How to Be a Super Ager (with Eric Topol)

Jun 23 2025

What if we could delay--or even prevent--Alzheimer's, cancer, and heart disease? What if much of what you know about aging is wrong? Listen as cardiologist and author Eric Topol of the Scripps Research Institute talks about his new book Super Agers with EconTalk's Russ Roberts. They discuss why your genes matter less than you think, how your immune system can help prevent cancer and Alzheimer's, and why a simple shingles vaccine could reduce the risk of dementia. From the surprising anti-inflammatory powers of Ozempic to the critical importance of deep sleep for brain detoxification, Topol shares insights that can extend your healthy lifespan.

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Time	Podcast Episode Highlights
0:37	Intro. [Recording date: May 28, 2025.] Russ Roberts: Today is May 28th, 2025, and my guest is doctor and author Eric Topol. This is his fourth appearance on the program. He was last here in June of 2019, talking about Deep Medicine. Our topic for today is his new book, Superagers: An Evidence-Based Approach to Longevity. Eric, welcome back to EconTalk. Eric Topol: Thanks so much, Russ. Great to be with you.
1:00	Russ Roberts: This book is quite an extraordinary summary of what we know and do not know about the human body and its health. And after reading it I was struck by two things, I'd like to start with. The extraordinary complexity of so many things we had little knowledge of--I would say 40 or 50 years ago but for some of these topics, I think it's less than that--and how little we understand despite the growth in knowledge. So, we know a lot more. We know about things being connected to other things. But, we are often missing some fundamental understandings of the processes that we want to make better. Is that a fair summary? Eric Topol: I agree with you totally. Yeah. Russ Roberts: Talk about that a little bit. Eric Topol: Well, one of the things that we had a misconception, which I think the data is clear, is how long it takes for these big-three diseases--cancer, cardiovascular, and neurodegenerative--to take hold in our body. Typically, as a cardiologist, we'd see somebody with a heart attack and say, 'Oh, well that must have been festering in the recent weeks or months,' when it's took more than 20 years. So this is, I think, a misconception we have. We also have this idea that it's all in our genes. And it isn't. So that--I think it's pretty darn clear that the studies that we've done, and particularly the wellderly study of the near 1400 people that were over age 85 had never been sick on no medications. I mean, they're hard to find, these people, right? But, very little showed up in their whole genome sequence. So, there's a lot of myths that we have to debunk and things that we don't understand. And, I think as you know Russ, the thing that I emphasize most importantly that we don't understand, is the--because we don't measure it--is how our immune system is either up- or down-regulated as we age. And, that appears of anything to be the most important part of the healthy aging process, this kind of balance between the immune system and inflammation in our body. But, a lot more work needs to be done there.
3:17	Russ Roberts: Yeah. I was struck by that--the importance of our very imperfect understanding of that. Also the rise of--again, correct me if I'm wrong--the importance of the gut microbiome: meaning what's going on in our digestive tract. And, just the complexity of the brain. I mean, some of the findings that you highlight in the book about the brain and what's going on in there, I'm thinking: we just found that out? Isn't that an important organ? Weren't people kind of looking at that? But, we've got a lot to learn. Eric Topol: It's actually kind of so striking to me how many brain breakthrough findings we've seen in the last year or two. I mean, just extraordinary. But, I want to touch on the gut story, the gut-brain axis, because as you know, there's all this tremendous interest now in these glucagon-like peptide GLP-1 [Glucagon-Like Peptide-1] family of drugs. And, what's fascinating about that is it's just the beginning of the story because we have a couple of them on the market--Ozempic and Mounjaro, Semaglutide, Tirzepatide. The problem was that it's just the beginning because there's 10 more gut hormones we haven't even started with, and there's going to be combinations of them. And they talk to the brain. And they also talk to the immune system. So, the interconnects between the gut--our microbiome in the gut--as well as these hormones, as well as through the vagus nerve to the brain and the brain stem--it's amazing. So that we're seeing the unexpected with the GLP-1 drugs. Like, not just reducing eating, but actually healthy eating. Changing reward circuits so that people stop at their addictions to cigarettes or alcohol or gambling, even. There's things that we didn't ever expect because of the circuitry in the brain and how the gut and brain interact. It's striking because, for example, Ozempic doesn't even really get in the brain, directly. It only gets its message through the gut-to-brain axis. So, this is one of the most important discoveries. Because we have a drug class now that's wildly outperforming expectations, and we are still learning about not just these gut hormones--the double receptor Tirzepatide--but there's a whole bunch more coming. And so, our ability to knock down inflammation and modulate our immune system is really going to be enhanced.
5:54	Russ Roberts: You mentioned--I'm going to talk about this for a little bit and I was planning to get to it eventually; I'm glad we're talking about it now--Knock down inflammation. That's another thing that sort of runs through the book commonly that, 'Oh, there's this problem with inflammation.' Talk about that. What is that about? What's going on there and why is keeping it down so important? Eric Topol: Right. So, as we age--I mean, we were talking about these age-related diseases--this process of inflammaging occurs. There's several reasons for that. One is we develop senescent cells in our body. And you think about senescence, I mean it goes along with aging. But, some of these are good-performing cells. That is, they can help for healing and they can't divide any longer so they're not really a source of potential for cancer. But, some of these are really bad actors of these senescent cells; and they secrete these very potent pro-inflammatory proteins. So, just like our immune cells that don't function as well as we get older--that's another term, Immunosenescence--that can also secrete these proteins called cytokines and chemokines. So, between these different cellular bad actors, if you will, we're prone to inflammation as we age. Now, why is that important? Well, it's one thing to get misfolded proteins in your brain, like amyloid and tau. It's another to have brain inflammation to those proteins. So, that's untoward inflammation. The same is occurring in our artery wall. If we have some cholesterol build-up plaque, atherosclerosis, but we get into more inflammation into artery wall, that's how we get cracks in the wall and heart attacks. And then, finally with cancer--this is a real problem. If our immune system isn't got full integrity and really guarding us against an alien cancer cell because of its different proteins on its surface, that's how cancer gets legs. And it can grow and spread, and it would be very hard for cancer to really take over in a body if we had intact immune system throughout our life.
8:17	Russ Roberts: Let's go back to the GLP-1 drugs like Ozempic. I haven't paid much attention to this. I would love to be thinner. The idea of taking a drug for the rest of my life that is brand new is not appealing to me. Seems like a high-risk strategy to get thinner. But what I didn't realize is--I knew it was developed for something else; and oh my goodness, it's great for weight loss. And of course, that's an enormous source of revenue for the companies that developed these drugs. But, the idea that it could do something other than that, and we've barely scratched the surface--I didn't know that. And shame on me, because it's obviously enormously high potential. Eric Topol: Yeah. I think, Russ, as you know, I talk through in the book this 20 years that we missed the whole story. I mean, twenty years that we could have been ahead of this. But, it was because the people with diabetes--Type 2 Diabetes--when they took these drugs at the exact same dose, the same drug, they only lost a few pounds. Whereas people with obesity, their loss of weight can be extraordinary: 30, 50, 60 pounds. Right? And, we still don't know why. So, going back to your first point, we still don't know why. Right? Russ Roberts: That's so weird. Eric Topol: Now, what's also interesting is not only have we seen the weight-loss-dependent effects on the heart--the so-called preserved ejection fraction heart failure--or on the liver, so-called NASH [Non-Alcoholic Steatohepatitis] or MASH [Metabolic Dysfunction-Associated Steatohepatitis], or on the kidney, but what's really amazing is we see reduction of inflammation before there's even a few pounds of weight loss. So, it isn't just that we get rid of adipose tissue that can make these--they were like a machine for inflammation, particularly belly fat. But, the drugs themselves have a potent anti-inflammatory effect in the brain and in the body. So, this is something that we learned a lot more about really in the last year, and it's why it's possible the Alzheimer's trials that are ongoing--and they'll be out early of 2026--if they click, and that's just where the Ozempic, which is a relatively weak single-receptor drug, I mean, that would take it to another complete level. And, we have some data to support that they will work, but we have to see the rigorous placebo-controlled trials to make the call.
10:56	Russ Roberts: I'm learning a new language--trying to--Hebrew. And, it's a hard language because its characters are different. Eric Topol: It's good for your brain. Russ Roberts: It's good for my--I'm hoping. I'm not taking the GLP-1, so I got to learn Hebrew instead. But, what I'm noticing is that it's hard to remember all the words. I'm 70 years old, as I think you are--at least something close to it. Hard to remember all the words. It helps to repeat them. Use them. There's all kinds of different ways. And a word that you think, I'll never remember the distinction between these two words, and you work at it and you work at it; and you get better. But, when you're 70, the pace is slow. And of course, there's some two steps forward, three steps back sometimes. How do you keep up--not with Hebrew--but with medical jargon? Just the discoveries that are coming out every day in your field. This book, it's not just--you're trained, I think, as a cardiologist. And, correct me if I'm wrong. But, the scope of this book and just in our first 10 minutes of conversation, a number of things that come off your tongue, so much better than my Hebrew. How do you do that? Obviously it's a gift. But, what do you do daily to stay on top of things? What's your workflow? Eric Topol: Well, I suppose it's like you, Russ, because I know you are an avid reader. I can just see your library right behind you. I read every day. A couple of hours when I wake up. That's my first thing that I do. Even before I'll have breakfast, I'm trying to be the infovore of just eating--ingesting--information. I've always been that way. It helps me feel like I'm on top of things. I still don't have enough hours in the day. Oftentimes in the evening I'll get back to reading, too. So, that's what I try to do, is like a daily dose of ingesting what I think is really interesting information. Not always pure medical. It could be AI [artificial intelligence], it could be something that's indirectly related. But somehow or other it comes together. Russ Roberts: How do you decide what to read? Where do to get your feed from? Eric Topol: Yeah. So, I concentrate on top medical journals like Nature, and Science, and the likes of those. So those are a very high priority. And I know each day of the week when they come out with the new stuff; so I'm right there, I'm reading it, and I'm trying to synthesize what's going on. And then, beyond the articles there, I'll read, of course, newspapers every day, and sometimes there's some really interesting nuggets in there. And books--worthwhile books. So, between them, it isn't like I'm on a vacation or holiday. I'm still reading a lot. I can never get enough of that. Russ Roberts: Yeah. So, I have something similar. I think of it as a blessing. I'm not sure my wife always agrees. But, she gets both what we call the positive and negative externalities for my reading habit. Let me make a small personal confession here and get your reaction to it. I have not slept particularly well, I would say, for the last--ehh--four years. COVID [Coronavirus Disease] had a huge effect on the quality of my sleep. My dreaming was different. I think there was some anxiety in there, especially in the beginning when we weren't sure how serious it was. Then I moved to Israel. I'm an immigrant. I have a new job. I'm learning Hebrew. My work life became much different than it had been. And I find myself sleeping, typically, five to six hours a night. I try not to drink too much near bedtime because at the age of 70 I find myself getting up, which is just a physical reality. But, I've always thought: 'You know, I can power through this.' I have nights where I get up in the morning after four and a half hours of sleep; and, you know, I just keep going. And I've always thought, 'Okay? I'm not a hundred percent.' I'm not as sharp, especially when I'm doing interviews. I don't remember everything I want to remember. But, your book reminds me that it's more than just your effectiveness. That, bad sleep has long-term health problems. So, talk about why sleep is important and what I ought to know about it. Eric Topol: Yeah. Well, we've learned a lot about that, again in recent times, and the data are pretty extraordinary, I have to say because I didn't realize how vital this was. So, there are several aspects of this. So, one is what's called the sleep regularity index, which I reviewed in the book. The data on that's pretty striking. That: we need to be on a clock. I had the problem perhaps you've had where I didn't have this regular bedtime. I tried to get more out of the evening than I should. And, that's not a good idea because what you see is the regularity is important, because it not only influences likelihood of dementia, but also cardiovascular and cancer outcomes. So, that's one thing, is establishing a time and trying to stick to it. I do that now just based on the data, although it might be on a Saturday night, that one deviation or something like that, going out with some friends or whatever. Now, the second thing is the breakthrough in understanding what happens during the night with respect to these metabolic waste products. Also, what you could say are toxins that we make in our brain. And they are pro-inflammatory, and we want to get rid of them--every night ideally. So, there's a channel called glymphatics, not lymphatics. And that glymphatics, we've made a lot of discoveries about that in recent times, but that's how we clear these waste products. And, they are particularly cleared in this slow wave of sleep called deep sleep, which is a subset or some part of the non-rapid eye movement sleep section or category of your sleep. Now, that usually occurs early in the night. It sounds like: Oh, deep sleep, that must be way into the night. No. Most of it usually occurs in the first couple of hours. And, it's not so much how many hours you get--like, if you get six hours--but if you get an hour at our age, 70, if you get an hour of deep sleep, you're golden. That's really what you want to get after. Now you mentioned alcohol, but there's a lot of things that influence deep sleep; and you can measure it now with a smart watch, with a ring, a mattress sensor. The ring might be the most accurate way, but they all give you an index of your amount of deep sleep. And, what I learned--you made a really good point--you don't want to have interrupted sleep. Definitely hydrate in the morning and during the day and really restrict fluids in the evening to not have interrupted sleep having a void. But in addition to that, you have relationships to what you eat, when you eat. You don't want to eat late in the day, in the evening. Also, with what you do for physical activity: the more the better, but not too late again, because that changes your sleep. So, lots of things influence deep sleep. Six hours may be fine if you have a solid component of deep sleep. And, what's amazing, it took us all this time to understand the glymphatics, deep sleep, the interactions. I mean, like, atrial fibrillation changes the glymphatics' performance so it can have an adverse effect on deep sleep. Who would have guessed that? So, all these interconnects that we just didn't know about.
19:39	Russ Roberts: I want to talk a little bit about something I think is--it fascinates me. I'll do another confession. Listeners, you can hear two old guys talking about--one of them is trying to get free medical advice and the other one's smarter than that guy. So, I am vitamin D deficient, as I think many Americans are. Comes from working inside at a desk and not getting enough sunlight. And, one of the risks of vitamin D deficiency is bone brittleness and vulnerability to falls and other--many bad things. So, many doctors have suggested to me, I should take vitamin D supplements. My main reaction to that--and we don't really have to get into my own personal vitamin D issues, but more the generic phenomenon here. My worry with that is always: Well, I'm going to improve my measured vitamin D when the test comes back, because what the supplement is designed to do. It's designed to increase my measured vitamin D, which is not the same thing. And, it strikes me it's better to get a little more sunlight. There's of course a risk of skin cancer. But, I think it's quite small at the levels we're talking about. And so--and the same thing I'm thinking about with sleep: Is sleep that's artificially induced, say, with a drug--I don't take any drugs to help me sleep. Obviously there's some things I can do that are non-pharmaceutical such as not getting on screens, eating earlier, and so on. But, I'm wondering about this general phenomenon; and I worry that a lot of our medical innovations are designed to improve the marker rather than the underlying condition. Comment on that. Eric Topol: Well, you really nailed it because so often we just assume that if you fix the blood test result that that changes the outcome. And, we don't have that data for vitamin D. And as you say, a large proportion of the population has got low vitamin D levels, but it's never been proven. And this is a across-the-board thing where you see it in lots of other examples. But this is a perfect example: It's never been proven that you jack up your vitamin D level and then it changes your osteoporosis or other vitamin D calcium-dependent pathways in the body. So, yeah, this is I think important. Now the other thing, just to go back for a moment on the sleep story, the shocker was that if you take Ambien--and this likely applies to other drugs, but it's been studied in the Ambien--it may make you feel like you slept, but it prevents the elimination of waste products. So, it actually makes things worse. So, you don't want to take those drugs. And so, that's something that, again, we only learned that in recent times. Russ Roberts: Yeah. My understanding is there have been a number of studies of the vitamin D question and there's no evidence that it reduces osteoporosis. What do you call it? All-blank mortality. All-cause. Eric Topol: All-cause. Russ Roberts: All-cause mortality. So, I'm not doing it, and I'm trying to get a little more sun.
22:56	Russ Roberts: Let's talk about the immune system. You write the following, which I think is really quite amazing. [From a pre-print of the book:] The recognition of the immune system is a common mechanistic underpinning for chronic diseases, whether it be related to why they occur or to the untoward sequelae that they induce is an historic turning point. These diseases--heart, cancer, neurodegenerative--take two or more decades to develop, giving us a long-time window of opportunity to prevent them. Atherosclerosis, which leads to heart attacks and strokes endures despite progress as the number one cause of death and disability globally. It is due to inflammation in blood vessel walls; and all inflammation is generated by our immune system. Cancer isn't usually a killer unless it spreads and our immune system can stop from happening. If there were an inflammation in the brain, it would be difficult for conditions like Alzheimer's or Parkinson's to take hold. And so, this idea that--and we talked about this already a little bit, but I want you to expand on it--this focus on the immune system, which--this a pretty recent understanding, it seems to me. So, tell if I'm right. So, tell me if I'm right about that and talk about the future for what we might learn about the immune system that would make a big difference. Eric Topol: Yeah. This is, I think, fascinating. And if there is one thing that comes out of this research that went into the book, it's related to this. So, going back when we sequenced those 1400 people that were extraordinary wellderly super-agers-- Russ Roberts: These are elderly people who don't have chronic diseases. They're called wellderly. Eric Topol: Yeah. No chronic disease. As opposed to the illderly, which is the common 60-some year old. Of course they have often multiple chronic diseases. So, these people, we thought we'd find a eureka effect in their genomes. And we found nothing. Now, the patient I present right at the beginning of the book, Lee Russal[?sp?]--she is typical. She's 98, and her relatives died--her parents in their 50s and 60s, her brothers in their 50s and 60s. That is what we saw in this wellderly super-age group. It wasn't a heritable pattern and it didn't show up in the genome sequence. So, now you say: Well, what accounts for these people? Is it just luck? It's some kind of stochastic event? Or is there a biologic explanation? I would submit to you that from everything we know--because the genome sequence doesn't tell us about the immune system--if we want to know what really accounts for why these people just have this amazing health span, we need to study their immune system. And, that has been done. In fact, one of the best studies, Russ, came out of Israel and to[?] reviewed in the book. But, as we age certain people, they could be in their 90s and their immune system is like they're in their 40s. And, we even have these immune age different clocks for the immune system. We even have an organ clock now for the immune system. So, if we want to really get these three age-related diseases to prevent--markedly delay--them, we need to be able to measure people's immune system as they get older. You know, once they get past 60, 70. Because we now have a way to up--like a rheostat--increase, decrease, fine tune this. And if we see somebody who is older and their immune system is down, that means they're going to be at risk for either cancer, or, on the other hand, they may have this dysregulation start releasing these inflammatory proteins. Which drive the other two major diseases. So, this is why keeping our immune system young is such a critical thing. And we're just now figuring out how we're going to measure it in people. What's amazing--I still can't get over this--in the clinic, if you come in and see me in clinic and I want to check your immune system, I have nothing--nothing--to offer. Zero. Okay? Here's what I get: a complete blood count to tell me the ratio of your neutrophil white cells to your lymphocyte. That is a joke. That's all I have, right? If I want to know, I got to study your T cells and your B cells and your autoantibodies. I got to do perturbations. So, people are working on this now. There's a human immunome project. That could be as important as a human genome project, or more important. Anyway, we will get there, but that is the missing hole in our whole ability to prevent diseases. Russ Roberts: But I assume at this current level of knowledge--which is embryonic, if I could use probably an appropriate word for this situation--even if we had that good measure, which is simply a descriptive tool which we are just beginning to develop, and we find out that mine is old, or too old for my age, or much older, or not healthy, or it's declining from the last year when we did this a year ago: Do we have any knowledge about how to make it better? Eric Topol: Yeah. Actually we do. Russ Roberts: Tell me. Eric Topol: So, striking. Yeah. So, the three natural experiments--which are, I would say even better than randomized trials for being an ideal way to look at cause and effect. So, these are hundreds of thousands if not millions of people that just because of their birthday or just because of a healthcare policy thing, half of them got a shingles vaccine to prevent shingles and half of them didn't. And, what's amazing is all three natural experiments showed that in follow-up, the people got 20 to 25% less dementia--less Alzheimer's--from getting a shingles shot. Now, we never would have guessed that that was going to occur. And, if that was a drug that prevented Alzheimer's, can you imagine? So, it doesn't seem that there's any real validity that these drugs take on herpes that causes Alzheimer's, but rather they dial up our immune system. And, almost any vaccine can do that, but this is certainly one that is quite a strong immune response. That's why some people when they get shingles vaccines, particularly on the second dose, they can feel like a bad flu illness because it's very immunogenic. It really activates our immune system. But, in the future, we may not use this just a shingles vaccine. We may have vaccines that are made just to rev up our immune system. And, that's how these cancer-preventive vaccines that are in the works, that's how they are fashioned, is: Just get our immune system amped up in a durable way for people who are vulnerable. Russ Roberts: Note to self: Get that shingles vaccine I've been putting off. Eric Topol: Yeah. Russ Roberts: Okay. Eric Topol: By the way, I did the same. When I saw the data, I didn't want to get it, but then I said I got to do this. Yeah.
30:23	Russ Roberts: Just as an aside, I took two doses of the COVID vaccine in America. Then I moved to Israel. I got the third dose six months after that. And then, of course, I was encouraged as many people were to take the fourth dose. And beyond. And, my attitude at that point was: the health risk of COVID for me, given it how it had evolved over time and given that I had very few comorbidities, was relatively low. I wasn't worried about getting COVID. I had gotten it in the meanwhile, so I had some natural immunity as well. It was like a flu and it was not frightening at all for me. And so, I decided I wasn't going to take those extra vaccines. And, somebody accused me of letting my politics overcome my judgment. I said, 'I don't think you know me very well, or how I think about risk.' But, I did wonder, and I'm curious what your thoughts on this are: that, a new vaccine--and it was a miraculous, as you point out in the book, 8-month, 10-month run. Unimaginable--unimaginable--that that was a drug and a process, the mRNA [messenger Ribonucleic Acid] drug that we didn't know much about. And taking four--which, knowing that it played with my immune system--didn't seem like the best idea to me. Was that a reasonable thought or was I just being silly there? Eric Topol: Well, no. I think--I mean, you got four shots, and you had COVID. Russ Roberts: I had three. Eric Topol: Three, and you had COVID. That's building up a lot of immunity towards the virus. So, you know, that's good. I think everyone has to make the call--those of us over at age 65--because that's where of course the risk really gets magnified. As to getting the additional shots: I mean, if you have comorbidities and you're over 65, or you have never had COVID--which of course is a minority now--or you're starting to see things really heat up in your region where you live in the world and you want to be able to have some resistance to--protection from--getting infected: I think it's a tough call because the additional shots--fifth, sixth, seventh shots--they're not going to have nearly as important impact as the early shots. The problem we had with this virus--and it was diagnosed in Israel--is that not only do we get these new variants, but unfortunately we have this waning immunity problem that we just can't keep up with that virus so that a year or two later--let's say in the next year, we get a big wave coming. Once that is starting to take hold, that might be because of the waned immunity to get another booster. This is a really difficult thing, because right now things have been relatively quiet. There's a couple of variants out there that maybe they'll get legs. Who knows? But, we're not done with this darn virus. And, the worst thing is, unlike so many other viruses and pathogens, our body doesn't get a sustained immune response. Even when you have a COVID infection--so you get to see the whole virus, not just a spike--we still don't get this durable, strong immune response against the darn virus. It's really a frustrating, vexing issue. It's why a lot of people got disenchanted with the vaccines, because they thought, 'Oh, it doesn't protect me from infection.' Well, yeah, it's not great for that, especially after a few weeks, but it does in older people help for reducing the toll of hospitalizations and even deaths. Russ Roberts: Butmy thought on this, of this being a relatively new technology, this vaccine--it reminds me a little bit of the Ozempic thing as well. There's real euphoria about its impact on weight loss. There's huge potential for it to do more than that. But, you have to take it for the rest of your life if you want to keep that weight loss off. And, I'm always uneasy about--we just don't know much about, quote, "the long-term effects." And, it's an example of where our lack of knowledge of the mechanism that's underlying the efficacy of it is part of the challenge, it seems to me. We don't fully understand some of these things and so to speculate what the long-term consequences are of staying on it just seems a little risky. Eric Topol: Yeah. The comments I would just make is we do have 20 years of these GLP-1 drugs, and we even have for obesity now six years of follow-up in large trials. So, we have a pretty good handle. It is not 20 years, or 30 years, but we have a--and on the mRNA front, the one thing good about the pandemic, you're right, they were new, this platform, the RNA [Ribonucleic Acid] and nanoparticles. Which, by the way, should have been improved. We should be using better nanoparticles and keeping that mRNA from ever having untoward side effects. But, we haven't. The companies that make these are stuck in the original version. But, we got about a billion people exposed to them. Russ Roberts: That's true. Eric Topol: So, wow. And the reason why it's important is that this same platform is great for delivering things to cells that we didn't have. So, whether it's like a gene-editing story or a cancer vaccine, we've seen some great results in intractable pancreatic cancer, renal cell carcinoma, and even autoimmune diseases. So, there's a place for this platform. And the problem is, of course, because of some of the side-effects of the mRNA vaccines we're seeing in the United States, this anti-mRNA, that would be really unfortunate because overall it's very safe. It should get better. It hasn't. And also, it's being applied well beyond vaccines. Russ Roberts: When you say companies are stuck with their original versions, is that because of the intellectual property protection that they're relying on and that it's expensive therefore for them to start from scratch, and therefore they just don't have an incentive to innovate? Or is there something else going on? Eric Topol: No, I think part of it is the intellectual property. Part of it is they have now had mass production of hundreds of millions of vaccines and to go to a new process--the point being, is: we've known that the nanoparticles can be optimized so they even have better penetration. We have these things called self-amplified vaccines where you give much tinier amounts of mRNA. And that's approved in Japan. But there's not even a bit of effort to get that going in the United States. That would help reduce the mRNA side effects. So, these companies, they did very well during the pandemic and they got things going quickly. That's great; but they're not keeping up with the field. And we're seeing in other parts of the world the innovations that we need.
38:14	Russ Roberts: What's a polygenic risk score? Why is it important? Eric Topol: Yeah. Well, it's quite important, because when you think about your parents and that one of them had this disease and one of them with this, had--and what we don't acknowledge is that we are not the product of just either parent. We are the admixture of their genomes. So, the polygenic risk score is, meaning that if you look at the common variants that account for--these are present in 5% or more than a few percent of the population. We each get variants from our mother and father. Now, when you get hundreds of these variants that predict the risk of heart disease, any of the common forms of cancer, Alzheimer's disease, they become useful because they're one layer of data to tell you if your risk is significantly increased. Right? So, it's not perfect because, you know, sometimes it's wrong. But for the most part, we're getting an idea that I have a high risk for this particular type of cancer, heart disease. It does help a lot to--a lot of people say, 'Should I take a statin?' Like you are going back to the LDL [Low-Density Lipoprotein] as a marker, fixing the LDL. Well, maybe you shouldn't fix the LDL; but if your polygenic risk score is high for heart disease, that's a really good test to tell you you'll benefit from a statin. So, they tell us about risk. But they're just one layer of data that we want to look at all the layers. We have lots of layers of data now. The problem for us is they don't tell us when. They just tell us Yes or No. So, if you're at high risk on your polygenic risk score for Alzheimer's, well, if that's age 98 or 68, right? So that's a big issue. Russ Roberts: When you say variants, you mean genetic variants, I assume? Eric Topol: Yeah. So, of those three billion letters, there's hundreds that are associated with each of these common diseases, conditions. And so, those are the ones that the polygenic risk score measures. And, you can get a score--a hundred is very high risk--and all the way down to zero. And, you basically--it's only meaningful if you're at high risk. Otherwise, you don't know what to do with it. Russ Roberts: And, going back to our previous discussion about how my immune system is doing: What are our mechanisms today for generating those scores? Eric Topol: Yeah. So, there's about 10 companies that do this, I mention in the book. It's very inexpensive. I mean, it can be done for less than $50, even $25 we've done it in academic labs. Because it's out of saliva. And it's an array. It's not a full genome sequence. So, it's just a chip. And it should be part of the routine medical assessment. As I mention in the book, there's certain health systems that are doing this on all their patients now, and it's proven to be very useful in partitioning risk. That's the key: is, we got to find out who are the high-risk people. Because, you're not going to just get it from family history. We just have had this notion that, 'Oh, our family--.' Wrong. I mean, like, for example, my family history, there's no heart disease. There's everything else. But, when I got my polygenic risk score for heart disease is really high. Right? So, and I'm sure it's accurate, because I have other ways to check it. So, you know, I think this is something that we're learning about. And there's resistance in the medical community to use it even when it's very inexpensive.
41:59	Russ Roberts: So, I think some of my unease when hearing about it is the same unease I have about a full body MRI [Magnetic Resonance Image], which you mention in the book and speak negatively about it--as I do. It's tempting to think, 'Well, better safe than sorry. Let's be cautious. Let's find out what we're at risk for so we can take account of it.' And of course, the full body MRI--first of all, it's very crude. It doesn't do a very good job as you point out in the book at perceiving things that are quite important It tends to lead to false positives. You look like you have something when in fact you don't. Which leads to interventions. Which leads to bad outcomes: anything from infection to failed interventions that are just further testing and diagnostics. So, what's the difference between that and the polygenic risk score? And, the other part of it that I worry about is, of course, anxiety. So, let's take both you and me. You go and get yours. You find out, 'Oh my gosh, even though my parents had very healthy hearts, it looks like I have a higher probability than otherwise might be the case from my particular genetic situation.' And, I find it for something else. I find some cancer. It turns out I have a high chance of--let's say prostate cancer. Now, what do I do with that? What do you do with that? I'm going to sleep less well; and that's going to raise my risk of cancer and Alzheimer's. And especially when you're young. Should young people be worrying about this? I mean, one of the themes of the book is this very nice insight that often you have a long time to find out about something developing. And, even something as nasty as cancer, if you catch it early enough, it hasn't metastasized, you're going to be okay. What do I do with that--except worry? And, what do you do with it in your own case? Eric Topol: Yeah. Do you want me to talk about the polygenic risk score or the MRI or both? Russ Roberts: No. Forget the MR MRI. It's a bad idea in my view. Eric Topol: I'm with you. I'm with you. Russ Roberts: Although we don't dispense medical advice on this show. Consult your own doctor and MRI provider. But, I'd like you to talk about what do you do practically if you find out you have a genetic variation, very different from what you expected in your own family history, say? Eric Topol: So, this is actually quite an important point you're raising. And let's use Biden, President Biden--former President--as an example. So, his doctors followed the recent preventive task force that says: Don't even check a PSA [Prostate-Specific Antigen]. Russ Roberts: I think you've said that on this program in the past, and you're not the only guest who said so. Eric Topol: Yeah. Well, you know what? That's a mistake because this thing about prescribing something for all people is so dumb--okay?--because what he should have had would be a polygenic risk score for cancers and particularly prostate cancer. And if he had a high polygenic risk score, which has been shown now in the recent paper in the New England Journal about this, that partitions risk: that's the person who needs to have very frequent assessment. And maybe not even just a PSA; maybe even more than that. So, this is the problem. Everything we have for cancer screening is so-- Russ Roberts: Blunt-- Eric Topol: dumbed down. It's like we're all cattle. We're not unique human beings. And, it's, like, the same thing for everybody. The same diet, the same alcohol, the same this, the same that. And it's really a mistake, Russ. And, this is why these groups like the Preventive Task Force, they just treat all humans in the species as the same. Now, I think the polygenic risk score is just one layer of data. We're going to have a lot more. For example, let's say you have that; it's high; and you have an immune system clock, and that's low. Your immune system's down. Say, oh, well, we're even going to up the surveillance to a higher level. Right? And then, there's other things, like if you're really worried, you don't want to find a tumor on a scan MRI because that's billions of cells. You could do a blood test for a multi-cancer, early-detection blood tests, which are getting better and better. You want to find a cancer, if it exists microscopically, not when it's already spread to the bones and whatnot in the body. So, we can do so much better, but we're not doing it.
46:40	Russ Roberts: But I'm thinking about intervention. Once I go through this, if I did, and I found out I have a high risk score and I've got a bad immune system, what's the behavior that's going to come next? Are you going to encourage me to go on--in your case--you don't have to talk about your own personal situation unless you feel like you need my advice--I am a doctor, just not the kind that helps people, as my listeners know--are you going to go on a statin? Are you going to get a preventive stent put in? In the case of cancer are you going to take out the prostate before it becomes cancerous? I mean, that's a very high-risk intervention for an uncertain thing. With breast cancer, it's well known in the Jewish community there's certain genetic variations, and you'll know the name, it's BRCA [breast cancer gene], I think. Eric Topol: BRCA1 and -2. Russ Roberts: You have a very high chance, and many women do interventions to avoid that risk. I don't know if that's a good idea or not. But, I'm just thinking, telling me that I have an elevated risk of something--I need more than that. I need to know what to do that's going to be good for me and it isn't--have these other downsides. Eric Topol: Yeah. Well, I just want to touch on the BRCA2 gene, because in the book I review that. Everyone in Iceland essentially has their BRCA gene--the whole genome sequence. Knowing that is a seven-year life difference. Because in men, people who are BRCA2-positive for mutations, they have a much higher rate of cancer, particularly prostate cancer. And that's another thing. So, if you want to see polygenic risk score, BRCA2 mutations--you know, I wouldn't take the prostate out prophylactically unless there's some horrible symptomatology. Right? But, what you get at is: I want to put this person under, you know, tight surveillance. And by the way, these things about lifestyle we talked about--touched onto sleep and exercise and diet--these things are really important because you can't get everybody to adopt a healthy lifestyle. That doesn't work. But, when you have a specific risk and you sit down with the patient and you say, 'You know what? We are going to go into high gear prevention now. We don't want you to get this--' whether it's cancer. And, 'This is when we're going to really go after the things that we know in lifestyle that will help you.' Now, the chances of somebody doing it is much higher, when it's for them. Russ Roberts: I just had the same thought. And I have to confess that reading your book has improved my dieting over the last three days since I read those sections about belly fat. So, I am making a joke out of it, but it's not funny. It's not a joke. It is funny, but it's not a joke And, I think your point about motivation is not a small thing.
49:36	Russ Roberts: You talk about gene editing. What is the opportunity for gene editing in general, and especially in these cases? As we get better at this, is there an opportunity to do something different than a prophylactic removal of a prostate? Eric Topol: Yeah. So, this is amazing, because genome editing--people think about that as just an approach to rare diseases. And there's thousands of them that are these classic Mendelian gene mutations that you could fix. And, not in the embryo, but in the actual somatic mutation in the body of a person, whether they're young as a baby or older. Now, the reason why this is so much bigger than that, because some of these rare diseases have common threads with the common diseases. And two that I'll just mention quickly and the book also highlighted: If we can completely get rid of the cholesterol production gene related to this PCSK9 [Proprotein Convertase Subtilisin/Kexin type 9]--fancy term--with one shot, or a similar gene, if we could give that to people that would basically markedly reduce throughout their whole life, they wouldn't have to take a statin. They wouldn't have take any drugs because we basically took that specific gene that was causing high cholesterol--we took it out. By the same token, many of us are APOE-4 [Apolipoprotein E] carriers, that carry a significantly higher risk of Alzheimer's disease. So, these are common diseases--heart disease, Alzheimer's. And, we could genome-edit our APOE-4 to make it APOE-2, which is a much more favorable form of that allele. So, that's what's so exciting is, it's not just rare diseases, this genome editing story. And it could even be applied to our gut microbiome to change the bacteria sequences in our gut. All sorts of opportunities there that are out there to develop.
51:52	Russ Roberts: Talk about where we are with AI. When I mentioned my feelings about vitamin D, I've had them for a while, this impression. But, I recently just because I love the tool, went on to ChatGPT's -03 [Generative Pre-trained Transformer 03] new research think longer thing, and asked it about vitamin D supplements. And, it was an incredibly thoughtful response. And, it also, of course, what's amazing about it gives you the sources. So, if you want to click through and see the study to evaluate whether it's a good study that it relied on in making its conclusion. Of course, it does hallucinate sometimes. When it tutors me in Hebrew, by the way, it'll often get the vowels wrong and sometimes get actual conjugations wrong. And, I'll give an answer and it'll say, 'No, that's wrong. That's we run.' And, I'll say, 'Well, no: we run and they run are the same.' And, it'll say, 'Oh, of course. I'm so sorry.' So, it has some funky problems and health is more important than getting the verb 'to run' conjugated correctly. But I'm curious where you think we are on this. Certainly as a tutor of my own health situation, it's somewhat dangerous; but also phenomenal because I can't call you all the time. You're in California. Tough time zone. It's a phenomenal diagnostician, and people--might think are using it like crazy to figure out whether they need to worry or what they should do about things. But, it's also going to do other incredible things, I suspect, in developing therapies and treatments. Where do you think we are, and what do you think is coming? Eric Topol: Yeah. I'm really impressed with -O3 and these deep research tools. They're incredible. I mean, as you say, you get a report and all the citations. When you check them, most of these are real citations. And they're very up-to-date, you know, right? To the last week. It's crazy. So, yeah. The main point about AI--I've been following the AI story, particularly in healthcare now for several years--but I do think what we're talking about today is the next frontier. And when I say that, I mean we have all these layers of data. We haven't even talked about the proteins, which turn out to probably be more important than the genes. These so-called organ clocks from the proteins, these protein markers; and yet the polygenic risk score, the usual stuff in medicine like the labs and the scans and the electronic records and whatnot. You have all these layers of data. You couldn't do anything with it as a doctor unless you had multimodal AI. Because now, what we're talking about is, you're not just saying the person's at high risk for this particular condition, but you're also saying when. So, no longer it's a yes or no. You're giving temporal account: 'Within a couple of years this is when this--if we don't do anything, this is when it's most likely to show up as a beginning of symptoms.' So, we're at this extraordinary time. We never had this ability for prevention. And so, a lot of people keep talking about how AI is going to change healthcare and all these AI drug discovery companies, they haven't yet discovered too much. But, there's lots of them. I'm thinking: No, that's good. Let them go find some new drugs and targets and candidates, whatnot. Let them rev up clinical trials. Good. Good for them. I love it. But, what I'm seeing, Russ, is that we have prevention. If you have prevention, you don't need new therapies. You just need to prevent. Prevention is a lot smarter than treating and trying to cure. [More to come, 55:44]

Time

Podcast Episode Highlights

0:37

Intro. [Recording date: May 28, 2025.]

Russ Roberts: Today is May 28th, 2025, and my guest is doctor and author Eric Topol. This is his fourth appearance on the program. He was last here in June of 2019, talking about Deep Medicine.

Our topic for today is his new book, Superagers: An Evidence-Based Approach to Longevity. Eric, welcome back to EconTalk.

Eric Topol: Thanks so much, Russ. Great to be with you.

1:00

Russ Roberts: This book is quite an extraordinary summary of what we know and do not know about the human body and its health. And after reading it I was struck by two things, I'd like to start with. The extraordinary complexity of so many things we had little knowledge of--I would say 40 or 50 years ago but for some of these topics, I think it's less than that--and how little we understand despite the growth in knowledge. So, we know a lot more. We know about things being connected to other things. But, we are often missing some fundamental understandings of the processes that we want to make better. Is that a fair summary?

Eric Topol: I agree with you totally. Yeah.

Russ Roberts: Talk about that a little bit.

Eric Topol: Well, one of the things that we had a misconception, which I think the data is clear, is how long it takes for these big-three diseases--cancer, cardiovascular, and neurodegenerative--to take hold in our body. Typically, as a cardiologist, we'd see somebody with a heart attack and say, 'Oh, well that must have been festering in the recent weeks or months,' when it's took more than 20 years.

So this is, I think, a misconception we have.

We also have this idea that it's all in our genes. And it isn't. So that--I think it's pretty darn clear that the studies that we've done, and particularly the wellderly study of the near 1400 people that were over age 85 had never been sick on no medications. I mean, they're hard to find, these people, right? But, very little showed up in their whole genome sequence.

So, there's a lot of myths that we have to debunk and things that we don't understand. And, I think as you know Russ, the thing that I emphasize most importantly that we don't understand, is the--because we don't measure it--is how our immune system is either up- or down-regulated as we age. And, that appears of anything to be the most important part of the healthy aging process, this kind of balance between the immune system and inflammation in our body. But, a lot more work needs to be done there.

3:17

Russ Roberts: Yeah. I was struck by that--the importance of our very imperfect understanding of that. Also the rise of--again, correct me if I'm wrong--the importance of the gut microbiome: meaning what's going on in our digestive tract. And, just the complexity of the brain. I mean, some of the findings that you highlight in the book about the brain and what's going on in there, I'm thinking: we just found that out? Isn't that an important organ? Weren't people kind of looking at that? But, we've got a lot to learn.

Eric Topol: It's actually kind of so striking to me how many brain breakthrough findings we've seen in the last year or two. I mean, just extraordinary.

But, I want to touch on the gut story, the gut-brain axis, because as you know, there's all this tremendous interest now in these glucagon-like peptide GLP-1 [Glucagon-Like Peptide-1] family of drugs. And, what's fascinating about that is it's just the beginning of the story because we have a couple of them on the market--Ozempic and Mounjaro, Semaglutide, Tirzepatide.

The problem was that it's just the beginning because there's 10 more gut hormones we haven't even started with, and there's going to be combinations of them.

And they talk to the brain. And they also talk to the immune system.

So, the interconnects between the gut--our microbiome in the gut--as well as these hormones, as well as through the vagus nerve to the brain and the brain stem--it's amazing. So that we're seeing the unexpected with the GLP-1 drugs. Like, not just reducing eating, but actually healthy eating. Changing reward circuits so that people stop at their addictions to cigarettes or alcohol or gambling, even.

There's things that we didn't ever expect because of the circuitry in the brain and how the gut and brain interact.

It's striking because, for example, Ozempic doesn't even really get in the brain, directly. It only gets its message through the gut-to-brain axis.

So, this is one of the most important discoveries. Because we have a drug class now that's wildly outperforming expectations, and we are still learning about not just these gut hormones--the double receptor Tirzepatide--but there's a whole bunch more coming. And so, our ability to knock down inflammation and modulate our immune system is really going to be enhanced.

5:54

Russ Roberts: You mentioned--I'm going to talk about this for a little bit and I was planning to get to it eventually; I'm glad we're talking about it now--Knock down inflammation. That's another thing that sort of runs through the book commonly that, 'Oh, there's this problem with inflammation.' Talk about that. What is that about? What's going on there and why is keeping it down so important?

Eric Topol: Right. So, as we age--I mean, we were talking about these age-related diseases--this process of inflammaging occurs.

There's several reasons for that. One is we develop senescent cells in our body. And you think about senescence, I mean it goes along with aging. But, some of these are good-performing cells. That is, they can help for healing and they can't divide any longer so they're not really a source of potential for cancer.

But, some of these are really bad actors of these senescent cells; and they secrete these very potent pro-inflammatory proteins. So, just like our immune cells that don't function as well as we get older--that's another term, Immunosenescence--that can also secrete these proteins called cytokines and chemokines. So, between these different cellular bad actors, if you will, we're prone to inflammation as we age.

Now, why is that important? Well, it's one thing to get misfolded proteins in your brain, like amyloid and tau. It's another to have brain inflammation to those proteins.

So, that's untoward inflammation.

The same is occurring in our artery wall. If we have some cholesterol build-up plaque, atherosclerosis, but we get into more inflammation into artery wall, that's how we get cracks in the wall and heart attacks.

And then, finally with cancer--this is a real problem. If our immune system isn't got full integrity and really guarding us against an alien cancer cell because of its different proteins on its surface, that's how cancer gets legs. And it can grow and spread, and it would be very hard for cancer to really take over in a body if we had intact immune system throughout our life.

8:17

Russ Roberts: Let's go back to the GLP-1 drugs like Ozempic. I haven't paid much attention to this. I would love to be thinner. The idea of taking a drug for the rest of my life that is brand new is not appealing to me. Seems like a high-risk strategy to get thinner.

But what I didn't realize is--I knew it was developed for something else; and oh my goodness, it's great for weight loss. And of course, that's an enormous source of revenue for the companies that developed these drugs. But, the idea that it could do something other than that, and we've barely scratched the surface--I didn't know that. And shame on me, because it's obviously enormously high potential.

Eric Topol: Yeah. I think, Russ, as you know, I talk through in the book this 20 years that we missed the whole story. I mean, twenty years that we could have been ahead of this. But, it was because the people with diabetes--Type 2 Diabetes--when they took these drugs at the exact same dose, the same drug, they only lost a few pounds. Whereas people with obesity, their loss of weight can be extraordinary: 30, 50, 60 pounds. Right? And, we still don't know why. So, going back to your first point, we still don't know why. Right?

Russ Roberts: That's so weird.

Eric Topol: Now, what's also interesting is not only have we seen the weight-loss-dependent effects on the heart--the so-called preserved ejection fraction heart failure--or on the liver, so-called NASH [Non-Alcoholic Steatohepatitis] or MASH [Metabolic Dysfunction-Associated Steatohepatitis], or on the kidney, but what's really amazing is we see reduction of inflammation before there's even a few pounds of weight loss.

So, it isn't just that we get rid of adipose tissue that can make these--they were like a machine for inflammation, particularly belly fat. But, the drugs themselves have a potent anti-inflammatory effect in the brain and in the body.

So, this is something that we learned a lot more about really in the last year, and it's why it's possible the Alzheimer's trials that are ongoing--and they'll be out early of 2026--if they click, and that's just where the Ozempic, which is a relatively weak single-receptor drug, I mean, that would take it to another complete level. And, we have some data to support that they will work, but we have to see the rigorous placebo-controlled trials to make the call.

10:56

Russ Roberts: I'm learning a new language--trying to--Hebrew. And, it's a hard language because its characters are different.

Eric Topol: It's good for your brain.

Russ Roberts: It's good for my--I'm hoping. I'm not taking the GLP-1, so I got to learn Hebrew instead.

But, what I'm noticing is that it's hard to remember all the words. I'm 70 years old, as I think you are--at least something close to it. Hard to remember all the words. It helps to repeat them. Use them. There's all kinds of different ways. And a word that you think, I'll never remember the distinction between these two words, and you work at it and you work at it; and you get better. But, when you're 70, the pace is slow. And of course, there's some two steps forward, three steps back sometimes.

How do you keep up--not with Hebrew--but with medical jargon? Just the discoveries that are coming out every day in your field. This book, it's not just--you're trained, I think, as a cardiologist. And, correct me if I'm wrong. But, the scope of this book and just in our first 10 minutes of conversation, a number of things that come off your tongue, so much better than my Hebrew. How do you do that? Obviously it's a gift. But, what do you do daily to stay on top of things? What's your workflow?

Eric Topol: Well, I suppose it's like you, Russ, because I know you are an avid reader. I can just see your library right behind you. I read every day. A couple of hours when I wake up. That's my first thing that I do. Even before I'll have breakfast, I'm trying to be the infovore of just eating--ingesting--information.

I've always been that way. It helps me feel like I'm on top of things.

I still don't have enough hours in the day. Oftentimes in the evening I'll get back to reading, too.

So, that's what I try to do, is like a daily dose of ingesting what I think is really interesting information. Not always pure medical. It could be AI [artificial intelligence], it could be something that's indirectly related. But somehow or other it comes together.

Russ Roberts: How do you decide what to read? Where do to get your feed from?

Eric Topol: Yeah. So, I concentrate on top medical journals like Nature, and Science, and the likes of those. So those are a very high priority. And I know each day of the week when they come out with the new stuff; so I'm right there, I'm reading it, and I'm trying to synthesize what's going on.

And then, beyond the articles there, I'll read, of course, newspapers every day, and sometimes there's some really interesting nuggets in there. And books--worthwhile books. So, between them, it isn't like I'm on a vacation or holiday. I'm still reading a lot. I can never get enough of that.

Russ Roberts: Yeah. So, I have something similar. I think of it as a blessing. I'm not sure my wife always agrees. But, she gets both what we call the positive and negative externalities for my reading habit.

Let me make a small personal confession here and get your reaction to it. I have not slept particularly well, I would say, for the last--ehh--four years. COVID [Coronavirus Disease] had a huge effect on the quality of my sleep. My dreaming was different. I think there was some anxiety in there, especially in the beginning when we weren't sure how serious it was. Then I moved to Israel. I'm an immigrant. I have a new job. I'm learning Hebrew. My work life became much different than it had been. And I find myself sleeping, typically, five to six hours a night. I try not to drink too much near bedtime because at the age of 70 I find myself getting up, which is just a physical reality.

But, I've always thought: 'You know, I can power through this.' I have nights where I get up in the morning after four and a half hours of sleep; and, you know, I just keep going. And I've always thought, 'Okay? I'm not a hundred percent.' I'm not as sharp, especially when I'm doing interviews. I don't remember everything I want to remember.

But, your book reminds me that it's more than just your effectiveness. That, bad sleep has long-term health problems. So, talk about why sleep is important and what I ought to know about it.

Eric Topol: Yeah. Well, we've learned a lot about that, again in recent times, and the data are pretty extraordinary, I have to say because I didn't realize how vital this was.

So, there are several aspects of this. So, one is what's called the sleep regularity index, which I reviewed in the book. The data on that's pretty striking. That: we need to be on a clock. I had the problem perhaps you've had where I didn't have this regular bedtime. I tried to get more out of the evening than I should. And, that's not a good idea because what you see is the regularity is important, because it not only influences likelihood of dementia, but also cardiovascular and cancer outcomes. So, that's one thing, is establishing a time and trying to stick to it. I do that now just based on the data, although it might be on a Saturday night, that one deviation or something like that, going out with some friends or whatever.

Now, the second thing is the breakthrough in understanding what happens during the night with respect to these metabolic waste products. Also, what you could say are toxins that we make in our brain. And they are pro-inflammatory, and we want to get rid of them--every night ideally.

So, there's a channel called glymphatics, not lymphatics. And that glymphatics, we've made a lot of discoveries about that in recent times, but that's how we clear these waste products. And, they are particularly cleared in this slow wave of sleep called deep sleep, which is a subset or some part of the non-rapid eye movement sleep section or category of your sleep.

Now, that usually occurs early in the night. It sounds like: Oh, deep sleep, that must be way into the night. No. Most of it usually occurs in the first couple of hours. And, it's not so much how many hours you get--like, if you get six hours--but if you get an hour at our age, 70, if you get an hour of deep sleep, you're golden. That's really what you want to get after.

Now you mentioned alcohol, but there's a lot of things that influence deep sleep; and you can measure it now with a smart watch, with a ring, a mattress sensor. The ring might be the most accurate way, but they all give you an index of your amount of deep sleep.

And, what I learned--you made a really good point--you don't want to have interrupted sleep. Definitely hydrate in the morning and during the day and really restrict fluids in the evening to not have interrupted sleep having a void.

But in addition to that, you have relationships to what you eat, when you eat. You don't want to eat late in the day, in the evening. Also, with what you do for physical activity: the more the better, but not too late again, because that changes your sleep.

So, lots of things influence deep sleep. Six hours may be fine if you have a solid component of deep sleep. And, what's amazing, it took us all this time to understand the glymphatics, deep sleep, the interactions. I mean, like, atrial fibrillation changes the glymphatics' performance so it can have an adverse effect on deep sleep. Who would have guessed that? So, all these interconnects that we just didn't know about.

19:39

Russ Roberts: I want to talk a little bit about something I think is--it fascinates me. I'll do another confession. Listeners, you can hear two old guys talking about--one of them is trying to get free medical advice and the other one's smarter than that guy.

So, I am vitamin D deficient, as I think many Americans are. Comes from working inside at a desk and not getting enough sunlight. And, one of the risks of vitamin D deficiency is bone brittleness and vulnerability to falls and other--many bad things. So, many doctors have suggested to me, I should take vitamin D supplements.

My main reaction to that--and we don't really have to get into my own personal vitamin D issues, but more the generic phenomenon here. My worry with that is always: Well, I'm going to improve my measured vitamin D when the test comes back, because what the supplement is designed to do. It's designed to increase my measured vitamin D, which is not the same thing. And, it strikes me it's better to get a little more sunlight. There's of course a risk of skin cancer. But, I think it's quite small at the levels we're talking about.

And so--and the same thing I'm thinking about with sleep: Is sleep that's artificially induced, say, with a drug--I don't take any drugs to help me sleep. Obviously there's some things I can do that are non-pharmaceutical such as not getting on screens, eating earlier, and so on. But, I'm wondering about this general phenomenon; and I worry that a lot of our medical innovations are designed to improve the marker rather than the underlying condition. Comment on that.

Eric Topol: Well, you really nailed it because so often we just assume that if you fix the blood test result that that changes the outcome. And, we don't have that data for vitamin D. And as you say, a large proportion of the population has got low vitamin D levels, but it's never been proven. And this is a across-the-board thing where you see it in lots of other examples. But this is a perfect example: It's never been proven that you jack up your vitamin D level and then it changes your osteoporosis or other vitamin D calcium-dependent pathways in the body. So, yeah, this is I think important.

Now the other thing, just to go back for a moment on the sleep story, the shocker was that if you take Ambien--and this likely applies to other drugs, but it's been studied in the Ambien--it may make you feel like you slept, but it prevents the elimination of waste products. So, it actually makes things worse. So, you don't want to take those drugs. And so, that's something that, again, we only learned that in recent times.

Russ Roberts: Yeah. My understanding is there have been a number of studies of the vitamin D question and there's no evidence that it reduces osteoporosis. What do you call it? All-blank mortality. All-cause.

Eric Topol: All-cause.

Russ Roberts: All-cause mortality. So, I'm not doing it, and I'm trying to get a little more sun.

22:56

Russ Roberts: Let's talk about the immune system. You write the following, which I think is really quite amazing. [From a pre-print of the book:]

The recognition of the immune system is a common mechanistic underpinning for chronic diseases, whether it be related to why they occur or to the untoward sequelae that they induce is an historic turning point. These diseases--heart, cancer, neurodegenerative--take two or more decades to develop, giving us a long-time window of opportunity to prevent them. Atherosclerosis, which leads to heart attacks and strokes endures despite progress as the number one cause of death and disability globally. It is due to inflammation in blood vessel walls; and all inflammation is generated by our immune system. Cancer isn't usually a killer unless it spreads and our immune system can stop from happening. If there were an inflammation in the brain, it would be difficult for conditions like Alzheimer's or Parkinson's to take hold.

And so, this idea that--and we talked about this already a little bit, but I want you to expand on it--this focus on the immune system, which--this a pretty recent understanding, it seems to me. So, tell if I'm right. So, tell me if I'm right about that and talk about the future for what we might learn about the immune system that would make a big difference.

Eric Topol: Yeah. This is, I think, fascinating. And if there is one thing that comes out of this research that went into the book, it's related to this.

So, going back when we sequenced those 1400 people that were extraordinary wellderly super-agers--

Russ Roberts: These are elderly people who don't have chronic diseases. They're called wellderly.

Eric Topol: Yeah. No chronic disease. As opposed to the illderly, which is the common 60-some year old. Of course they have often multiple chronic diseases.

So, these people, we thought we'd find a eureka effect in their genomes. And we found nothing.

Now, the patient I present right at the beginning of the book, Lee Russal[?sp?]--she is typical. She's 98, and her relatives died--her parents in their 50s and 60s, her brothers in their 50s and 60s. That is what we saw in this wellderly super-age group. It wasn't a heritable pattern and it didn't show up in the genome sequence.

So, now you say: Well, what accounts for these people? Is it just luck? It's some kind of stochastic event? Or is there a biologic explanation? I would submit to you that from everything we know--because the genome sequence doesn't tell us about the immune system--if we want to know what really accounts for why these people just have this amazing health span, we need to study their immune system. And, that has been done.

In fact, one of the best studies, Russ, came out of Israel and to[?] reviewed in the book. But, as we age certain people, they could be in their 90s and their immune system is like they're in their 40s. And, we even have these immune age different clocks for the immune system. We even have an organ clock now for the immune system.

So, if we want to really get these three age-related diseases to prevent--markedly delay--them, we need to be able to measure people's immune system as they get older. You know, once they get past 60, 70. Because we now have a way to up--like a rheostat--increase, decrease, fine tune this. And if we see somebody who is older and their immune system is down, that means they're going to be at risk for either cancer, or, on the other hand, they may have this dysregulation start releasing these inflammatory proteins. Which drive the other two major diseases. So, this is why keeping our immune system young is such a critical thing. And we're just now figuring out how we're going to measure it in people.

What's amazing--I still can't get over this--in the clinic, if you come in and see me in clinic and I want to check your immune system, I have nothing--nothing--to offer. Zero. Okay? Here's what I get: a complete blood count to tell me the ratio of your neutrophil white cells to your lymphocyte. That is a joke. That's all I have, right? If I want to know, I got to study your T cells and your B cells and your autoantibodies. I got to do perturbations.

So, people are working on this now. There's a human immunome project. That could be as important as a human genome project, or more important. Anyway, we will get there, but that is the missing hole in our whole ability to prevent diseases.

Russ Roberts: But I assume at this current level of knowledge--which is embryonic, if I could use probably an appropriate word for this situation--even if we had that good measure, which is simply a descriptive tool which we are just beginning to develop, and we find out that mine is old, or too old for my age, or much older, or not healthy, or it's declining from the last year when we did this a year ago: Do we have any knowledge about how to make it better?

Eric Topol: Yeah. Actually we do.

Russ Roberts: Tell me.

Eric Topol: So, striking. Yeah.

So, the three natural experiments--which are, I would say even better than randomized trials for being an ideal way to look at cause and effect. So, these are hundreds of thousands if not millions of people that just because of their birthday or just because of a healthcare policy thing, half of them got a shingles vaccine to prevent shingles and half of them didn't. And, what's amazing is all three natural experiments showed that in follow-up, the people got 20 to 25% less dementia--less Alzheimer's--from getting a shingles shot.

Now, we never would have guessed that that was going to occur. And, if that was a drug that prevented Alzheimer's, can you imagine?

So, it doesn't seem that there's any real validity that these drugs take on herpes that causes Alzheimer's, but rather they dial up our immune system. And, almost any vaccine can do that, but this is certainly one that is quite a strong immune response. That's why some people when they get shingles vaccines, particularly on the second dose, they can feel like a bad flu illness because it's very immunogenic. It really activates our immune system.

But, in the future, we may not use this just a shingles vaccine. We may have vaccines that are made just to rev up our immune system. And, that's how these cancer-preventive vaccines that are in the works, that's how they are fashioned, is: Just get our immune system amped up in a durable way for people who are vulnerable.

Russ Roberts: Note to self: Get that shingles vaccine I've been putting off.

Eric Topol: Yeah.

Russ Roberts: Okay.

Eric Topol: By the way, I did the same. When I saw the data, I didn't want to get it, but then I said I got to do this. Yeah.

30:23

Russ Roberts: Just as an aside, I took two doses of the COVID vaccine in America. Then I moved to Israel. I got the third dose six months after that. And then, of course, I was encouraged as many people were to take the fourth dose. And beyond. And, my attitude at that point was: the health risk of COVID for me, given it how it had evolved over time and given that I had very few comorbidities, was relatively low. I wasn't worried about getting COVID. I had gotten it in the meanwhile, so I had some natural immunity as well. It was like a flu and it was not frightening at all for me.

And so, I decided I wasn't going to take those extra vaccines. And, somebody accused me of letting my politics overcome my judgment. I said, 'I don't think you know me very well, or how I think about risk.'

But, I did wonder, and I'm curious what your thoughts on this are: that, a new vaccine--and it was a miraculous, as you point out in the book, 8-month, 10-month run. Unimaginable--unimaginable--that that was a drug and a process, the mRNA [messenger Ribonucleic Acid] drug that we didn't know much about. And taking four--which, knowing that it played with my immune system--didn't seem like the best idea to me. Was that a reasonable thought or was I just being silly there?

Eric Topol: Well, no. I think--I mean, you got four shots, and you had COVID.

Russ Roberts: I had three.

Eric Topol: Three, and you had COVID. That's building up a lot of immunity towards the virus. So, you know, that's good.

I think everyone has to make the call--those of us over at age 65--because that's where of course the risk really gets magnified. As to getting the additional shots: I mean, if you have comorbidities and you're over 65, or you have never had COVID--which of course is a minority now--or you're starting to see things really heat up in your region where you live in the world and you want to be able to have some resistance to--protection from--getting infected: I think it's a tough call because the additional shots--fifth, sixth, seventh shots--they're not going to have nearly as important impact as the early shots.

The problem we had with this virus--and it was diagnosed in Israel--is that not only do we get these new variants, but unfortunately we have this waning immunity problem that we just can't keep up with that virus so that a year or two later--let's say in the next year, we get a big wave coming. Once that is starting to take hold, that might be because of the waned immunity to get another booster.

This is a really difficult thing, because right now things have been relatively quiet. There's a couple of variants out there that maybe they'll get legs. Who knows? But, we're not done with this darn virus.

And, the worst thing is, unlike so many other viruses and pathogens, our body doesn't get a sustained immune response. Even when you have a COVID infection--so you get to see the whole virus, not just a spike--we still don't get this durable, strong immune response against the darn virus.

It's really a frustrating, vexing issue. It's why a lot of people got disenchanted with the vaccines, because they thought, 'Oh, it doesn't protect me from infection.' Well, yeah, it's not great for that, especially after a few weeks, but it does in older people help for reducing the toll of hospitalizations and even deaths.

Russ Roberts: Butmy thought on this, of this being a relatively new technology, this vaccine--it reminds me a little bit of the Ozempic thing as well. There's real euphoria about its impact on weight loss. There's huge potential for it to do more than that. But, you have to take it for the rest of your life if you want to keep that weight loss off. And, I'm always uneasy about--we just don't know much about, quote, "the long-term effects."

And, it's an example of where our lack of knowledge of the mechanism that's underlying the efficacy of it is part of the challenge, it seems to me. We don't fully understand some of these things and so to speculate what the long-term consequences are of staying on it just seems a little risky.

Eric Topol: Yeah. The comments I would just make is we do have 20 years of these GLP-1 drugs, and we even have for obesity now six years of follow-up in large trials. So, we have a pretty good handle. It is not 20 years, or 30 years, but we have a--and on the mRNA front, the one thing good about the pandemic, you're right, they were new, this platform, the RNA [Ribonucleic Acid] and nanoparticles. Which, by the way, should have been improved. We should be using better nanoparticles and keeping that mRNA from ever having untoward side effects. But, we haven't. The companies that make these are stuck in the original version. But, we got about a billion people exposed to them.

Russ Roberts: That's true.

Eric Topol: So, wow. And the reason why it's important is that this same platform is great for delivering things to cells that we didn't have. So, whether it's like a gene-editing story or a cancer vaccine, we've seen some great results in intractable pancreatic cancer, renal cell carcinoma, and even autoimmune diseases. So, there's a place for this platform.

And the problem is, of course, because of some of the side-effects of the mRNA vaccines we're seeing in the United States, this anti-mRNA, that would be really unfortunate because overall it's very safe. It should get better. It hasn't. And also, it's being applied well beyond vaccines.

Russ Roberts: When you say companies are stuck with their original versions, is that because of the intellectual property protection that they're relying on and that it's expensive therefore for them to start from scratch, and therefore they just don't have an incentive to innovate? Or is there something else going on?

Eric Topol: No, I think part of it is the intellectual property. Part of it is they have now had mass production of hundreds of millions of vaccines and to go to a new process--the point being, is: we've known that the nanoparticles can be optimized so they even have better penetration. We have these things called self-amplified vaccines where you give much tinier amounts of mRNA. And that's approved in Japan. But there's not even a bit of effort to get that going in the United States. That would help reduce the mRNA side effects.

So, these companies, they did very well during the pandemic and they got things going quickly. That's great; but they're not keeping up with the field. And we're seeing in other parts of the world the innovations that we need.

38:14

Russ Roberts: What's a polygenic risk score? Why is it important?

Eric Topol: Yeah. Well, it's quite important, because when you think about your parents and that one of them had this disease and one of them with this, had--and what we don't acknowledge is that we are not the product of just either parent. We are the admixture of their genomes.

So, the polygenic risk score is, meaning that if you look at the common variants that account for--these are present in 5% or more than a few percent of the population. We each get variants from our mother and father. Now, when you get hundreds of these variants that predict the risk of heart disease, any of the common forms of cancer, Alzheimer's disease, they become useful because they're one layer of data to tell you if your risk is significantly increased. Right?

So, it's not perfect because, you know, sometimes it's wrong. But for the most part, we're getting an idea that I have a high risk for this particular type of cancer, heart disease. It does help a lot to--a lot of people say, 'Should I take a statin?' Like you are going back to the LDL [Low-Density Lipoprotein] as a marker, fixing the LDL. Well, maybe you shouldn't fix the LDL; but if your polygenic risk score is high for heart disease, that's a really good test to tell you you'll benefit from a statin.

So, they tell us about risk. But they're just one layer of data that we want to look at all the layers. We have lots of layers of data now. The problem for us is they don't tell us when. They just tell us Yes or No. So, if you're at high risk on your polygenic risk score for Alzheimer's, well, if that's age 98 or 68, right? So that's a big issue.

Russ Roberts: When you say variants, you mean genetic variants, I assume?

Eric Topol: Yeah. So, of those three billion letters, there's hundreds that are associated with each of these common diseases, conditions.

And so, those are the ones that the polygenic risk score measures. And, you can get a score--a hundred is very high risk--and all the way down to zero. And, you basically--it's only meaningful if you're at high risk. Otherwise, you don't know what to do with it.

Russ Roberts: And, going back to our previous discussion about how my immune system is doing: What are our mechanisms today for generating those scores?

Eric Topol: Yeah. So, there's about 10 companies that do this, I mention in the book. It's very inexpensive. I mean, it can be done for less than $50, even $25 we've done it in academic labs. Because it's out of saliva. And it's an array. It's not a full genome sequence. So, it's just a chip.

And it should be part of the routine medical assessment.

As I mention in the book, there's certain health systems that are doing this on all their patients now, and it's proven to be very useful in partitioning risk.

That's the key: is, we got to find out who are the high-risk people. Because, you're not going to just get it from family history. We just have had this notion that, 'Oh, our family--.' Wrong.

I mean, like, for example, my family history, there's no heart disease. There's everything else. But, when I got my polygenic risk score for heart disease is really high. Right? So, and I'm sure it's accurate, because I have other ways to check it. So, you know, I think this is something that we're learning about. And there's resistance in the medical community to use it even when it's very inexpensive.

41:59

Russ Roberts: So, I think some of my unease when hearing about it is the same unease I have about a full body MRI [Magnetic Resonance Image], which you mention in the book and speak negatively about it--as I do. It's tempting to think, 'Well, better safe than sorry. Let's be cautious. Let's find out what we're at risk for so we can take account of it.'

And of course, the full body MRI--first of all, it's very crude. It doesn't do a very good job as you point out in the book at perceiving things that are quite important It tends to lead to false positives. You look like you have something when in fact you don't. Which leads to interventions. Which leads to bad outcomes: anything from infection to failed interventions that are just further testing and diagnostics.

So, what's the difference between that and the polygenic risk score?

And, the other part of it that I worry about is, of course, anxiety.

So, let's take both you and me. You go and get yours. You find out, 'Oh my gosh, even though my parents had very healthy hearts, it looks like I have a higher probability than otherwise might be the case from my particular genetic situation.' And, I find it for something else. I find some cancer. It turns out I have a high chance of--let's say prostate cancer.

Now, what do I do with that? What do you do with that? I'm going to sleep less well; and that's going to raise my risk of cancer and Alzheimer's. And especially when you're young. Should young people be worrying about this? I mean, one of the themes of the book is this very nice insight that often you have a long time to find out about something developing. And, even something as nasty as cancer, if you catch it early enough, it hasn't metastasized, you're going to be okay. What do I do with that--except worry? And, what do you do with it in your own case?

Eric Topol: Yeah. Do you want me to talk about the polygenic risk score or the MRI or both?

Russ Roberts: No. Forget the MR MRI. It's a bad idea in my view.

Eric Topol: I'm with you. I'm with you.

Russ Roberts: Although we don't dispense medical advice on this show. Consult your own doctor and MRI provider.

But, I'd like you to talk about what do you do practically if you find out you have a genetic variation, very different from what you expected in your own family history, say?

Eric Topol: So, this is actually quite an important point you're raising. And let's use Biden, President Biden--former President--as an example. So, his doctors followed the recent preventive task force that says: Don't even check a PSA [Prostate-Specific Antigen].

Russ Roberts: I think you've said that on this program in the past, and you're not the only guest who said so.

Eric Topol: Yeah. Well, you know what? That's a mistake because this thing about prescribing something for all people is so dumb--okay?--because what he should have had would be a polygenic risk score for cancers and particularly prostate cancer. And if he had a high polygenic risk score, which has been shown now in the recent paper in the New England Journal about this, that partitions risk: that's the person who needs to have very frequent assessment. And maybe not even just a PSA; maybe even more than that.

So, this is the problem. Everything we have for cancer screening is so--

Russ Roberts: Blunt--

Eric Topol: dumbed down. It's like we're all cattle. We're not unique human beings. And, it's, like, the same thing for everybody. The same diet, the same alcohol, the same this, the same that.

And it's really a mistake, Russ. And, this is why these groups like the Preventive Task Force, they just treat all humans in the species as the same.

Now, I think the polygenic risk score is just one layer of data. We're going to have a lot more.

For example, let's say you have that; it's high; and you have an immune system clock, and that's low. Your immune system's down. Say, oh, well, we're even going to up the surveillance to a higher level. Right?

And then, there's other things, like if you're really worried, you don't want to find a tumor on a scan MRI because that's billions of cells. You could do a blood test for a multi-cancer, early-detection blood tests, which are getting better and better. You want to find a cancer, if it exists microscopically, not when it's already spread to the bones and whatnot in the body. So, we can do so much better, but we're not doing it.

46:40

Russ Roberts: But I'm thinking about intervention. Once I go through this, if I did, and I found out I have a high risk score and I've got a bad immune system, what's the behavior that's going to come next? Are you going to encourage me to go on--in your case--you don't have to talk about your own personal situation unless you feel like you need my advice--I am a doctor, just not the kind that helps people, as my listeners know--are you going to go on a statin? Are you going to get a preventive stent put in? In the case of cancer are you going to take out the prostate before it becomes cancerous? I mean, that's a very high-risk intervention for an uncertain thing.

With breast cancer, it's well known in the Jewish community there's certain genetic variations, and you'll know the name, it's BRCA [breast cancer gene], I think.

Eric Topol: BRCA1 and -2.

Russ Roberts: You have a very high chance, and many women do interventions to avoid that risk. I don't know if that's a good idea or not. But, I'm just thinking, telling me that I have an elevated risk of something--I need more than that. I need to know what to do that's going to be good for me and it isn't--have these other downsides.

Eric Topol: Yeah. Well, I just want to touch on the BRCA2 gene, because in the book I review that. Everyone in Iceland essentially has their BRCA gene--the whole genome sequence. Knowing that is a seven-year life difference. Because in men, people who are BRCA2-positive for mutations, they have a much higher rate of cancer, particularly prostate cancer. And that's another thing. So, if you want to see polygenic risk score, BRCA2 mutations--you know, I wouldn't take the prostate out prophylactically unless there's some horrible symptomatology. Right? But, what you get at is: I want to put this person under, you know, tight surveillance.

And by the way, these things about lifestyle we talked about--touched onto sleep and exercise and diet--these things are really important because you can't get everybody to adopt a healthy lifestyle. That doesn't work. But, when you have a specific risk and you sit down with the patient and you say, 'You know what? We are going to go into high gear prevention now. We don't want you to get this--' whether it's cancer. And, 'This is when we're going to really go after the things that we know in lifestyle that will help you.' Now, the chances of somebody doing it is much higher, when it's for them.

Russ Roberts: I just had the same thought. And I have to confess that reading your book has improved my dieting over the last three days since I read those sections about belly fat. So, I am making a joke out of it, but it's not funny. It's not a joke. It is funny, but it's not a joke And, I think your point about motivation is not a small thing.

49:36

Russ Roberts: You talk about gene editing. What is the opportunity for gene editing in general, and especially in these cases? As we get better at this, is there an opportunity to do something different than a prophylactic removal of a prostate?

Eric Topol: Yeah. So, this is amazing, because genome editing--people think about that as just an approach to rare diseases. And there's thousands of them that are these classic Mendelian gene mutations that you could fix. And, not in the embryo, but in the actual somatic mutation in the body of a person, whether they're young as a baby or older.

Now, the reason why this is so much bigger than that, because some of these rare diseases have common threads with the common diseases. And two that I'll just mention quickly and the book also highlighted: If we can completely get rid of the cholesterol production gene related to this PCSK9 [Proprotein Convertase Subtilisin/Kexin type 9]--fancy term--with one shot, or a similar gene, if we could give that to people that would basically markedly reduce throughout their whole life, they wouldn't have to take a statin. They wouldn't have take any drugs because we basically took that specific gene that was causing high cholesterol--we took it out.

By the same token, many of us are APOE-4 [Apolipoprotein E] carriers, that carry a significantly higher risk of Alzheimer's disease. So, these are common diseases--heart disease, Alzheimer's. And, we could genome-edit our APOE-4 to make it APOE-2, which is a much more favorable form of that allele.

So, that's what's so exciting is, it's not just rare diseases, this genome editing story. And it could even be applied to our gut microbiome to change the bacteria sequences in our gut. All sorts of opportunities there that are out there to develop.

51:52

Russ Roberts: Talk about where we are with AI. When I mentioned my feelings about vitamin D, I've had them for a while, this impression. But, I recently just because I love the tool, went on to ChatGPT's -03 [Generative Pre-trained Transformer 03] new research think longer thing, and asked it about vitamin D supplements. And, it was an incredibly thoughtful response. And, it also, of course, what's amazing about it gives you the sources. So, if you want to click through and see the study to evaluate whether it's a good study that it relied on in making its conclusion.

Of course, it does hallucinate sometimes. When it tutors me in Hebrew, by the way, it'll often get the vowels wrong and sometimes get actual conjugations wrong. And, I'll give an answer and it'll say, 'No, that's wrong. That's we run.' And, I'll say, 'Well, no: we run and they run are the same.' And, it'll say, 'Oh, of course. I'm so sorry.' So, it has some funky problems and health is more important than getting the verb 'to run' conjugated correctly.

But I'm curious where you think we are on this. Certainly as a tutor of my own health situation, it's somewhat dangerous; but also phenomenal because I can't call you all the time. You're in California. Tough time zone.

It's a phenomenal diagnostician, and people--might think are using it like crazy to figure out whether they need to worry or what they should do about things. But, it's also going to do other incredible things, I suspect, in developing therapies and treatments. Where do you think we are, and what do you think is coming?

Eric Topol: Yeah. I'm really impressed with -O3 and these deep research tools. They're incredible. I mean, as you say, you get a report and all the citations. When you check them, most of these are real citations. And they're very up-to-date, you know, right? To the last week. It's crazy. So, yeah.

The main point about AI--I've been following the AI story, particularly in healthcare now for several years--but I do think what we're talking about today is the next frontier. And when I say that, I mean we have all these layers of data. We haven't even talked about the proteins, which turn out to probably be more important than the genes. These so-called organ clocks from the proteins, these protein markers; and yet the polygenic risk score, the usual stuff in medicine like the labs and the scans and the electronic records and whatnot. You have all these layers of data. You couldn't do anything with it as a doctor unless you had multimodal AI. Because now, what we're talking about is, you're not just saying the person's at high risk for this particular condition, but you're also saying when. So, no longer it's a yes or no. You're giving temporal account: 'Within a couple of years this is when this--if we don't do anything, this is when it's most likely to show up as a beginning of symptoms.'

So, we're at this extraordinary time. We never had this ability for prevention.

And so, a lot of people keep talking about how AI is going to change healthcare and all these AI drug discovery companies, they haven't yet discovered too much. But, there's lots of them. I'm thinking: No, that's good. Let them go find some new drugs and targets and candidates, whatnot. Let them rev up clinical trials. Good. Good for them. I love it.

But, what I'm seeing, Russ, is that we have prevention.

If you have prevention, you don't need new therapies. You just need to prevent. Prevention is a lot smarter than treating and trying to cure. [More to come, 55:44]

How to Be a Super Ager (with Eric Topol)

Peter Attia on Lifespan, Healthspan, and Outlive

Kieran Setiya on Midlife

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How to Be a Super Ager (with Eric Topol)

Peter Attia on Lifespan, Healthspan, and Outlive

Kieran Setiya on Midlife

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