 CM: Yeah. I would say that, really, those things do improve quality of life. I do wanna make a distinction between these super-centenarians, and what we're talking about. I think the rest of us are mere mortals, right?

0:53:35 SC: Yeah. We, mortals.

0:53:37 CM: Exactly. And I think that the centenarians, and certainly, the super-centenarians, they may be people who, just through genetic luck, are impervious to all those damages that other people... So if I were to smoke or do all these things, it would probably cause me to live shorter, definitely would make me live shorter. It's not clear that that's true for the super-centenarians. So that's the other question I ask: What is different about this population? Because the funny thing is, I've started collecting these stories about... 'Cause people always interview them, and ask this question, "What do you do that makes you live so long?" And they always have an explanation. And for about 70% of the women, the answer is, "I stayed away from men."

[laughter]

0:54:14 CM: But they always say... And there's things like, "I drink a glass of whiskey every day, or have two boiled eggs." And of course, that's ludicrous. That's an N of 1. But I think it doesn't matter what they did. Most of them drink, and a lot of them smoked, because that was the thing, and I think it didn't matter. But for us, the rest of us, we have to take care of our bodies a little bit better.

0:54:34 SC: They were born on third base, and think that they hit a triple.

0:54:36 CM: Exactly. Exactly.

0:54:38 SC: But from everything that you've been saying, there's things we, as individuals, can do to live a little bit longer, a little bit healthier, etcetera, but there's also, we can let our imaginations run about therapies and drugs and treatments in the future. I'm not gonna say when. Maybe you'll say when, but that could extend lifespan more or less indefinitely, in principle.

0:54:58 CM: There are certainly people who are working on those kinds of things. And they have taken it to the point where they're actually developing drugs to do things like get rid of senescent cells, because senescent cells, for example, are very toxic to the rest of the body. So those kinds of drugs, like senolytics, or activate the kind of metabolism that we're talking about in DAF-2 worms, turning on those pathways, basically tricking their bodies into thinking that you're calorically restricted, and doing all those things.

0:55:23 SC: Fix yourself, body.

0:55:23 CM: Exactly. And then there's this idea that you could take certain drugs that are already being used for other diseases, and those are helping people live longer beyond what they were expecting with just fixing that disease. So that's the idea behind metformin, for example. Now, I'm not involved in any of those studies. I'm more interested in the question of like, what is quality of life? Can we improve that, and can we model it? And can we figure out what the molecular components that help us improve quality of life? And hopefully, those things will extrapolate as well.

0:56:00 SC: Can we be extrapolating enough to say that the 21st century is the last century that human beings will be dying of old age?

0:56:08 CM: Maybe, if they're rich enough.

0:56:10 SC: Well, that's the whole thing. What if there's a therapy that says, "Oh, you can live for 1000 years. It costs $1 million." There's a social problem that comes up very, very strongly right there, right?

0:56:21 CM: And I think that is part of the thinking among some of the people who are doing some of the work, not doing the science, but... But I think we have to get away from that, 'cause that's already true. If we think about the way people get treated for other diseases like cancer, sadly, because of the way our healthcare system still works, you have a better chance of living if you're rich than if you're poor. And so I think that anti-aging drugs, or pro-longevity drugs, those would be things that would be the extreme of that situation.

0:56:50 SC: Yeah. I think it will become a lot more vivid when the rich people do start living a lot longer. That'll be something... I don't know, it'll be very interesting. I'm not quite sure what will actually happen, I'm very bad at predicting these political changes.

0:57:05 CM: Yeah. It rattles around in the brain when you're working on some of these things, like what are the ramifications of that? In general, what we really hope, though, is that if you were to find something that every person could take, would be relatively inexpensive, and it would just help them avoid something, like cardiovascular disease, or diabetes, or all these metabolic syndromes that people develop in developed countries with age. That would be something that really would help all of us be healthier, and live maybe not hugely longer, but somewhat longer, but with higher quality of life. That's really what we're going for, at least those of us who work on the things that we do. I know that that other thought is that you can have somebody live forever. I just... I'm not sure that I will ever get there, and I'm not so sad that that would be the case.

0:57:56 SC: Yeah, and I think that's okay. I just wanted to let ourselves go wild. But I think that you're right, that it seems sensible, it seems reasonable to imagine that it's not that we'll go exactly as we are now, and then someone will discover an immortality drug. It's that, along the way, we'll learn to fix some of the problems, knock out some of the worst things, that will make us healthier for longer.

0:58:18 CM: Exactly. And I think the biggest area where we need to think about that is cognitive decline. Because now, people are living long enough that they are developing dementias and things at a rate that people didn't have before, simply because they didn't live long enough to get them. And so that's what we really have to figure out now, is how to avoid... How can we really treat Alzheimer's disease and other things like that, that really impact quality of life in a way that's beyond just, I run slower. We really wanna help people be functional until the end of their lives, and I think that's really where the major focus is going to be now.

0:58:52 SC: But it sounds, from everything you said so far, that there is grounds for optimism, on some time scale. It's always hard to predict how quickly things happen, but these are not intractable problems.

0:59:00 CM: They're not. We have to do a better job of identifying the cause of some of those problems. And Alzheimer's is really, I think, the big one, because that just... The longer we have people live, eventually, if we don't figure out that problem, they could be walking around just fine, but getting Alzheimer's. So there seem to be... The relationship between the longevity and Alzheimer's is not entirely clear to us, and so I think we have to work on that, while we work on these other quality of life issues as well. But that's really a big one.

0:59:30 SC: And meanwhile, I can't let you quite get away without raising this other issue that you ran into over the course of your investigations, about... 'Cause you're studying... Reproduction obviously plays a large role in this lifespan issue. And so, what gets passed down to the different generations of the worms you're studying? And you came across a little bit of a surprise, is that right?

0:59:50 CM: Yeah, but I don't know if I should talk about it.

0:59:54 SC: Talk about it, and we'll erase it if you don't want me to.

0:59:56 CM: Okay. So, yeah, so I was one of...

0:59:58 SC: By the way, so it's not that you can't talk about it 'cause it's bad.

1:00:00 CM: No.

1:00:00 SC: It's that we don't want it to get out there before it's published.

1:00:03 CM: Exactly. And also, we don't know the whole mechanism yet. So we just know this phenomenon that we discovered recently, that when the worms encounter a pathogen, which they actually, really, initially like. I think it smells like hamburgers or something to them, they love it.

[laughter]

1:00:17 SC: Pizza, yeah.

1:00:17 CM: And they start eating it, but it's bad for them, and it makes them sick. And so other people had figured that out already. So Cori Bargmann's lab and Yun Zhang had already figured out that when they eat this Pseudomonas bacteria, that they then feel sick, and they later know to avoid it. And so that's the... What we consider the mother is doing that.

1:00:33 SC: And that's learning, we've already established, they can learn these things.

1:00:34 CM: That's learning. Yeah, so that's olfactory learning. And so what we recently discovered, kind of because we were looking for it, but a little bit accidentally, that these animals pass that information on down to their progeny, so their kids already know to avoid Pseudomonas, even though they've never seen it before, and they certainly haven't eaten and gotten sick from it. So it's basically like, if my mom had gotten food poisoning, and then from there on out, I could never eat that food again, potato salad or something.

1:01:07 SC: Was the food poisoning, or the negative stimulus, before they even had the children?

1:01:13 CM: Well, that's what we started asking next, because you could have reasoned... So in the case of my mom, if she had that potato salad that made her sick while she was pregnant with me, then that's kind of one phenomenon, that's different from if she ate it, and then 20 years later had me. And so we ask that by asking, how many generations do these worms know to avoid Pseudomonas? And so far, it's out to the great-great granddaughters.

1:01:41 SC: Is it possible they're being taught? Do they go to little C. Elegans school, where they say, "Avoid this stuff"? Or is it...

1:01:47 CM: It must be already passed down to them. Their neurons already know to avoid that, yeah.

1:01:50 SC: Their neurons know. I think that this leads us to this issue that we have a cartoon of how inheritance works, that we get from high school biology. There's a code, there's a DNA, there's a set of base pairs, and there's information encoded there, and that's what we pass down. But in fact, where it's increasingly becoming clear, that more than that gets passed down, there are other chemicals that go along when you give birth to somebody, and information can somehow be encoded in there. Is that probably what's going on in this case?

1:02:21 CM: Yeah, we think it's probably modifying that DNA.

1:02:25 SC: So it's modifying the DNA directly, not just...

1:02:26 CM: Sorry, let me... We don't think it's modifying the DNA. We think it's modifying the structures that protect the DNA, called "histones." So these chromatin... So we think that's part of it, and there may be other factors as well. But we still have to figure it out, so we'll know soon. But there are enzymes that do the job of doing these modifications and undoing them. So the idea is you could rewrite this, what's called "histone code." We don't really know yet, and so we'll try to figure that out. But it could be something else.

1:02:53 SC: But there are memories being passed down, and it's not just the DNA, but you're born knowing something, because your great-grandma learned it.

1:03:00 CM: Yeah. So this is still blowing my mind, and we still have to figure this out, if it's true.

[laughter]

1:03:04 SC: I think it should, yeah.

1:03:05 CM: But I think that we're on to something. And it would make sense for these worms, because if they encounter specific pathogen, it may be worth remembering. I don't know whether... One really weird question is, why don't they just always avoid it? And so I don't know if this pathogen smells like something else that's normally nutritious for them, but it's there in their environment. And they have to know not to eat it, or maybe eating a little bit of it's not terrible.

1:03:31 SC: And it's a good reminder that even if you knew the entire genetic code of the organism, you don't know the whole organism.

1:03:36 CM: That's right.

1:03:37 SC: Because there's more things in life than our DNA. Yeah.

1:03:40 CM: That's right. Nature is fascinating. We're still trying to figure everything out.

1:03:44 SC: And on that note, Coleen Murphy, thanks so much for coming on the podcast.

1:03:45 CM: Thanks for having me.

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