In this conversation with Coleen T. Murphy, Professor of Molecular Biology and Director of the Lewis-Sigler Institute for Integrative Genomics at Princeton University, she spoke about her book How We Age: The Science of Longevity. We explored how recent discoveries in longevity research may be bringing us closer to understanding how to live longer and healthier lives. Murphy discussed her work on aging’s connections to reproduction, cognitive function, ancestral inheritance, and the gut microbiome.
Lecturer bio:
Coleen T. Murphy is the Director of LSI Genomics and the James A. Elkins, Jr. Professor in the Life Sciences in Molecular Biology at Princeton University. She graduated from the University of Houston with a B.S. in Biochemistry and Biophysics, then earned her doctorate in Biochemistry at Stanford University, studying the structure-function determinants of pre-steady state kinetics and motility of the motor protein myosin. During her postdoctoral work at UCSF, Dr. Murphy built C. elegans microarrays and used them to identify the set of genes downstream of the insulin signaling/FOXO longevity pathway. This work revealed that insulin signaling coordinates the expression of a vast array of downstream cellular processes, including stress response, proteostasis, metabolism, immunity, autophagy, and intercellular signaling, to extend cellular and organismal maintenance with age.
In her own lab, Dr. Murphy’s team has developed C. elegans models of human “quality of life” aging phenotypes, including cognitive aging and reproductive aging, using genetic, genomic, and microfluidic approaches; they have identified genetic pathways that can extend each of these processes with age. At the molecular level, these processes are remarkably well-conserved through humans. Dr. Murphy’s team has developed new genomic approaches to isolate and transcriptionally profile all of C. elegans’ adult cells, in order to better utilize this system as a model for human disease, and developed assays to model human neurodegenerative disease, including learning, memory, and movement disorders. Most recently, her team has shown that a memory pathway they first identified to rescue memory in old worms can also rescue memory in old mice, using the same molecular pathways. Dr. Murphy’s lab made the surprising discovery that mating induces rapid post-reproductive aging, utilizing the same genetic pathways that extend longevity. Her lab discovered that C. elegans can interpret the small RNA code of the bacteria that they ingest to direct an avoidance response, and that information can be transmitted transgenerationally. Her group has now shown that this mechanism is conserved in wild bacteria and wild C. elegans strains.
Murphy’s awards for her research include being named a Pew Scholar, March of Dimes Basil O’Connor Scholar, Keck Scholar, McKnight Fellow, Sloan Fellow, Glenn Medical Research Foundation awardee, Howard Hughes Medical Institute-Simons Faculty Scholar, AAAS Fellow, and she was awarded the New Innovator, Transformative R01, and two Pioneer awards from the NIH Director’s office. She has won both the Women in Cell Biology Junior and Mid-Career Awards for Excellence in Research from the American Society for Cell Biology. She is the Director of the Glenn Foundation for Research on Aging at Princeton, and she is the Director of the Simons Collaboration on Plasticity in the Aging Brain, and is the author of the upcoming book, “How We Age” (Princeton University Press), a 2024 PROSE Finalist.
Transcript:
Seth Green: Well, welcome all! We are thrilled to have you here for The Science of Longevity, a conversation with Colleen Murphy. I am Seth Green, and on a morning like this one, I’m especially grateful to say I’m the dean here at the Graham School at the University of Chicago, and I will welcome you to our gorgeous campus, where big ideas are born that shape the world. And I will just say that if you are unfamiliar with the Graham School, you should be, because we are a trailblazer in lifelong learning, and we’ll talk with Colleen about longevity, but I am guessing one element is to constantly be learning and developing and growing. And we are a place where that happens intellectually every day for people across all ages and stages of life. I’ll share as well that we have a number of other exciting events coming up.
For those of you who want to be in person with your peers in lifelong learning, we have our Liberal Arts and Society Symposium coming up on September 5th. And actually, pictured there is Nick Epley in conversation with our learners, and he does a lot of research on social connection and the value that may play in themes related to longevity. We’re going to have a discussion next week with Harry Davis, Nancy Tennant, and Charlie Newell, who are the instructors of a new program called Navigating My Life Studio, and it’s about navigating life’s turning points. And then, very much building on this conversation, we’ll be having a conversation on the art and science of thriving in life’s second half with Dr. Kerry Burnright. But the reason that you are here today is for our conversation with Colleen Murphy. She is a professor of molecular biology and the Lewis Sigler Institute for Integrative Genomics director at Princeton University. She is also the director of the Paul Glenn Laboratories for Aging Research at Princeton. And so, Colleen, thank you for joining us, and I’ll start by kind of aiming to set the table a bit for the rest of our discussion. Your research really looks at the growing understanding that aging is a regulated process rather than simply cumulative cellular damage. And I’m curious if you can walk us through the paradigm shift itself. And then what it means, for the people out here who are very interested, but without your level of molecular biological knowledge.
Coleen Murphy: Sure. First, I want to say just thank you, Seth, for inviting me. It’s a pleasure to be able to talk about the stuff that I love working on. So, yeah, so I’m in the field of longevity regulation, which means that we’re trying to understand this idea, exactly as you said, a paradigm shift. This actually happened probably in the early 90s, really, with the discovery that there were these mutants, so not normal animals, that could actually live twice as long. And so that was work done by my postdoctoral advisor, Cynthia Kenyon. And, we’ll probably get into it, but that was in C. elegans, so this tiny little nematode. And the reason that that’s such a powerful system is because of that little tiny worm, which is really easy to work with in the lab. It shares about 75% of its proteins with us, so most of its genome is shared with us. So when we discover something in this really tiny little organism that only lives for 3 weeks, it means that we can extrapolate off, and we can find the exact same gene in us. And so there’s, … then we can better understand these molecular processes. Okay, so let me just back up and say what the state of the field was before the early 90s was this idea that it was sort of aging was going to happen, there’s nothing you could do about it, it was this cumulative process that, you know, you accumulate damage, and there’s just nothing you can do about it. But, nature turns out to not work that way, and so this discovery that there were tweaks that you can make to the genome that would allow these tiny organisms to live twice as long, and when that turned out to be the insulin receptor, then immediately that gave us some, insight into the idea that perhaps the whole aging process could be regulated. And if that’s true, then of course, immediately you can make the inference that, of course, then you could modulate it, you know, maybe with drugs, maybe with other interventions. And so, that’s really what opened up the whole field in about… she published that paper in 1993, and really built on it ever since. At first, everybody kind of ignored that, because it was, you know, you discovered a little tiny worm that’s just used in labs, and people are like, well, who cares? But then, later on with Gary Rubkin, so I don’t know if you know him, but he’s the guy who won… one of the two who won the Nobel Prize last year for RNA interference and small RNA, so he actually cloned that gene. And so, once we found out it was the insulin receptor, then it, like, sort of broke open the whole field. And so now, there’s really a ton of labs working on this idea that, in fact, aging is not just, like, this inevitable process that we can do nothing about, but there’s lots of different ways that we can intervene, and so I’m sure that you’re going to ask me about some of those, Seth, because there’s a bunch of different ones, and it’s actually kind of, I think a ray of sunshine for us to be able to hope that we can actually do something to slow the process of aging.
Seth Green: Yeah, so that is a very exciting discovery, and yes, I want to spend a lot of our conversation going through the different strategies that people can think about as they aim, not necessarily to avoid aging, but to take it on gradually and be able to continue their thriving mis-aging. Let’s start, though, with a bit of history, Colleen, because your book beautifully describes both the history and the current state of aging research, and you cover genetics, the gut microbiome, cognitive function, and so can you paint a bit of a picture about, you know, kind of… What we knew….
Coleen Murphy: And then maybe we’ll come after that, where the kind of most promising frontiers are now, and how that’s changing. Okay, so, I’m just gonna give a little background. So, for those of you who don’t know, I’m at Princeton University, and one of the… I finally got to teach the class I wanted to teach, which is on the molecular regulation of aging, and so, that allowed me to gather all these materials, so a lot of what I’m going to tell you about is not work from my own lab, which I’m very happy to spend a ton of time talking, but I really like the whole field. Okay, and so before this, idea that you could regulate aging, there was… there was a hint of that, based on the, you know, back in the 30s, there was the observation that rats that were deprived of enough calories actually, surprisingly, to the researchers doing the work, they actually lived longer, and they had less disease. So that sort of there’s been in the field for a long time this knowledge that caloric restriction, which probably most of the listeners have heard of, it could be beneficial.
Okay, and so I would say in that field, we’re recognizing that it may not in humans extend lifespan so much, but caloric restriction could actually reduce things like the onset of disease, etc. I’m not a big fan of caloric restriction, because I think it’s a terrible way to live, and so one of the things that I’m excited about in the field is this idea that you could intervene if you know the molecular processes. So that’s what I kind of think often gets lost in the news, is the reason… we’re not just doing the same experiments over and over again to just, you know, show that animals can live longer. What we’re trying to discover is what are the molecules that regulate the proteins. That regulates these processes, so then you could do things like design drugs that would intervene. And I think, actually, one of the… and I’m kind of getting off track with your original question, but I think one of the original, observations that you could caloric restrict, you know, soon after my book was finished, I turned it in, and there’s all, you know, an immediately or exciting thing. That’s right, right when Ozempic and all the GLP-1 agonists came out, and, that’s really starting to show that intervention with obesity and diabetes and those kinds of things actually have really beneficial effects on all kinds of processes, okay? So that’s sort of the caloric restriction field, and there’s other drugs. You guys might have heard of metformin. That’s another thing that’s supposed to intervene in the caloric restriction area. But, while we’ve been in the process of discovering all, you know doing, for example, genetic screens to identify new pathways that would regulate aging. We found all kinds of other pathways that could, can actually slow aging, and so it’s not just all about caloric restriction. I open with that because that’s really what was known in the field, and insulin signaling is a separate pathway, and then we have all these other functions that happen in the cell. For example, the recycling of proteins through a process called autophagy. That’s actually one of the… that’s actually turned out to be really helpful for not just aging, but also things like cancer treatments. Proteostasis, keeping all of your proteins healthy and turning them over when they get damaged, that’s hugely important. And so, in the book, what I do is I try to help readers go through all these different processes that have been discovered, because in some ways, they’re additive, and sometimes they’re, like some things are additive, and other things are controlled by the same regulatory pathway. And so that’s what the field has been discovering. There’s all these different ways to slow the aging of the cell, or in some cases, help regeneration. Like, if you can help cells replace themselves. And so, there’s… there’s just been an explosion of new pathways, and what that means for people is that eventually we’ll be able to find interventions that can really help with a lot of the age-related diseases that we’re experiencing. And so, I think there’s going to be many, many options for that approach. So we’re kind of in this interesting time right now where we’re moving from lab observations and identification of possible molecules to affect, to really, like, starting biotechs, and eventually those will become drugs.
Seth Green: Well, so let’s dig into these different areas, and since you start with caloric restriction, maybe we’ll start there. Yeah. Your point, I know, is that there are multiple ways to potentially achieve this, including through medicines like GLP-1s that might lead someone to have less appetite. Can you talk a little bit first about why, as… according to what we know, and I know we don’t know everything yet, you know, in the 1930s, we started noticing caloric restriction might actually positively impact. You know, it’s 2025, I know we’re still learning about why, but as far as the field has gone today why would caloric restriction, whether individually, you know, disciplined or through some, you know, drug encouragement, why that is positive? And then I’ll just maybe add on another piece to this question, Colleen, because I’ve been fascinated by some of the writing of Derek Thompson at The Atlantic. And I don’t know if you’ve come across his work, but recently he wrote about caloric restriction, and he wrote about how we’ve gone from a relatively scarce world, from a caloric standpoint, to one today, which is a caloric-rich world, and the foods are highly palatable. So he did some research that I hope you find is not entirely off-base, because he’s not a molecular biologist like you, but to basically say that per person, for example, in the U.S, we went from a place where there were something like 3,200 or 3,300 calories available per person, to now it’s over 4,000, just as the food industry grew. And so suddenly we’re in a world where there’s caloric abundance, but our bodies were built for the presumption of caloric scarcity, and so I’m curious to hear generally what we know about why caloric restriction works, and then I’m curious your thoughts on that. Potential context that we’ve gone from this shift in caloric scarcity to caloric abundance, and yet, at the same time, our bodies can’t shift overnight from an evolutionary perspective.
Coleen Murphy: Yeah, and so if… I think that’s a great entree, but I would start… we probably shouldn’t… Well, I’m not going to start with humans, because actually all of these pathways are present all the way down at least to see elegance, so, you know. And they work in exactly the same way at the cellular level. And the reason I’m emphasizing this is because I think we have to often back up and view these regulatory processes about how they evolved in the first place, before and when there’s, like, you know, the original, the ancestor of all of us. And the truth is, these pathways, what they do is really… what they’re regulating is not lifespan. They are regulating the ability of an animal to have enough nutrients and make a decision to reproduce or not. Okay, so if we think about a tiny worm, it’s making a decision, okay, I’m sensing I have nutrients, so all systems go. Develop as fast as possible, have as many progeny as possible, and then, I think we have to view this post-reproductive lifespan, it’s just extra. In fact, I had a student who did a cute senior thesis where he looked at post-reproductive lifespan across all kinds of organisms, okay? And it turns out that time actually scales with the size of the progeny that the mother’s trying to have. And so every woman who’s been pregnant can relate to this. And so if you think about it, you’re most likely to live longest if you have this excess health, basically, whatever in an animal who’s, like, some high level of fitness, post, like, reproductively, then will live longer, okay? And so, these animals, they’re shifting, they have to have this ability to regulatorily shift their development and reproduction and overall health in response to nutrients. Okay, so think about it this way. So, an animal, let’s say just, like, just imagine a random, like, whatever animal, is in an environment where suddenly they have no nutrients. It’s not a smart decision then to reproduce and put out your progeny into an environment where they’re going to starve to death. So the best thing would be to put the brakes on. Slow things down and so then, like, stretch, you know, stretch out this time of pre-reproduction so that then you get to a place where there’s more nutrients, and then turn off the brakes and start reproducing, okay? So that was a regulatory pathway that existed in our, you know, far back ancestors. And so, if we’re trying to think about humans, it’s a little bit hard to think about just in the past, like, 100 or 200 years, because it’s true, it’s a time of scarcity, but these regulatory pathways didn’t evolve in a small time, right? Now, as far as our health goes it is true that we basically were not, like, the people normally didn’t have not only the access to calories, but, I will say, and you saw this in my book, there’s, you know, considerable, especially in the United States, considerable, subsidies to companies to put a lot of excess things, like, especially from the corn industry, into, foods, and so we’re actually, even when we think we’re eating kind of healthy, we’re probably not eating as healthily as we can. And so, yeah, it’s hard to avoid having too many calories. So, but if we think about the cellular level, the cells are taking in a lot of calories, or a lot of energy, and so they’re working at high speed, but the result of that is that then your proteins actually get made, and they can start to accumulate damage. And so if the… if the cell can’t keep up with protein, like, damage to all its components, it’s gonna do badly. And what is the caloric restriction… This has been universally across all these model systems that have shown that, slowing down, like, reducing nutrient intake slows down the production of everything at the cellular level, which gives it time, gives the cell time to repair. So that’s kind of at the cellular level, that’s what’s happening with caloric restriction. And so you can imagine, like, at a systems-wide level, if you’re slowing things down a bit so they can repair, that’s kind of what’s going on. But again, like, who likes to not eat? Not me. So I’m kind of interested in figuring out how we can do things that are healthy for us, but still have a high quality of life.
Seth Green: Well, so let’s dig in beyond caloric restriction, because your book looks at a lot of different strategies, and maybe we can start with the strategy that you think is the most effective as we think about healthy aging. What is that strategy? Why is it important? And how do we understand how to apply it to our own lives?
Coleen Murphy: Okay, so, like I said, I’m very enthusiastic for the, the direction that we’re going from labs to biotechs to drug companies, but the truth is, no matter what, everyone in the audience, whatever you’re doing, you should try to find some form of exercise. Because the more that we learn about exercise. The more beneficial we find out that it is. And so, for people who are relatively sedentary, even starting to walk is actually super helpful. The thing that’s been kind of a shift in the exercise field, you know, in the past decade and a half or so, is that really using our muscles, like strength training, is actually super beneficial, and the older you get, the more beneficial it is. Because it does a different kind of thing than just cardio to your body. So that’s just a general thing, and I’m not a doctor, so it’s not like a prescription, but I’m just saying that’s an easy thing if ever… whatever you can do to increase your, sort of, daily use of your muscles turns out to be highly beneficial. And from the scientific point of view, we can see some of that. For example, for the muscles themselves, actually stimulating… helps them grow mitochondria, so using your muscles actually helps your mitochondria turn over and do better. And then there’s actually that one of the really exciting parts of the field is the idea that when muscles are exercised, they actually release chemicals into… called, … well, there’s mitochondria, but there are various factors that get released into the blood. And the things that go in the blood actually end up going to your brain, and so exercise is not just helpful for keeping your body generally healthy, but also can it help with your cognitive function? And cognitive function, to me is probably the most important thing for us to maintain, and so that’s where I’m kind of interested in, like, can we develop drugs that will help with cognitive aging, but certainly at a base level, exercise seems to be really beneficial for almost, like, everything, not just our bot… the rest of our bodies, but our brains as well.
Seth Green: And as we think about exercise, Colleen, you’ve said, you know, moving, just getting going if you’re sedentary. Are there specific interventions that we’re learning about that are particularly valuable from an aging perspective, and when I say that, I’m thinking both physically, but also brain function, mentally, agility, all of those pieces.
Coleen Murphy: Yeah, that’s why I’m focusing on the things like strength training, resistance exercise, and not so much on, like it’s nice to do crosswords, but it turns out that’s really not very… It turns out a lot of the brain training things are actually specific for that function and not generally applicable. But I would say, I think that’s probably, like, from one study where they, like, looked at, like, just specific things. I think there’s something that we cannot study in celligans and… or Drosophila and mice, and that is this general idea that being interested in life and learning more things all the time, and having… The other part is the social aspect. So, making sure that people continue to interact socially, those are the kind that we observe from human studies are actually very, very beneficial, but harder for me to, like, model in a, you know, in a genetic system. So, I think that keeping engaged in life and, and keeping socially active, there’s actually good evidence that those are very beneficial on top of the exercise. So, I guess if I were making a plan, I would say, you know, get some exercise every day, try to eat some fruit, hang out with your friends a bit, and try to read something that you find interesting. So those would be, like, kind of the things that I would say were really beneficial, and probably the people who are listening to this right now kind of can attest to that, right? Learning something new actually keeps you young. So, I want to come in a moment to some of the ethical questions around all of this, but before we get there, I just want to lay one more thing on the table.
Seth Green: We talked about nutrition from a caloric restriction standpoint. You name that is not necessarily the happiest way to age well. Another piece, though, I know is nutrition itself, so not just how many calories, but what you are actually taking in. Can you just talk briefly about some of the findings you lay out in your book there, and then we’ll jump into some of the bigger intellectual questions around this whole space of longevity.
Coleen Murphy: Okay, so again, I’m not a clinician, so I don’t think that, I think there’s probably better nutritional studies that can be talked about. I will say that one of the goals of the field for a long time has been to ask this question, for example, is it better to, you know, you always read about all these different diets, right? Like, high protein, low protein, low carb. And what’s been confusing, I think, for everyone is that almost every study comes to a slightly different conclusion. And I think part of that is because you know, evolutionarily, if you study something in C. elegans or Drosophila, and you want to do… there’s been a beautiful study. For example, Scott Pletcher’s lab did this really nice matrix of carbohydrates and proteins, and they found, like, a perfect, you know, like, what was the optimal for a Drosophila lifespan. And so, while I usually like to extrapolate from, like, model systems to humans, I kind of suspect that actually what’s happening with nutrition is every organism has an optimal set point that’s not necessarily the same as another organism, based on what they evolve, what kind of, you know, environment they evolve to be in. And so I think that’s the core reason that you read in the newspapers, like, it seems like the dietary field, you get different advice if you wait 5 years. And so I think that’s been really confusing for people, and … and that’s why I kind of am being evasive, because I actually don’t know if there’s going to be something in 2 years that says that’s all wrong. You might have noticed in my book, I did mention a study you know, one of the things I was very…has been very popular is this idea of intermittent fasting, okay? The idea that you would, like fast all day, and then, like, only eat, like, in certain periods. And so, there are certain people, I will note, mostly men, who, like, really adhere to that and say, this is… they’re the healthiest they’ve ever been and so there was a really interesting study where they took a lot of people and had them do this and compared them. This is important, because most people, you know, can’t study by themselves, because you don’t have control, right? And so they compared with people who also came in and just kept track… they didn’t tell them when to eat, they just kept track of what they ate. And they got the same results. In fact, actually, the intermittent fasting group did worse, because what they lost was, they lost muscle, and so you don’t want to do that. So the truth is, I think, you get the same results in all these studies if you compare them against people who actually just kept track of what they eat, because we do a lot of, like, I don’t know, mindless eating, and so… and I’m not actually, like, I’m not a person who thinks a lot about dietary stuff, but I think it was really interesting that that study, showed that it kind of didn’t matter when you ate, despite all this… this stuff that we’d seen. I think it’s confusing… My own lab doesn’t study dietary restriction, because I have been so underwhelmed by all the work in it, even though I understand it’s very popular, because it feels like something everybody could do. Okay, there was something that just popped up, and it’s great that somebody reminded me. Sleep. I forgot to mention sleep, and one of the… one of the commenters wrote, that actually is, becoming… We’re becoming more and more aware of how important sleep is and, in fact, one of my other roles is I’m the director of the Simons Collaboration on Plasticity and the Aging Brain, because cognitive aging is really what I’m interested in. And, we have a whole… actually, two groups that are really focused on the role of sleep, and why does sleep help us are, like, clean up our brains and help us function better. And so, I should have added that. And it’s, you know, sometimes longevity, the field is a little weird, because a lot of the stuff is exactly what, you know, like, your mom would have told you. Get enough sleep, eat right, get some exercise, you know. Which is a little bit of a drag, but now we’re understanding molecularly why that might be true, and then I really want to make this point, because you mentioned the ethical point. A lot of times.
Seth Green: Colleen, before we leave to sleep, though, I just want to hear the, so what. Is it the amount of sleep? Is it the quality of sleep? Is it the combination? Is there an amount? Because I’ve seen vastly different reports. Sleep is viewed as important, but I’ve seen things that go from 6 to 8 hours as the needed, and then I’ve seen, you know, you may have your own sleep needs versus a global one, and so I’m curious just for… it’s important that and what is the recommendation for laypeople like us who are.
Coleen Murphy: Okay, so I think that the jury’s still out, and that’s why there’s so much excitement about the field, and it’s like, because people are trying to answer those questions. So, and your last point that, like, it would be… there’s optimum… there’s an optimal probably for every single person. I know a guy who only needs to sleep 4 or 5 hours a night like, you know, he’s probably a mutant, right? So there’s probably something that allows him to do that that doesn’t allow the rest of us to function that way. And so there’s going to be, like, average suggestions, like 7 to 8 hours of sleep, I think. But sleep deprivation is really bad, and that seems to be because of this basically, glymphatic system that needs… you need to rest in order for your brain to clean out toxins, that’s the thought. And so, getting sleep deprivation is super damaging, and you can actually see this in these scans that people do. So, that was one thing. But, you had mentioned… you’d asked a question about ethics.
Seth Green: Yeah, no, and I want to, you know, just put out that question, then we’ll hear your response. So, you know, this is a field that is, as you said. Moving deep into biotechnology and innovation you know, the kind of classic, almost stereotypical example now is the Silicon Valley bro who is, you know, figuring out how to gamify this and get to 150, potentially. And what that really, I think, speaks to, which is a true thing, because I think that’s still an aberration, is we are seeing a huge death gap in society today, and that is likely to grow as we know more about aging, but only a certain group of people have access to actually apply all of that knowledge, and so I’m curious, kind of, how you think about the ethical implications of all these discoveries. You know, we’re at the frontiers. And then there’s all this biotechnological development, but access to this innovation is still relatively narrow, and so what do we think about, you know, obviously it’s great for society to have innovation, it’s great to have new discoveries. At the same time, you know, how do we think about the access and other implications?
Coleen Murphy: Yeah, so as you know from reading my book, that’s one of my deep concerns as well. And that’s part of why, when I… my lab does things, we actually do, … we do, for example, our drug screens on, FDA-approved drugs that are relatively cheap, so that… because you can have second uses for things that have… and metformin is an example of that, right? So that’s a relatively cheap drug. Of course. All the new discoveries. There’s not really… not really a good way to get around the fact that when you, like, do all these studies, you find some new protein that nobody knew about, you need to find a drug that activates it. There’s a certain amount of research and funding that needs to go into that development. And so, in order for that to eventually make it out to patients there has to be a lot of money put into that, okay? So, there is going to be a problem at some level that some things are not going to be very, equitably distributed. And I think that that’s true of almost every medicine you see, right? So there’s cancer drugs, all kinds of things that, like, because of that necessary step to get them to the point where they can actually make it out to patients, things are expensive. And so, I think the only way around that is to move forward with developing them, and then hope that eventually those become cheaper. But there are a lot of things, just health inequities in general. Like, our society is very, you know, the sad truth is, even if you didn’t ever receive any drug from any of these, like, longevity trials, the way to live long is to be white and rich. And so, because there’s so many barriers to health.
For many people, so if you are of a lower income, you might have, for example, you might be working more night shifts. You might have far less access to grocery stores in your neighborhood. You might have access to no, like, fresh fruit or vegetables in your neighborhood, you may never have an opportunity to exercise. So, you may not get enough sleep. So there’s lots of things that happen that are not to do with the science that we do in a lab, but basically just with society that keeps people from living as long as they possibly could, and I actually think that that would… That’s one role that we all need to be aware of, that, like, making society more equal actually will raise our average lifespan. Before we ever like a drug.
Seth Green: Very compelling point in the sense that, you know, you’re developing some of these frontiers for people who may have these other pieces.
Coleen Murphy: Yeah.
Seth Green: But if you’re thinking about how I can best improve longevity in the country.
Coleen Murphy: For example, how do we raise life expectancy?
Seth Green: The first thing you do is address poverty, because that’s probably the least expensive way to get a big bump. And indeed, you know, when you look at comparative studies, I know you’ve done this, and the U.S. has a lower life expectancy. Then lots of our industrialized peers who spend half as much on healthcare, and the context is just that they have a much more even spread and, you know, this low tail that, you know, coincides with poverty. I know there’s, you know, debates about exactly the cause, but coincides, you know, that is a place where we see a lot of decline compared to our peers in terms of longevity.
Coleen Murphy: And I just want to make the point, given the news. that the reason that we live as long as we do today is not because of any longevity drug. I mean, we do have had bumps from, like, statins and other treatments of some age-related diseases, like cardiovascular disease, but let me make it clear, the reason that all of us have made it to adulthood is because of vaccines. Right. And, the assault on vaccines in our country is going to kill people, and it will definitely shorten lifespan, and we’re going to see that immediately if access to, COVID-19 vaccines are limited, and things like… we already see it with things like measles in children. And so, I really… I… I can’t, …in good… good conscience, leave this conversation and pretend that things are still the same as when I published this book two years ago. They are… we are in dire straits, as far as public health goes today, because of the choice that’s been made by the current administration.
Seth Green: Well, so we have a lot of questions for you, Colleen, and I’m going to start them off, but we’ll make them almost cower around, because I think we have about a dozen for you in the next dozen or so minutes. So we’re going to start with Sheila Barrett. She says, there have been villages in Italy and Greece, and you’ve probably heard about Blue Zones as well, where the population has demonstrated exceptional longevity. Have these people studied? Is it primarily a factor of genetics? What aspects of their lifestyle can we apply in our lives? What can we learn from these longevity innovators?
Coleen Murphy: Yeah, I think… Okay, so probably most of you have heard something about Blue Zones, and that’s actually been recently debunked a bit. Part of that is because a lot of times for these original studies, some of the health records, like, the actual birth certificates were not people didn’t know how old they were, but it is true that one of the things that a lot of these, for example, these cities and… or villages and things in Italy and Greece are, people walk. People carry stuff, and they walk around a lot, and they actually are, like, using their bodies their whole lives to do things, and it’s not because they have… they’re eating fewer carbs. So, like, they really… it really seems to be about, like, their lifestyle. Yeah. And so there… but, you know, you could also argue probably most of the people in those villages share the same genetics, so maybe… we just don’t know how to end. So I think we can take some lessons from them, but I don’t think we actually know anything about the causes, like, why people live that long.
Seth Green: 15 years ago, James Mesrobian writes, there was considerable attention upon polyphenols and sirtuin proteins, with many proposed health benefits. Are polyphenols still an area of active research?
Coleen Murphy: That was a case where I think there was, and it was actually damaging to the longevity and aging field when, one, there’s so much focus on one particular thing. So, James is absolutely right. There was this idea that resveratrol would be some magic drug. And in fact, actually, I did a study in Seattle which showed that it actually does… did increase lifespan pharmaceutically kind of went nowhere. It was a company that was bought, and then, like, the company that bought it shut down the program because they couldn’t, they couldn’t see the same results. And so, there’s considerably less interest, although now we know, besides the original SIR2, there’s lots of other proteins in that field, in that category called sirtuins that do other jobs in the cell. So I’m not writing that off completely, but, you know, this idea, this all came, you know, often it was the French paradox, right? French people drink wine and still live long and stuff, but, you know, they walk around a lot, and they have socialized healthcare. So, I think that you know, attributing that all to the polyphenols in red wine was a mistake in the first place.
Seth Green: Although, a very happy mistake, what a great way to interpret the thing. It wasn’t them walking, it was just drinking wine. What a better way to get that longevity benefit? Not all things can just be based on what we want. Greg Gosick writes, what is the most plausible estimate of the ultimate longevity bottom line. In other words, if you’re adopting these best practices, is there likely a hard constraint to maximum obtainable lifespan? I was fascinated on this note, Colleen, to realize that the person who had lived the longest died a number of years ago, so it’s not like we’ve seen that longevity, in number, in a total number, like that heroin longevity of the person who’s lived the longest changing dramatically based on all of this, but can you talk a little bit more about that, and maybe, you know, separate out healthspan? Because I know people are getting a lot of healthspan benefits, versus lifespan, and how, as I understand it, a lot of this innovation is extending our healthspan but not necessarily changing the possibility of the number of years that people will live, but you can, I’m sure, share more about that.
Coleen Murphy: Okay, so let’s just back up and say, like, every single person who’s lived a long time, say, like 114 to 118 years, has not had access to anything we’re talking about, not resveratrol, metformin, or any other, like, longevity drugs, right? So that’s kind of the case of, like, almost the baseline of what a human maximum lifespan is, but we don’t really know what that maximum is. And there was a controversial paper that was published in Nature maybe a decade ago, where they claim to say that 115 was the maximum lifetime, which obviously isn’t true, because, like, there’s people, a few people, every once in a while who live longer than that. But it does seem to hover around, like, the sub-120 years. What would be the maximum if you actually did all the things that we are in the process of discovering. I don’t think we know that. And then there are, of course, these, like, completely wild claims that the person who’s gonna live 500 years already has already been born. You know, who knows? I don’t think we know that answer, and for me, it’s kind of like, I guess, a fun thing to talk about, but Yeah, and all those people who did that, you know, if you look at what they say about their own lives, which you… it’s always a funny story, they’re always like, oh, you know, it’s from drinking, like, a glass of whiskey every day, or something, you know, something completely that we know is not the reason they live long. The people who live an exceptionally long time are probably blessed with an ex… like, exceptional genetics, and we’ve learned some by looking at collecting together all the information we can from people who are, these supercentenarians. We can glean, like, there’s a few genetic mutations that help people live a long time. Like, they might have all the other diseases in their background, but they just don’t succumb to them. And so there are a few things and those usually turn out to be in the pathways we’re already studying. These things with cholesterol or insulin signaling. So you know, maximum lifespan may be around 115 to 120 without any interventions. So, we’ll see what happens in the next couple years. All right, well, it will be a very big suspense as we discover what the possibilities are.
Seth Green: We have a number of questions about sleeping. I’m going to combine them here. So one is about this idea that it’s, you know, helping to filter out toxins. And they wonder, is napping effective for that, or is it only the deep sleep, potentially at night? And then another question here is about, for older people who have trouble going to and staying asleep, should they be taking medication to help them sleep better on a regular basis, or you made the point, it’s really about avoiding sleep deprivation. So, I guess just your tips on how to think about, you know, sleep cycle, does napping work, could medication to help sleep be effective isn’t necessary.
Coleen Murphy: There’s a sleep collaborative group, through the Simons Foundation, and these are exactly the questions they’re asking.
Seth Green: Yeah.
Coleen Murphy: But I don’t know the answers yet. I’m always the one, like, because I want to know, right? Because there’s these terrifying studies, like, oh, someone who has, like, interrupted sleep, they’re going to eventually suffer from Alzheimer’s disease, and you can’t know what’s cause and effect, right? And I’d really love to know that so I wish I knew the answer, and I don’t know… they’re studying exactly… Those are great questions, and they’re exactly the questions that these groups are studying. It does suggest there’s certain phases of sleep that are more beneficial, and I don’t know… it is a great question. If you just nap, are you getting into that phase right away? I don’t know. And so that’s, … but you can see these… There’s these amazing videos, looking at, I think it’s fMRI, but they’re looking at the brains as someone sleeps, and you can see this sort of washing off, like, you know, and they’re looking at damage, and so, I wish I had an answer. I’m really sorry to the crowd that I don’t have an answer. It’s ongoing research that I think will be coming out in the next, like, probably 3 or 4 years.
Seth Green: All right, great. Well, we will make sure we’re wide awake for those answers. There is another set of questions here around this idea of what is described as cliff-like aging. Where new research is suggesting that aging is not necessarily a gradual, linear process, but rather involves distinct cliffs, or sudden shifts in biological or molecular processes, with some studies indicating these changes can happen around 34, 44, 60. They’re wondering if you could talk about that, and then they’re asking for people over 70, which maybe they have personal interest in. You know, are there additional clips that they should be ready for?
Coleen Murphy: Yeah, so this was research… you’ve got a very well-informed crowd. So, this is research that came out in the past year or so, looking mostly at these, sort of molecular, like, biological clocks. Now, I’m gonna make a catty comment. I think that every woman in the crowd knows exactly that, like, there’s some shifts that have been noted and completely ignored by science for too many years. For example, menopause. And, There already have… there’s an… it’s been noted that there’s actually a time of accelerated aging for women. In the menopause period. And so, I’m… I was kind of surprised when this came out that anyone was surprised by this, because we all have witnessed this. But maybe it’s just… it was a surprise to the dudes. Okay, I think that, yeah, the typical… The two that they noted were around the 40s and 60s. Post-70s, they didn’t notice a real cliff, but I think, if we’re talking about healthspan, I think we all know that there’s this idea of comorbidities. They’re basically things that seem to all sort of, like, pile up at the same time. So the question is, why didn’t that study come out with something that appears at that period? Because I think we know that that exists. And so I think that, post-70 here is a cliff, and I think we all kind of observe it, so the question is, why didn’t they observe it there? Now someone… I’m gonna fold into this… this idea, this maximum lifespan, because there was an interesting observation when people… when people have been trying to understand demographers, trying to understand, this idea of maximum lifespan, that once people hit an age of 105, they seem to, like. Almost have, like, a sh… like, they didn’t experience any acceleration of mortality. So, that’s not helpful if you’re not planning to make it 105, but I think we’re still learning what exactly is this, like, cliff-like thing, because that study didn’t associate with any particular molecular signature. Like, we don’t know what that meant. It was just sort of an observation.
Seth Green: So we have a handful of questions left. I’m going to try to group them together, Colleen. And one is about how well we do in science and medicine with what sounds like a multidisciplinary set of factors. But then you’re seeing individual physicians, and they’re looking at a very particular piece. We have another question here about what factors or biometrics you recommend. And I’m familiar with the rise of functional health, where you’re trying to look across all these biometrics, and then be more proactive and see how things connect within the body rather than treat things as individual diagnosis and intervention. And so, to link all those things together, I’m curious if you could talk a little bit about… there’s all of this scientific innovation happening. Then you have the medical complex that is still kind of looking at a disease and intervening. Can you talk a little bit about where you think we are in being able to bring what is interdisciplinary knowledge into our current medical system, and maybe in that context, give us any of your perspective on this rise of functional health.
Coleen Murphy: Okay, all right, so let me just say that, because there’s a question about collaboration. So, the way scientific research used to work, until the NIH has been destroyed, was that we would receive funding, to study a question in great detail, so we really understand it, and then we just, you know, disseminate that information through publications and through going to give talks, and at a lot of these meetings, like, I go to a bunch of different types of meetings, some are really narrow and some are really broad And at these broad meetings, we get to know people and hear information about all these different types of studies, okay? How that gets to the medical field is, like, as you mentioned, it’s a little bit, like, not as clear, but there’s been an interesting rise of things called longevity clinics. And so, longevity clinics, people running… They’re really interested, and this really happened post-COVID, because a lot of people suffering from long COVID, have noticed that they experience accelerated aging. There’s a lot of hallmarks that are similar to accelerated aging and to, some other, disorders, and so…Several groups have gotten together and said, okay, we’re gonna look at it holistically and try to really track, like, biometrically, like, what are the things that actually, tell us how… What kind of health is someone in? Usually middle aged. Usually, people who are in their 50s or 60s get interested in this, 40s to 60s. And then, what can we do to, like, improve those metrics, the things that we can measure? Things like resting heart rate, sleep, that’s actually, like, you can measure sleep, right, right, with your FitBit. CO2… VO2 max, so those kinds of things are getting measured. I don’t think… that part, I think, is not an exact science. That part is where people are trying to, like take what they know from all these different areas and put it together and give a particular patient some advice. Some of which I’ve already told you about, like, kind of like, you know, things you already know, but somehow, like, having someone else tell you to do it often results in it happening, right? I think the awareness, the fact that you have a whole group here listening to this, is one of the things that’s gonna get this out to the general public, right? Things that we should be doing And then eventually, someone asked about metformin and some other things, like, there’s something called the TAME trial, and that’s the… the idea behind that, since that’s a cheap drug, is to ask, if you give people this affordable drug, will you see improvements in things like healthspan, age-related diseases? And so, I think that is the kind of thing where then a physician might be more comfortable than prescribing something like metformin, even to people who don’t have diabetes. And I think that’s the real thing that’s going to change, is allowing prescriptions for you know, aging, which is not technically, by the FDA, right now, considered a disease, but you could imagine getting treatment for it from some of the already available drugs that are not even that expensive.
Seth Green: Well, Colleen, this has been a fascinating conversation. I will say I feel lucky every day to be in my role, but especially when I’m not only learning intellectually, but also I have a list of items I want to now incorporate into my lifestyle, so that I can hopefully age well and continue to learn from incredible people like you. Thank you for what you’ve done for the field. And maybe I’ll just close with a quick story, I’ll give you the final word. We have a wonderful initiative here called Leadership in Society Initiative, where individuals at the end of their long-standing career, but who want another generative chapter of purpose come to the university for a year and think about where they want to go next. And one of the fellows who just completed her fellowship, she had been the CEO of Deloitte Consulting And she came here and worked with a number of biologists here, and actually came to the same observation that you shared earlier, that women are living longer, but their healthspan goes earlier. And so they lived nearly twice as many years with life and not health, and they then saw that there was a huge lack of investment in this whole marketplace, because the people that had often been doing the investing just didn’t have proximity. And so anyway, has built this fund now an impact investment fund with that exact goal in mind to try to address that issue. So as you shared your observation about how, you know, it might be the dudes who are unaware of these clips, I wanted you to know that we have a business leader, but now empowered by wonderful biologists here who’s trying to address it, And hopefully build a new market for what could be a really important health intervention. So, any final words for our audience before we go?
Coleen Murphy: I think that a lot of people have the general intuition of the things that will keep them living longer and healthier. My book is a little bit on the science side of understanding the genetics and molecular biology underlying that, but I hope that you do come away with this idea that there are things that we can do at least even before we develop these interventions, to stay healthy longer. And so, if you do nothing else, exercise and sleep, because those are the things that are going to help you no matter what.
