What Super Agers Reveal About Preventing Disease

0:01American healthcare isn't crisis. We have a path to preventing disease. It isn't reversing aging. It's just preventing the age -related morbidities of the big three. If we can keep people healthier, healthier people would be much less expensive. Seven years more of health spend, three of the major three diseases. Seven years? Who wouldn't take seven years? There's just billions of data points for each person. There should be a reboot, new standard of care based on intelligent partitioning of risk. We have to do better. The human obsession with living longer is as old as time. But in the last 20 years, we have learned so much more about human health and biology.

0:49So what do we know today? But what makes humans live longer? And do we have real evidence that longevity is an attackable target? Today, you'll get to hear A16Z General Partner Vijay Ponday in conversation with Eric Topol, who recently released his new book, Super Agers, an evidence -based approach to longevity. Eric is among other things the founder and director of the Scripps Research Translational Institute. He's also published over 1200 peer -reviewed articles with more than 300 ,000 citations, making him one of the 10 most cited researchers in medicine. That resume puts Eric in a perfect position to write this book, teasing the signal out from all the noise around health in 2025.

1:30One of those inputs was the welderly group that Eric studied, which was a study of 1400 people, 80 plus, who had never developed a chronic illness. For comparison, according to Eric's book, among those 65 plus, 80 percent have two or more chronic diseases, and 23 % have three or more, while about 7 % have five or more. And again, that was the 65 -plus group versus the welderly group of 80 -plus. So what do we know about these quote, super -aggers? People who not only have a longer lifespan, but a longer health span. It's a genetic, or human agency, and do technologies like AI, GLP1s, gene therapies, or the ability to understand organ clocks, meaningfully change that equation for the masses?

2:14If so, what difficult decisions do we have to make to rewrite this system today? Let's find out.

2:23As a reminder, the content here is for informational purposes only. Should not be taken as legal business, tax, or investment advice, or be used to evaluate any investment or security, and is not directed at any investors or potential investors in any A16Z fund. Please note that A16Z and its affiliates may also maintain investments in the company's discussed in this podcast. For more details, including a link to our investments, please see a16z .com forward slash disclosures.

2:54My joy to welcome Dr. Eric Topol to the podcast Eric. Thanks so much for joining us. I'm glad to be here, Rea. So you've written this really exciting book, Super Agers and Evidence -based Path to Long Jeviti. And I think it's a very timely topic and I was curious for you to maybe set the stage for why you wanted to write it and how you see it in the context of other books that have been coming out recently as well. Yeah, there were a few things that came together. We had done a big study we called the Welderly where we basically found very little in the genomes of people who had gone to the age of 87 on average with never having had an age -related disease.

3:35So that was of course one thing that was part of it. The second was I got inspired by a patient I saw recently, who was 98 and had never been sick. So, never been sick? Yeah, her name was Lee Rissol and her relatives had died in their 50s and 60s. That's her parents, her uncles and aunts. She was the outlier and said, why? And then there were the books they came out. I had patients coming to me and they wanted me to write a prescription for Apple Mison or order a total body MRI. I said, we got to get the story straight. So these three things together were the impetus that why don't I really get deep into this everything we know today and then see if I could lay out some blueprint for where we can go.

4:21It's coming into a world where American healthcare is in crisis. Now I was curious to get your take on where we are now in healthcare in the US and where do you think we can get to? Yeah, so there is this bifurcation as I see it. You could call it like the grand slam where you get Reversing of aging so you keep people healthier bodywide and that's where we see all this remarkable investments in companies like Outtos and reprogramming Synolytics and a long list But they're really focused on a monumental task which hasn't been shown in people But rather in rodents and some of the results are striking and I hope at least one if not all these are successful The other side of this is we've made these big strides in the science of aging with all these layers of data that are using the metrics of aging.

5:13And why don't we use that to prevent the age -related diseases, cancer, cardiovascular, neurodegenerative? We've never done that in medicine to any appreciable extent. And this is the opportunity because we have a path to preventing disease. it isn't reversing aging, it's just preventing the age -related morbidities of the big three. I think there's something that a lot of people may not realize is that the big three that you mentioned cancer, heart disease, and Alzheimer's and dementia, that they're greatly exacerbated by age. And it's interesting because if you ever wanted to have something that could be a cure for multiple diseases, which would be the one of Holy Grails of Medicine, it would be understanding the biology we are we now in terms of things that we can use today.

6:01The first and perhaps the most extraordinary thing is it takes 20 years to get these diseases with rare exception. You know, heart disease, almost all cancers, and neurogeneral, they are incubating for a very long time. They all have a common thread of a defective immune system and inflammation underpinning. underpinning. They are preventable, invariably. So a cardiovascular 80 and 90 percent from lifestyle and related factors, modifiable factors like your LDL cholesterol, that kind of thing. And cancer and neurodegenerative, just from what we know today with lifestyle factors, we're about half that can be prevented.

6:46So we have some knowledge about averting these diseases. But we have a lot more with all these clocks and new layers of data that are really changing the face of all outgross of understanding the biology of aging. So maybe let's double click on that. So you in your book outlined the five dimensions of health. I was wondering maybe you could walk us through them. Yeah sure. So the first most important one is AI because you need that to pull this other data we're going to talk about together. This moment that is so exciting is because we have multimodal AI, not only large language, but large reasoning models.

7:27Now, especially I think when you're talking about AI, it's all the things people have seen with generative AI and so on, but also just the ability to understand all this data that you're measuring from people. Yeah, because the other four are such big domains or dimensions. So the omics, it includes not just gene sequence or arrays, but it has all the proteins, all the proteomic panels that we can get, which we never could get before, inexpensively. It includes the gut microbiome, metabolism, and certainly epigenome or epigenetics. So the omics are rich. We are now seeing moving in towards things like the virtual cell.

8:07Then there is, of course, cells that have become a live drug where we can reset the immune system and cure autoimmune diseases like we've never done before. Could you give examples of that? Yeah, so in the last couple of years we've seen unprecedented cures, I mean, never had anything lupus progressive systemic sclerosis, even cases of multiple sclerosis, Dermatomyocytus. So basically it's a depletion of all the B cells and when they come back, they have forgotten what they were attacking. It's amazing. Yes, it's a really amazing. It leads to the autoimmune reaction. But the bigger lesson is we have learned how to control our immune system, like a Rheostat, and we're going to keep getting better and better as we measure our immune zone.

8:56But when you can do that, when you can quash an autoimmune disease, or when you're trying to cure a cancer, by just whatever it takes to keep bringing up that immune system specific to the tumor. So the immune system is fundamental and that also now is involving cells and vaccines. So vaccines now are capable of cures of pancreatic cancer, kidney cancer with these personalized vaccines using the proteins of the person's tumor. And these are in clinical trials right now. Yeah, I mean, stuff like we've ever seen. And that's just a front runner of what vaccines, that's to treat cancer. We're going to be using vaccines to prevent cancer.

9:41Again, as we get older, some of us, especially, our immune system is getting senescent and weak and a vaccine before there's any cancer, before there's anything else could prop it up. We also have drugs to modulate our immune system well beyond checkpoint inhibitors. And so whether it's antibody drug conjugates, tumor infiltrating lymphocytes, and all these different ways. It's hard to imagine that in the future we're going to lose people with cancer because of being able to bring your immune systems to the highest level when we need it. But more importantly, preventing the cancer. We can do that now.

10:19That's what's exciting. Well, and so if we put all this together, what does this mean for the individual? Like, how would their life change? What should people be doing? Yeah, so I call it lifestyle plus. It's a lot bigger than diet, sleep, and exercise. It's involving, you know, all the environmental burdens, air pollution, the plastics, microplastics, nanoplastics, and forever chemicals. And then there's other things like time and nature. So if each of us pulled out all the stops for the lifestyle factors, which is a long list, that will help. But it's not going to be only lifestyle factors that are the ways to prevent the big three age -related diseases.

11:02You know, you described a large range of things. From the sort of most almost sci -fi like drugs that are in trials for preventing cancer to lifestyle. When people think about lifestyle, it's maybe a little vague in their mind for what to do. How do you make that into a science or how do you help people take that to the next steps of bringing evidence into that? I go into perhaps great pains, high density to cite all the studies that link, like for example, when you have really good sleep health and deep sleep, what does that do to slow your brain aging? Or, you know, if you drink sugar, sweet, and beverages, what does that do to specific, not just risk of type 2 diabetes, but, you know, all cause mortality?

11:45So there are very compelling sets of data about lifestyles and these key outcomes and the link to healthy aging. I was amazed how much data is out there that can help us. It's not just like in the year when we had polygene at risk scores. I mean, you say, oh, you're risk for Alzheimer's. But we don't know when you're age 56 or 96. So what good is that? Yes. Now we're saying, we know it's within a couple of years between 77 and 79 that you're going to have myelotogin of impairment, if we don't do these things, which includes the lifestyle factors. And it's much harder to get people to do all those stuff.

12:25They have no specificity that's about them, that they can change the arc of a condition, especially when it isn't our genes. The healthy aging story about a genetic underpinning is just not there. We studied that. It's minimal. I mean, maybe it's 10 % of what accounts for LB aging. Most of it is in the lifestyle factors and related matters, such as the immune system, not functioning properly too much too little. Well, I was generally believed that just telling someone to eat better and exercise doesn't work. But what I'm hearing you say is that you have a way to do that by making it very personalized.

13:04Yes, I mean, there was a finished study that was on just polygons at risk or which is rudimentary and they gave that to a large cohort and they studied whether that affected their lifestyle and the results were remarkable the people who got the data stopped smoking change their diet change their physical activity really amped it up so we know when people get data that specific to them a large proportion, much more likely to make changes. Now, I'm not claiming that lifestyle is gonna be the only part of the prevention story, but once you define the high risk and it's particularized to a person, that's a big part of how we're gonna succeed.

13:47I could also imagine AI coming into this, because one of the things AI is very good at is to take a set of data and maybe you can mask out the last bit so you can maybe have someone's health records over 30 years and train on that except for the last five years and see if you can predict the last five from the first 25. And once it gets really good at that, you can take my records and say, hey, look, VJ, you don't do anything. This is where you're going to be. And we have 99 % confidence on this. That would be pretty chilling. Yeah. Well, you're exactly right because the pin pointing here about the timing is so extraordinary.

14:22For example, with Alzheimer's, since we were talking about that. You get a P -Towel 217. It's modifiable by lifestyle. You check it again in six months or a year. Now you have two data points and you can say with all the other data that's available, when you're going to see 18 years from now, 12 years for you, mild cognitive impairment, unless these steps are taken. This was fully dependent on AI. I models that can just take all this data. If we didn't have the science of aging and the AI, we'd be nowhere. We wouldn't be talking about this today. I wouldn't have written a book. Yeah. Well, it's important for people out familiar with the term of health span that's basically not just lifespan, but how long you can be healthy.

15:07Yeah. I don't think we really want to get to some age and be demented or compromised. What we're talking about is if you don't have heart disease, cancer, or neurodegenerative, you're pretty darn intact. You may have some achy joints. matters, but those are the things that really interrupt our health span. Now we're talking about healthcare meaning something different. It's a be preventative and we'll talk about chronic in a second. How do we help make that mind shift? This is perhaps the biggest point so far that we've been discussing because in medicine and I've been in it for almost 40 years, we don't do primary prevention.

15:46The person has a heart attack and then we get all over it. But for the The most part, we don't prevent cancer, we don't prevent Alzheimer's and new diseases. It's been a desire, I would say, a fantasy for millennia. But we are at a very different point right now. We have a path to prevention, primary prevention, not after somebody has one of these diseases. And that is what is extraordinary. And it was all these recent advances that led to this capability. And we've got to jump on it because it's exciting that we could actually do this. Well, also the thing about prevention is that I've talked to doctors who very boldly assert that prevention doesn't work.

16:30Yeah. And I look at them a bit confused because I say, well, there's been numerous examples and they're like, well, name one. I was like, well, how about smoking? That's the first time. We have this huge incidence of lung cancer, which has just disappeared now because we don't smoke in restaurants or airplanes and so on. But one of the things that I think about about that movement is that while doctors played a significant role in that, that was also very much a cultural movement. And so we talked about lifestyle changing people's behaviors. I think some of this or much of this has to be as much cultural as medical.

17:02There's a definite cultural component in tobacco is one of the most impressive, but there's so many others. Yes. I think what we've learned, like for example, with sleep, I didn't pay enough attention to that. But with sleep, when you promote your own deep sleep, which we tend to lose a lot as we age, then you see much less dementia, Alzheimer's, even less cardiovascular and cancer related illnesses, cases and mortality, sleep regularity. We need to be more ritualistic about it. And there are many things just on sleep itself, no less about physical activity, about, for example, not just even resistance training, but balance, posture, things like that.

17:47So, the more you go deep, nutrition especially, we've learned a lot about that, convincing, compelling evidence, I would say, that you say, these effects, we're talking about just with that, seven years more of health span, free of the major three diseases. Seven years? Who wouldn't take seven years? That's just what we know today. Once we can define high risk, which is one of the things we turn to with AI, that changes everything because then you focus on that. Maybe let's turn to another aspect of it, which is the chronic disease aspect. When we're talking about chronic disease, we're talking to people about diabetes, heart disease, cancer.

18:26How do we start to make an impact on that? I don't know if you want to pick one, if you want to start with cancer. I think we can make a huge impact in cancer because we have just simple polygene riskers for all the common cancers. that's like one layer of data to say you're at higher risk. And we have multi -cancer early detection tests that can pick up microscopic cancer. Why people would get a total body MRI when you could find microscopic cancer, not a mass on a MRI, which may or not be cancer? So we have some tools for cancer, but the one thing that I think is unanticipated is the Glipp -1 drugs.

19:04The ozimpic, Zeppbound world. It's the most momentous drug class in medical history. And we've only seen part of the story so far. In the book, I write about how it took 20 years to figure out that it wasn't just about diabetes, which is amazing. What if we had AI today and said, should we test this for obesity? Because the developers, no one orders and later Lily of these drugs, they only saw three or four pounds that people would type to diabetes, would lose with these drugs. And this woman in Norway, scientist, Latta Newton, she kept pushing, we got to try it in obesity. And they wouldn't listen to her because, well, she said, Diabetics are not losing weight.

19:50They finally did it. And everyone knows a story, 20, 30, 50, 80 pounds of weight loss. Now, when you lose that much weight for people who are obese, you reduce the risk of cancer. you reduce the risk of heart disease and neurodegenerative disease. It wouldn't be surprising to me that now with pills that are remarkably effective to substitute for injections that can be much less expensively, that a large proportion of the population would be taking one of these drugs or even their successors, that is those that are even more potent and potentially with less side effects. So we have a drug class now, added to lifestyle factors we didn't have before.

20:34As you know, they are in big trials for preventing Alzheimer's in people who are not overweight. Yes. Okay. We're going to be doing a long COVID trial in people who are not overweight. The effects are really quite extraordinary. The ability to crack obesity. Yes. We would have been happy just to do that. But all the other things that are coming from it, who would have thought that you could treat preventive? addiction. That's remarkable. The ability to reduce alcohol intake from heavy intake, gambling, I mean, the list just goes on because we're learning about the brain circuitry on how these drugs.

21:13So some of the secrets of the gut brain axis, which is tied into the immune system and it's tied into the science of aging. This is what's given us this newfound potential to change. we don't have to only rely on drugs, but there's as we discuss this kind of interdependence. Well, and I think having lifestyle infrastructure with these drugs, that combination's particularly interesting, because you can make sure that you can lose weight while keeping muscle, and also, hopefully, patients can go off the drugs, at least for some periods of time, and not rebound. We don't have encouraging data at the moment, because at least half of people gain weight back when they stop, and that's not good.

21:54but I do think that will come up with the ways to hopefully not rely on such a long -term commitment. The results on muscle mass, we've been very worried about that, and I think when people combine taking the drugs with strength training, and we do know there's muscle mass loss just with weight alone, but that looks encouraging, even though the companies have been acquiring muscle -making drugs, that may not prove to be particularly necessary. Well, and I think one thing that's interesting is that another knock on lifestyle is if you're extremely obese, telling someone to exercise, it's a hard road to just get started.

22:33Absolutely. And so this could jump start a better lifestyle that could get locked in. That could be really more. I've seen it in many patients, just what you said. Couldn't get them to really increase their activity, but when they were thinner, everything changed. When you think about if we can make a huge dent, there's nothing more economically favorable for us at the public population health level if we can achieve this. And so what else would you put into the chronic bucket? I think one of the things that you've written about is AI plus all the things you can track. I think the ability to look at the organ clocks, which was initially reported here at Stanford by Tony and Whist Korean as colleagues, and now validated and replicated by multiple groups.

23:21The fact that we can do that and have the brain, the heart, the immune system, and other vital organs, and we can say this one organ of yours is five years out of pace with your real age. Then we can integrate that with these other layers of data. Oh, if that's the case, What about your polygenic risk or is there anything pointing to that disease or organ? We can look at your whole body aging, epigenetic, whoreveth clock. We can also look at specific proteins like, for example, for the brain, P2 -17. And what's amazing about that protein, which we can get now, and it's not that expensive, But that in itself gives us over a 20 year warning about myotogative impairment.

24:10It's modifiable by exercise and lifestyle. We've seen people in studies that drop more than 50 % even up to 80%. And it's intriguing that it's not binary too, so you could track the gradient. Exactly. And that would get particularly scary if it's increasing. So we're talking about in people without symptoms, but are at high risk having this I don't recommend any of these things that we're talking about until you know you have an increased risk. But once you do, then you can say, hmm, I can do something about it and change the course of what otherwise would be that person's natural history. But the molecular clocks, this collection of proteins, this is something else that's striking.

24:53The O -link and Somalogic, there, between six and 11 ,000 plasma proteins. What we've learned from them, the fact that there's three bursts of aging during our life is not just a linear story and the fact that we're learning about the underpinnings of diseases, but most importantly, we have these organ clocks that are inexpensive to get. The UK biobank is only paying $50 per participant. And they've done 50 ,000 and didn't have amazing data coming from it, but another 500 ,000 is in process. So it's not that expensive to get such rich data. And when you start having genes and proteins in these other layers of data, that's when you find out what is making us unique and what we are at risk for during our extended time.

25:43And therefore what we should do to change it and improve. Yeah. Well, let's take a step back because I think you've been laying out a very appealing picture for what we as individuals could do to improve our health span, and get at least seven more years easy, maybe more and more and more as the science improves. But you can also think about this from a societal level that the cost of healthcare is immense. Yes. Just the cost of healthcare to the US government through Medicare and Medicaid is approaching $2 trillion. And we live in a time where the United States is an asset debt. There's a great desire to reduce the deficit or make the deficit negative would be ideal.

26:19And you look at healthcare and people are scared that healthcare could be cut or something like that. And I think no one wants to remove services. But there is this alternative that is very natural from everything you're talking about, which is that if we can keep people healthier, healthier people would be much less expensive. Right. And we could have a win -win. How do we shift the system, whether we're talking about CMS, or we're talking about insurers, or providers, how do we shift the sick care system to be thinking about preventative and chronic? We have a barrier here because although Malin Senos people could change their insurance companies at any time so the insurance company doesn't have a long view whereas other countries like when I did the review of the NHS for the government there they're well positioned in the UK and in many countries except for the US have a better positioning for this.

27:13If we could make prevention now that it is emerging as a reality The priority and say every insurer, whether it's Medicare, Medicaid, private insurers, if they don't pull out all the stops and make this a priority, then we have to make some pretty drastic policy changes. We've not actually accepted yet that we have this newfound capability, which completely changes the economics beyond making a case for health span for a population possible and as the people who need this the most are currently the least likely to get it to access and so this is another issue which if this only is for the affluent, if we don't take care of everyone, we're not going to achieve that goal.