#412 ‒ The evolving science of cancer: emerging approaches to prevention and early detection, and the advances reshaping treatment | Siddhartha Mukherjee, M.D., Ph.D.

View the Show Notes Page for This Episode https://peterattiamd.com/sidmukherjee3/?utm_source=podcast-feed&utm_medium=referral&utm_campaign=261019-pod-sidmukherjee3&utm_content=261019-pod-sidmukherjee3-podfeed Become a Member to Receive Exclusive Content https://peterattiamd.com/subscribe/?utm_source=podcast-feed&sidmukherjee3%20=referral&utm_campaign=261019-pod-sidmukherjee3&utm_content=261019-pod-sidmukherjee3-podfeed Sign Up to Receive Peter's Weekly Newsletter https://peterattiamd.com/newsletter/?utm_source=podcast-feed&utm_medium=referral&utm_campaign=261019-pod-sidmukherjee3&utm_content=261019-pod-sidmukherjee3-podfeed In this episode, Peter welcomes back Dr. Siddhartha Mukherjee, a physician, oncologist, researcher, and the Pulitzer Prize-winning author of The Emperor of All Maladies. Fifteen years after the book was first published, Sid released an updated edition. This conversation examines what has changed in our understanding of cancer—not only in how we treat it, but in how we think about its causes, prevention, detection, and biology. Sid explores the contributions of genetics, environmental exposures, random mutations, and inflammation to cancer risk, including the emerging role of hyperinsulinemia and metabolism. He discusses why detecting cancer early remains so difficult, particularly in pancreatic cancer, and how advances in immunotherapy, CAR T cell therapy, and targeted treatments such as KRAS inhibitors are changing the treatment landscape. The conversation then broadens beyond cancer to what Sid calls "regenerative failure"—the declining ability of tissues to repair and replenish themselves with age. Peter and Sid explore how this process may contribute to conditions such as osteoarthritis, and whether longevity should be approached less as the prevention of individual diseases and more as the preservation of regenerative capacity. Sid weighs in on the potential for chemoprevention, metabolic interventions, and AI to transform cancer prevention and treatment. Finally, they discuss what it would take to develop meaningful biomarkers of longevity that could ultimately help to extend human healthspan and lifespan. We discuss: What oncology has learned in the 15 years since The Emperor of All Maladies was published [2:45]; The contributions of genetic risk, bad luck, and inflammation to cancer [14:45]; The role of metabolism and hyperinsulinemia in cancer [31:00]; Osteoarthritis: the role of inflammation and regenerative stem cells [40:45]; How cancer escapes the immune system—the subtleties of neoantigens and immune checkpoints [49:45]; AI and the thymus as a predictor of longevity, and T cell aging and immune regeneration [57:15]; How CAR T cell therapy works and why solid tumors are harder to treat [1:04:00]; Targeting KRAS in pancreatic cancer [1:10:45]; The rise of colorectal cancer in younger adults [1:19:15]; How AI may transform drug discovery [1:23:00]; The future of cancer prevention: chemoprevention [1:33:15]; Challenging the current model of longevity—disease prevention versus targeting regenerative failure [1:37:45]; The need for a biomarker of longevity—comparing geroscience to atherosclerosis [1:50:30]; Clinical trials targeting cancer metabolism [1:56:00]; What Sid is currently writing about and a glimpse into his writing process [1:58:00]; and More. Connect With Peter on Twitter https://twitter.com/PeterAttiaMD, Instagram https://www.instagram.com/peterattiamd/, Facebook https://www.facebook.com/peterattiamd/ and YouTube https://www.youtube.com/channel/UC8kGsMa0LygSX9nkBcBH1Sg

Speaker names marked ? are inferred from speaking time and the show’s known hosts — they are not voice-verified.

• 0:11Dr. Peter Attia?

  Hey, everyone. Welcome to the Drive Podcast. I'm your host, Peter Attia. This podcast, my website, and my weekly newsletter all focus on the goal of translating the science of longevity into something accessible for everyone. Our goal is to provide the best content in health and wellness, and we've established a great team of analysts to make this happen. It is extremely important to me to provide all of this content without relying on paid ads. To do this, our work is made entirely possible by our members, and in return, we offer exclusive, member-only content and benefits above and beyond what is available for free. If you want to take your knowledge of this space to the next level, it's our goal to ensure members get back much more than the price of a subscription.

• 0:54Dr. Peter Attia?

  If you want to learn more about the benefits of our premium membership, head over to peterattia MD dot com forward slash subscribe.

• 1:04Dr. Peter Attia?

  My guest this week is Dr. Siddhartha Mukherjee, a returning guest to the Drive. Sid is a physician, oncologist, researcher, and a Pulitzer Prize-winning author of The Emperor of All Maladies, as well as other books, The Gene and The Song of the Cell. I wanted to have Sid back on because frankly, there are few people who can move as easily between the molecular details of a disease and the much bigger questions of why we age and what we might be able to do about it. We begin our conversation with cancer, as this is the 15-year anniversary it's hard to believe, of his remarkable book, An Emperor of All Maladies. We talk about where it comes from, how much it is driven by genetics versus chance, the challenges

• 1:48Dr. Peter Attia?

  of detecting it early, and how treatment has advanced, before broadening our discussion to what Sid calls regenerative failure, the declining ability of our tissues to repair and replenish themselves as we age. Throughout this episode, we discuss how genetics, environment, and random mutations contribute to cancer risk. We talk about the challenges of cancer screening and early detection across all cancers, but especially pancreatic cancer, why aging isn't simply the accumulation of diseases, but also the loss of our ability to regenerate, how declining stem cell function may contribute to osteoarthritis and other age-related conditions, the relationship between inflammation, the immune system, and regenerative failure, what it would take to meaningfully extend human health span

• 2:32Dr. Peter Attia?

  and lifespan, and how AI may help us better understand and potentially address the biology of aging and cancer. So, without further delay, please enjoy my conversation with Dr. Sid Mukherjee.

• 2:49Dr. Peter Attia?

  Sid, awesome to see you, as always. And it's hard to believe it's been 15 years since Emperor of All Maladies. I remember reading it as soon as it came out, and that, I think, makes me feel a little old, that 15 years has gone by so quickly. If we take a step back, what would you say is true today in the field of oncology that was not true? Or maybe phrased another way, what do we know today about cancer that we did not know when you published this remarkable book?

• 3:23Speaker 01

  Well, Peter, first of all, thank you for having me. It's been a pleasure throughout. We've spoken in the middle and learned more about cancer in the middle. Let me divide it very simply into three large sections, and ask the question, what do we know more about early diagnosis, or prevention, early detection, and treatment? So, three broad categories. So, prevention. What do you know about prevention? Well, good news and bad news. The good news is that we know a lot more about how cancer can arise, not just

• 4:07Speaker 01

  out of being exposed to the traditional carcinogens, the cancer-causing agents that you and I know very much about, you know, x-rays and benzene and, you know-

• 4:19Dr. Peter Attia?

  Tobacco and-

• 4:20Speaker 01

  Tobacco, et cetera. So, we now know that there is almost certainly inflammatory states that cause cancer. We know a lot about the nature of these inflammatory states. We know that it's not that there is a kind of a gun and trigger effect, the gun being the inflammatory state, the trigger being the mutations that cause cancer, or a mix of some states like that. The bad news is that we are still early in that story. In other words, I can't look at a person, a patient, my own patient, and say to them, "Oh, my goodness, I know that

• 5:02Speaker 01

  you're in an inflammatory state. You have that inflammatory state, which is going to be procarcinogenic." I don't have a biomarker, in the same sense that I have a biomarker for, let's say, cardiovascular disease, being hypertension or high cholesterol levels. I don't have a high cholesterol for cancer. Almost certainly, we will find it. We will find that high cholesterol for cancer, and we will find people who are at risk and put them in clinical trials to follow them and figure out how we can prevent cancer. The second piece of good news in prevention, we're still in prevention, is that we now

• 5:42Speaker 01

  know much more about genetics. We know much more about people who are at higher risk. It's not, for instance, in breast cancer, we now know it's not just BRCA1-carrying patients, mutation-carrying patients, or BRCA2 mutation-carrying patients, but actually, many other genes that are involved in breast, and prostate, and other cancers. In fact, in some cases, it's not a single gene, it's a multiplicity of genes. We know what they are. So, I could actually quantify, really quantify, by genetic sequencing, your relative risk of having

• 6:22Speaker 01

  some cancers, breast, ovarian, and more and more and more and more, some other cancers. We know almost with great certainty that obesity is a risk factor for certain kinds of cancers, endometrial being one of them. We know for sure, I'm now speaking in the realm of prevention again, we know almost certainly that most cancers are in mortality across the population in the United States are going down. So, we are actually making progress. The idea that cancer is exploding and killing everyone in the population is

• 7:04Speaker 01

  nonsense. But, but, there's a very important but, we know that colorectal cancer is on the rise in young people. We know that the gains that we had made over the last 20 years in breast cancer have started to plateau. So, something is going on. Another way of saying that is that, you know, breast cancer mortality was coming down year after year after year after year, and now it's beginning to sort of not come down as rapidly as we had hoped in the years before. We know that a couple of cancers are on the rise. I told you about colorectal cancer in younger people. We know that esophageal cancer, esophagus,

• 7:48Speaker 01

  is on the rise. We know that cancer of a couple of other cancers are on the rise in younger people. We don't know why. In the case of endometrial cancer in women, it's most likely because of increasing rates of obesity. But, the rest of it is a mystery, and the colorectal cancer business is a complete mystery. The esophageal cancer is probably because of alcohol and tobacco mixed together, but that's half a mystery.

• 8:18Dr. Peter Attia?

  Especially given that the trend appears that people are actually drinking less today, although maybe that hasn't caught up to where the cancer is actually arising.

• 8:28Speaker 01

  Yeah, there's always a lag. There's always a lag. There's always a five- to 10-year lag. So, that's all we know about prevention. Big deals. We can talk about each of those individual pieces that I spoke about separately, and each one of them is a full conversation. All right, let's talk about early detection. We know that there are tests in patients, for instance, blood tests, that will enable the early detection of some cancers. We know that if you just, at least for now, we know that if you just take those tests and unloosen them on a general population, so without selecting for high-risk people, without selecting

• 9:11Speaker 01

  for people who have had cancer before, we know that those tests are probably not going to work. They're going to lead to false positives, they're going to lead to extra biopsies and extra, you know, tests, more tests following tests, et cetera. But, those are not going to decrease, are unlikely to decrease, the mortality from cancers. That's the bad news. The good news is that probably, if you had used those tests, or if you were to use those tests in patients who are at high risk, for instance, those with carrying genetic mutations that put them at high risk, or those who have had previous cancers, those tests may

• 9:52Speaker 01

  actually yield very important results. And we know also that we're inventing a whole host of new ways of detecting cancer early using imaging technologies that are new. Whether they will work or not, I don't know. So, one example of this is what's called more continuous rather than discrete imaging. So, by discrete imaging, I mean, you know, people used to go and have their mammograms once a year. By people, I mean women above a certain age. The mammograms themselves were of relatively poor quality, though once a year was a discrete test. We know that potentially, having mechanisms to follow

• 10:32Speaker 01

  over time, less in episodic ways, but more in continuous ways, is likely to bring a different set of answers. So, that's in the realm of early detection. In the realm of treatment, there's lots of things. We know since the last 15 years that immunotherapy, activating the immune system, is extremely productive against some cancers. Just to give you one example, I had sort of written a personal note to myself, saying that, this was 15 years ago, that there would be, that I would not live to a time where I would,

• 11:13Speaker 01

  where there would be a medicine that would potentially extend the lifetime of a smoker with lung cancer.

• 11:22Speaker 01

  That's not true anymore. Immune therapy is now known to extend the lifespan of smokers with lung cancer if given to the right population of people. These are drugs that unveil or unleash the immune system to recognize cancers as foreign cells and enable treatment of cancers. We know that in some cases, activated T cells, genetically engineered T cells, so called CAR T cells, can cure liquid cancers such as leukemias, blood cancers such as leukemias and lymphomas. And by cure, I mean not make you live five years, but make you live 15 years or 20 years after your diagnosis.

• 12:06Speaker 01

  There are people walking around on earth that have had CAR T cell therapy for unresponsive leukemias and lymphomas who are 15 years post therapy. We know, and we were talking about it a little bit before, that early, the early signs that metabolic therapies against cancer, so using the idea that cancer metabolically is different from normal cells, is a potential way to treat cancers. We know that there are second line and third line therapies in certain cancers that will truly expand your lifespan.

• 12:48Speaker 01

  So two good examples are the use of a drug called NHER2 in breast cancer, which works even after, even after many, many lines of therapies have stopped working. In myeloma, there are three or four new medicines. In lymphoma, there are two or three new medicines. So, so in prostate cancer, there are two or three new medicines. And we know that there are now treatments, surgical treatments for many of these breast, prostate and other cancers, which are much more sparing of normal tissue so that you can regain functionality more easily and better and yet remove as much cancer as possible.

• 13:33Speaker 01

  And finally, in treatment, we know that there are radical new set of medicines on the horizon. You've seen cases of pancreatic cancer treated with the Daxon rasib, a new medicine against the, one of those killer genes called RAS. It's extended the life of patients. We've seen videos of these patients on television. They're now living with pancreatic cancer, you know, months, if not years after their, of the cancer has spread, which would have been impossible 10, 15 years ago.

• 14:12Speaker 01

  So immunotherapy, novel biologics and novel small molecule therapies are here, they're on the horizon. They're not just, they're not just, you know, making people live longer by one month or two months, two months. They're sometimes actually making people live longer than, you know, into the, into the five year range and extending survival meaningfully. So that's kind of my, that's kind of what the landscape looks like right now.

• 14:45Dr. Peter Attia?

  I mean, Sid, that's fantastic because everything you've covered there is sort of where we want to go with one exception. We didn't touch on AI, which we will touch on.

• 14:52Speaker 01

  Yes.

• 14:52Dr. Peter Attia?

  I'm sure. But let's go back and look at something that we learned in the last 15 years, courtesy of Brett Vogelstein and his colleagues. So in 2015, they published a paper in Science. Both you and I remember this very well. The entire oncology community was sort of divided a little bit on this. In 2017, they came out with another paper that kind of revisited it, but the gist of the paper was that if you looked at all cancers by tissue type, if I'm remembering the math correctly, Sid, about 5% of the mutations, because again, cancer is a genetic disease. It is driven by genetic mutations. About 5% of these mutations were hereditary. And you already alluded to some of these, you know, HER2 new and, pardon me, BRCA, BRCA1,

• 15:37Dr. Peter Attia?

  et cetera, et cetera. But, but there are many others that we don't necessarily talk about as frequently. On the order of 30% of the mutations appeared to arise from environmental triggers or carcinogens. So when you smoke, you're increasing your risk of a mutation. When you're exposed to lots of UV light, you're going to have a mutation, et cetera. But the part that I think really was sobering for us was that two thirds, 66 ish percent of mutations were purely random. And this is where the idea that stuck from Vogelstein's paper was this idea of cancer is a bad luck disease, right? You can do everything right, Sid, and you, more than anybody else knows this, you're a practicing oncologist.

• 16:22Dr. Peter Attia?

  You can have the healthiest person who's done everything correct and yet this random mutation occurs and that may explain up to two thirds of the mutations we see. And we don't see that in cardiovascular disease, right? We don't see the perfect pillar of health who's done everything right, who's managed cholesterol and blood pressure, et cetera, et cetera. So what, how do we make sense of this beyond the observation? In other words, how do we take that observation and, and do something about it?

• 16:54Speaker 01

  So first of all, let's, let's really take the observation seriously. Let's take it totally seriously. 5% of mutations hereditary, that number is most likely no longer 5%. In, at Vogel, during Vogelstein's.

• 17:13Dr. Peter Attia?

  Yeah, because that last paper, sorry to interrupt, was, was actually nine years ago and I'm not, I don't know if there's been a follow up. So yes, yeah.

• 17:18Speaker 01

  So, you know, Bert Vogelstein is a close friend, one of the great scientists of the world, one of the greatest cancer scientists of the world. But obviously the field changes, the field moves.

• 17:27Dr. Peter Attia?

  Yep.

• 17:28Speaker 01

  Five, that 5% is going to change. So, and how is it going to change? Well, that 5% was a, was usually focused on single gene mutations. So BRCA1, BRCA2, you know, P53, I can rattle them off, your, your listeners won't know them, they'll know BRCA1, they'll know BRCA2. So just to give you, let's just take breast cancer. So hereditary breast cancer, where you know that there's a hereditary breast cancer. So you know that your, your, your mother had it, your mother's sister had it, your aunt had it, your grandmother had breast cancer and you sequence your genome and there's

• 18:13Speaker 01

  no BRCA1 mutation, there's no BRCA2 mutation. So now we've added many more mutations, single point, single mutations in single genes that increase risk. But we still, we know that about, that that only covers, we're now talking only about hereditary breast cancer. If you take all the single genes that we know increase the risk of hereditary breast cancer, that still only covers a fraction, about a third, maybe a fourth of hereditary breast cancer. So the question is, what's the other mystic? So again, remember we're talking about just hereditary breast cancer.

• 18:56Speaker 01

  So what's the, what's the other whatever percentage? And the answer now is that that other fraction in hereditary breast cancer, not breast cancer caused by random mutations or by exposure to environments, et cetera, is a combination of multiple genes, not one, not two, but probably hundreds of genes that are pushing your risk by a small percentage. So the way I try to describe this to my patients is I say, in hereditary cancers, there are two kinds of mutations. I call them shove mutations and nudge mutations. BRCA1 is a shove mutation.

• 19:40Speaker 01

  It shoves you off the cliff and puts you at a ninefold, tenfold risk above the normal population to get hereditary breast cancer at an early age. BRCA2 is a shove mutation. It shoves you off the cliff. But there are also patients who have nudge mutations. They're not shoved off the cliff. They're just sort of given little nudges. Each of these changes gives you a little nudge. And of course, there's environmental factors that come into it, but they give you a little nudge along with the environmental factors until you fall off the cliff and get cancers. That's hereditary. So that number 5% is no longer the number 5%.

• 20:24Speaker 01

  Second big major point, cancer as a disease of bad luck. Yes, it is still a disease of bad luck, but it's not a disease of bad luck in the same sense that we imagined it 10, 15 years ago when Bert wrote his paper. Yes, there's bad luck involved, but it's also bad luck plus something else bad that's going on in the body.

• 20:47Dr. Peter Attia?

  Such as inflammation.

• 20:48Speaker 01

  Such as inflammation. And the best example of that is recent papers that have come out from many laboratories. I specifically wanted to point out Charlie Swanton's lab in London, in, in, in the UK, but many laboratories that show that.

• 21:06Speaker 01

  You can have cancer that you and I, right now, if we were to biopsy every cell in our lung, if we magically had the capacity to biopsy every cell in our lung, we would find almost certainly, and I don't smoke, you don't smoke, we would almost certainly find cells that genetically speaking would bear all the hallmarks of genetic mutations of cancer.

• 21:38Speaker 01

  But you and I don't have cancer. So what's with that story?

• 21:45Speaker 01

  The answer to that story takes us back to the 1950s. And this is a very important idea that I often emphasize. It's something that's gone out of the scientific literature. It's sometimes very important, Peter, to publish an observation without explaining it. You know, I'm going to take a philosophical aside here. I'll come back to the real point in a second. I'm going to take a philosophical aside here. Our scientific publication strategy

• 22:18Speaker 01

  has become a form of magic storytelling. By magic storytelling, I mean you have to tell a full story about what you observe, what the mechanism is, what the explanation is,

• 22:35Speaker 01

  and how it's working at a molecular level.

• 22:39Speaker 01

  That was not the case in the 1950s. In 1950s, 1940s, 1960s, you could say, listen, I don't know the answer. I don't know why this is happening. I can just tell you it's happening. You go figure it out. Five years later, when you have the technology to figure it out. I can't emphasize how important that is. You know, we have writers, I'm a writer myself, you know this. We have writers like Oliver Sacks, whose legacy has depended on the idea that they made very thorough, important observations.

• 23:14Speaker 01

  William Osler, perhaps the greatest of physician scientists, said, observe the patient first, explain later. So this is a philosophical observation that I want to make. So let's go back. So in the 1950s, a team of doctors, of scientists from Oxford, published a paper which remained unexplained. And this was a very simple paper. They took a carcinogen, let's call it, whatever you want to call it, let's call it DMBA. It's a chemical carcinogen. Makes mutations. Should cause cancer.

• 24:00Speaker 01

  And they painted it on the back of a mouse. And sure enough, a few cancers grew.

• 24:08Speaker 01

  And then they went back, and get this, this is a super interesting story. Then they went back and said, okay, fine, just a few cancers grew. But we painted it on the entire back of the mouse. Why was it like four, that four cancers grew?

• 24:24Speaker 01

  So they then, after painting the back with this chemical carcinogen, they added an inflammatory agent, croton oil, something that you can buy from Amazon.

• 24:38Speaker 01

  And all of a sudden, 80 cancers grew.

• 24:44Speaker 01

  Years and years later, in experiments by Alan Balmain in UCSF,

• 24:53Speaker 01

  they genetically engineered a mouse to get cancer.

• 24:59Speaker 01

  So this mouse was genetically predisposed, just like a human being with BRCA1 may be predisposed to get a cancer.

• 25:07Speaker 01

  They made a, so, and sure enough, when the mouse grew up, it had four or five or six cancers where, you know, obviously where the gene was making cancer cells. And here's the interesting thing that happened. They made a little slit or a cut, an inflammatory wound in the mouse. And again, nothing very impressive happened. The next thing they did was very interesting. This is by chance. And this is why science is very important. It's very important to do experiments, it's important to report experiments. And it's important to report just observations. They stapled where the wounds were. And wherever there were staples, of course, you got an inflammatory response.

• 25:52Speaker 01

  And exactly, exactly the place where they put the staples, outgrew massive cancers. Now, what does that tell us? It tells us something very important. It tells us that this whole idea, that there's bad luck. Yes, there's bad luck. Let's say you, when I biopsy your lungs, I get, you know, you have several million, maybe a billion cells in your lung. I'll find, let's say, 2,000 cells that have already obtained or carrying cancer mutations. Let's say I biopsy my cells

• 26:34Speaker 01

  and I find that that number is not 2,000, but 750. You have some bad luck, I have some bad luck. Your bad luck is 2,000, my bad luck is 750. Those cells with mutations, most likely, and I'm just saying most likely because we don't know, most likely arose because you and I had bad luck. And when the cells grew, they made mistakes. They caught up, they made genes that are cancerous and so forth. But those cells are dormant, I call them sleeper cells.

• 27:07Speaker 01

  The real bad luck that happened between you and me is that you had some kind of inflammatory response. And it's not, when we say inflammation, it's like using the word motion before Newton. Before using the word energy before Newton. Or using the word atom before Dalton. When you say the word inflammation, you know, it's a loose word. It's not like, oh, you know, I had a fever, I had a cold, I had a virus. There's something very particular about the inflammation. We can talk a little bit more about it.

• 27:42Speaker 01

  You had a particular kind of inflammatory response in your body and your 2,000, in one of your 2,000 cells, which already was carrying a mutation, turned from a sleeper cell, a dormant cell, a doing nothing cell, into a tumor, into an active cancer cell. And from there on, you developed cancer. I was lucky. I didn't have that inflammatory stimulation. My 750 cells were, remained dormant, remained quasent, remained asleep, and I don't have cancer.

• 28:22Speaker 01

  So now, let's go back to Bert Vogelstein. That, the number 5% is not 5% anymore. It's a much larger number than 5%. And we can detect that larger number now with greater and greater accuracy. Not in all cases, not in all cancers. Breast cancer, yes. Ovarian cancer, yes. Maybe in some other cancers more and more. And that number unlucky, the cancer of bad luck, is no longer a cancer of bad luck. Very, very soon, I hope, I can't give you a date, very soon, I will be able to tell that, that, that I will be able to tell you that you have bad luck and I don't have bad luck.

• 29:04Speaker 01

  And it's not bad luck, it's just the nature of our inflammatory response. So this whole idea of dividing up, creating a typology of cancer, every typology of cancer evolves. It's evolved since the beginning of any typology of cancer. And, and so those numbers are all going to change. And going to change in a way that makes, is sensible. So Bert is not wrong. He is just early.

• 29:34Dr. Peter Attia?

  And maybe there's another point to just double click on this, Sid, which is... The way that that paper described it suggested that these are discrete types of mutations. But as you pointed out, and I love, I'm gonna borrow this, by the way, so thank you. This idea of shove versus nudge mutations, they can both arise as hereditary mutations. But here's where the environment overlaps. So instead of saying that hereditary mutations are a discrete bucket, environmentally acquired or triggered mutations are a discrete bucket, it could be no. You, if you have a bunch of shove mutations, or pardon me, a bunch of nudge mutations that are acquired, you know, or pardon me, that are passed through the germline,

• 30:18Dr. Peter Attia?

  the environmental mutation is really a push or a gentle nudge.

• 30:23Speaker 01

  The final shove.

• 30:23Dr. Peter Attia?

  Yeah, exactly. So in other words, these are not discrete, they're gonna start to overlap a little bit more.

• 30:28Speaker 01

  Absolutely, and this is super important because this is not just theorizing, right? This is, these have very practical implications for patients. Because if I could figure out, you know, where you are in the nudge versus shove cascade, I could tell you, I could quantify your risk. I could tell you what your risk is, and you should be maybe in a clinical study. You should maybe be in a prevention program or a trial prevention program. So these are not just sort of abstractions, these are realities. The last thing we didn't touch upon is metabolism. We talked about inflammation.

• 31:07Dr. Peter Attia?

  Yep.

• 31:07Speaker 01

  We didn't talk about metabolism. So metabolism is becoming very important. We know, I mean, just to give you the most obvious example, you know, we know that there's a a enormous risk between, and we don't know why exactly, but enormous risk that connects, for instance, endometrial cancer with obesity. And endometrial cancer is one of those cancers which is either plateauing or maybe on the rise in women, maybe because of obesity, but what's the connection? Is it through inflammation again? Is it because there is a hormone that's making, you know, the sleeper cells alive?

• 31:49Speaker 01

  Obesity itself is unlikely, I would say, to cause mutations. It's not a, obesity is not a mutagen, but obesity is a physiological state. And those physiological states, of course, are important because we've already seen, in the case of inflammation, a physiological state that can take a dormant cell and convert it into a cancer, into a cancerous or cancerous tumor cell.

• 32:15Dr. Peter Attia?

  And Sid, how much of it do you think is obesity per se with its adiposity versus insulin resistance, hyperinsulinemia? And the sort of metabolic milieu that accompanies obesity often, but not always?

• 32:32Speaker 01

  So in humans, we don't know. But about five years ago, Luke Cantley and I wrote a paper in Nature, which actually you were, you inspired in some ways, where we know that in, at least in animal models, you don't need to be obese in order to unleash, or at least in order to have a cascade that sustains a cancer. I have to be careful with my words because that paper was really a paper about treatment. But what we, what we can surmise from that paper, and it's, I'm being careful with my words,

• 33:13Speaker 01

  surmise, is that it's not being obese. It is the insulin and it's the cascade of insulin and what follows the insulin cascade that is responsible, at least, for the resistance of cancer cells to therapy. Now, from that, you could extrapolate, and I'm using again, being careful with my words, you can extrapolate the idea that insulin and insulin resistance and the presence of chronic insulin response

• 33:56Speaker 01

  may have something to do with releasing cancer cells in the body. But if that's an extrapolation, it would be a complicated experiment, but a doable experiment, in which you chronically exposed animals to hyperinsulinemia in the way that obese people are exposed to hyperinsulinemia without the appropriate insulin response, which normal, non-obese people have, and figure out whether it was truly that that was causing the cancerous cells to develop. The general hypothesis I have, and again, I have to say this is a hypothesis,

• 34:39Speaker 01

  is that that's, that's the case.

• 34:42Dr. Peter Attia?

  Yeah, Mitch Lazar at Penn wrote a paper, it's been, it's been about 15 years as well. And he looked at the incidence of cardiometabolic disease. And he sort of created a two by two, right? So you were either obese and/or metabolically unhealthy. But there were states, as you know, where you can have lean individuals who are still metabolically unhealthy. You can actually have obese individuals who are metabolically healthy. And when you, when you do the two by two of that, what Mitch's paper found, again, this was focused on cardiovascular disease, not oncology. But it showed that the prevalence of disease didn't track with the adiposity,

• 35:27Dr. Peter Attia?

  it tracked with the hyperinsulinemia and everything you just described that accompanies it. So it's, I mean, that would at least suggest plausibility that the same thing could be true in oncology, although of course, the diseases are different.

• 35:40Speaker 01

  Yeah, the diseases are different, but, but again, you know, as I said, our work has been, and it's now a full-fledged clinical trial, we can talk about the trial. But our work has focused on treatment. And we know that chronic insulin tone, I use the word tone like, you know, like the tone of muscles, but chronic insulinemic tone has the capacity to make cancers grow and be, become or be or remain resistant to some forms of therapy. And that you need to remove that chronic insulinemic tone for those cancers to become vulnerable.

• 36:25Speaker 01

  That, these are facts. From those facts, you may extrapolate that chronic insulinemic tone is also responsible for the sustenance and maintenance of cancerous cells that have mutations. And in the same way that inflammation is making those cells sustain, maintain and grow, that chronic insulinemic tone maintains those cells in a chronic state. Now, I would be so happy if someone did that experiment. It's not, it's not a, it's not that complicated an experiment to do. It, it just takes a lot of very careful controls and careful,

• 37:09Speaker 01

  it's, it's a fussy experiment to do. And good experimental people can do fussy experimental science.

• 37:17Dr. Peter Attia?

  Sid, the GLP-1 agonists, while potentially in the very near term will transiently raise insulin levels to aid with glucose disposal, ultimately tend to reduce hyperinsulinemia. It's not entirely clear why, of course, it could be that with enough weight loss and, you know, a reduction in energy balance, that insulin, hyperinsulinemia goes down. But, but has anyone proposed doing a study of using a GLP-1 agonist as an adjuvant to conventional cancer therapy? Where you would just have a simple randomization of standard of care versus standard of care plus GLP-1 agonist?

• 37:58Speaker 01

  No, many people have thought about it. I don't know if there's been a formal proposal to either, you know, Novo or Lilly or the NIH. This is a, this is a fundable and thoughtful study. You'd have to do it, again, it's a fussy.

• 38:13Dr. Peter Attia?

  You'd have to pick the right cancer, you know.

• 38:15Speaker 01

  You'd have to pick the right cancer, you know, I would pick endometrial or ovarian or some obesity.

• 38:20Dr. Peter Attia?

  Even breast, potentially.

• 38:21Speaker 01

  Breast, yeah. And really think through it, this is a, you wanna do this thoughtfully. You don't wanna just run into this and just do it in a silly way.

• 38:30Dr. Peter Attia?

  Yep.

• 38:30Speaker 01

  You wanna do this thoughtfully. I think it's a beautiful study, it would be a beautiful study. You would randomize to patients with on GLP-1 versus on, with not GLP-1. You would study their insulinemic response versus their weight loss response.

• 38:48Dr. Peter Attia?

  Yep.

• 38:49Speaker 01

  And with AI, which we'll talk about in a second, you could probably dissociate those two and disconnect them and ask the question, which one is leading and which one's following? But it would, it's a beautiful study. And, you know, look, we could do a very broad, sweeping epidemiological study, which you could do in five years or 10 years. So that's just a little bit too early. And just ask the question, listen, if, you know, people who are on GLP-1 versus not GLP-1, you know, is there a lower risk of endometrial cancer now?

• 39:20Dr. Peter Attia?

  See, I prefer the experimental approach here, Sid.

• 39:22Speaker 01

  Of course.

• 39:23Dr. Peter Attia?

  Yeah, not just because of time. I think there might be too many confounding factors if we just do it observationally.

• 39:29Speaker 01

  Of course, I mean, of course. But the observational study is much easier to do, it's, you know, you don't have to.

• 39:35Dr. Peter Attia?

  Yeah, you don't have to intervene.

• 39:37Speaker 01

  You don't have to intervene, no, no. So yeah, of course, we all prefer the real, proper study. And I think someone should fund this study. I mean, you know, if it's not the NIH, if it's not the Eli Lilly or Novo or whoever else is now making, you know, any of the GLP-1s, you know, any of the people, anyone in the audience who's, you know, interested in longevity. Because I'm interested ultimately in, you know, what, what these drugs do, not just to cancer, but to the overall.

• 40:11Speaker 01

  Physioinflammatory state, which is certainly pushed by insulin. And I would love to ask the question of what happens to longevity markers? What happens to? You know, so this is a study that that one of the many, very many people in, who have the means and capacity to do so can can fund through a, you know, a remarkable institute like UCSF or Columbia or Stanford or Harvard. I'm just going to name some names, but there are many.

• 40:47Dr. Peter Attia?

  Yeah, yeah. And by the way, there is a bit of a precedent on some of this. I don't know if you've been following the literature on osteoarthritis, but.

• 40:54Speaker 01

  Oh, I, this is, you know, one of my favorite topics.

• 40:57Dr. Peter Attia?

  Yeah, it's again, maybe just explain the observation to people and how it points or shines a light on inflammation, independent of weight loss, because it's quite fascinating.

• 41:09Speaker 01

  Well, so osteoarthritis is my neck of the woods because my laboratory discovered the first osteoarthritic stem cells. We published that in Cell and then subsequently in Nature and Nature Medicine. I have never believed from the beginning of the time I began to study osteoarthritis. I had never believed that osteoarthritis was an obesity disease. There are not obese people who have osteoarthritis. There are obese people who have osteoarthritis. It's much larger. But the idea, there was something kind of like, it didn't make sense. And also, it was sort of like, let's blame the victim. Let's say fat people get osteoarthritis.

• 41:54Speaker 01

  And let's just say, oh, you know, that's a fat people problem. And it just didn't make sense. It doesn't make sense for many reasons. Look, I'll tell you some of the reasons. So, yes, of course, the weight bearing limbs, the knees, the hips, get osteoarthritis and people complain about knees and hips. And they get hips replaced, knees replaced, et cetera. Great, fine, makes sense. Usually people who are obese, usually women who are obese. Point number one, it seemed to be like many things that we've done in in medicine for women, a backwards problem, which is to say, oh, you know, they have, they are obese and therefore they must have

• 42:37Speaker 01

  weight bearing problems and therefore it's a weight, it's a weight problem. But then you you meet a person who's, you know, just completely has no obesity, a woman. And their osteoarthritis is in their hands. They have these massive nodes, you know, inflammatory nodes, inflamed nodes in their hands. A hand is not a weight bearing joint. Some of them have, you know, degeneration of their upper neck joints. Their complaint is upper neck pain, shoulder pain. And they're not obese. And you say, well, this this observation can't be true. This, it just doesn't make any sense.

• 43:19Speaker 01

  So now we know that there, that osteoarthritis is almost certainly a combination of two problems. One that we've, that my lab has been a big proponent of, which is that the stem cells that grow cartilage in the joints, over time, those stem cells, there's a balance. So during our lifetime, cartilage is being generated and is being destroyed, generated, being destroyed, generated means destroyed. If that genesis and destruction is in adequate balance,

• 44:00Speaker 01

  then we maintain cartilage and we don't get osteoarthritis. If the genesis gets stopped with the destruction remains the same, then of course, you know, you won't get new cartilage. And over time, you'll eat up the cartilage that you have and you'll get osteoarthritis. So the question then becomes, well, what causes this imbalance? So the, if you imagine them as weights on a scale, remember, normal is equal weight, genesis and destruction, genesis destruction, genesis destruction. In women who have obesity and in very older men and women,

• 44:43Speaker 01

  genesis goes down, destruction remains the same or goes up. And all of a sudden you have an imbalance. So the question becomes, well, what's driven genesis down? Well, we now know, at least in animals, what's driven genesis down? Then it's the stem cells that form cartilage, the cells that create real cartilage have gone down. We've measured it. We know this is, this is a fact. Now the question is, why have they gone down? Well, some of it is age, age because, you know, in over age, all of our stem cells go down, skin stem cells go down, your bone marrow stem cells that make blood go down. So some of it is age. If you inject in a young animal,

• 45:28Speaker 01

  young mouse, if you inject an inflammatory response into a joint and it's a young animal has no reason to have any other problem, we know that that inflammatory response will cause the stem cells to stop making cartilage.

• 45:48Dr. Peter Attia?

  And sorry, when you say inflammatory response, do you mean like LPS or bacteria?

• 45:52Speaker 01

  Yeah, it could be, it could be, it could be like a bacterial mimic.

• 45:56Dr. Peter Attia?

  Yep.

• 45:57Speaker 01

  Yes.

• 45:57Dr. Peter Attia?

  So something to activate the immune system.

• 46:00Speaker 01

  Yeah, something to activate the immune system, exactly. And we now know that if you activate the immune system, either using a small molecule or using a some kind of stimulation, the inflammatory response, you'll start an inflammatory response in osteo, and it will create, it will mimic, almost exactly mimic osteoarthritis in the animal. The balance, remember, again, the weight scales genesis, destruction. The destruction goes up, the genesis goes down, and you have osteoarthritis.

• 46:34Dr. Peter Attia?

  And so let's think through why that might be happening. Because that's also not entirely intuitive that an immune response, which serves the purpose of trying to eliminate a foreign pathogen, would also in its wake have its host's stem cells reduce their output.

• 46:57Speaker 01

  Well, you're asking a really hard question and the answer is, I don't know. I just, I don't know. I think that, I think that it's actually not uncommon in the stem cell world across different kinds of stem cells, skin, bone marrow, blood stem cells, and in this case, cartilage forming stem cells, that certain immunological responses tend to make the stem cells reduce their capacity to regenerate. And we, it's a common theme. This is not an uncommon.

• 47:37Dr. Peter Attia?

  I mean, there must be some at least teleologic explanation that I'm just missing.

• 47:40Speaker 01

  No, but the problem, as you know, Peter, teleology, teleology is not biology.

• 47:50Dr. Peter Attia?

  No, it's rationale. It's a way we tell our story to ourselves that we like.

• 47:54Speaker 01

  It's like Rudyard Kipling's just so story.

• 47:56Dr. Peter Attia?

  Yeah.

• 47:57Speaker 01

  Teleology is like saying, oh, I think it's because in ancient times.

• 48:02Dr. Peter Attia?

  Right, right, exactly. Yep, yep.

• 48:04Speaker 01

  And, you know, when people were hunting and gathering and fighting lions and running from woolly mammoths or whatever, you know, crazy nonsense.

• 48:14Dr. Peter Attia?

  Yeah, yeah.

• 48:15Speaker 01

  You know, stem cells had to shut down because they had.

• 48:19Dr. Peter Attia?

  That's right, they were, they were too energy demanding and when the immune system. Yeah, yeah, exactly.

• 48:24Speaker 01

  I mean, you know, great. Some of this can be, some of this can be observed. Some of this can be experimentally tested. But you can't put a human being in, you know, prehistoric times, you know, a hundred thousand years ago or a, or a pre-human being or a monkey or a god knows ancestral, common ancestor in some stress condition and, and ask the question, well, why do their stem cells not stop working?

• 48:50Dr. Peter Attia?

  Yeah, the more relevant question, the more relevant question is how, right? If we knew the how, then we could intervene because that's what we have to figure out.

• 48:58Speaker 01

  Well, you know, again, so let's, let's talk philosophically. Biology, and, and, and maybe I should say this as a, I'm not taking off my hat as a, as an immediate scientist and talking to you as a science philosopher.

• 49:15Speaker 01

  Why questions are very hard to answer in science? How questions are what science, science can do? I can tell you how something happens. I can tell you if I, I can do how an apple falls from a tree and with what velocity and, and how. Now, if you would ask me, why? Why does the apple fall from the tree and go towards the ground? I would say, I have no idea. Who knows? Why are planets attracted to each other? I don't know. I mean, you know, this is like lives in the depths

• 49:56Speaker 01

  of very abstruse physics and biology is so many degrees removed. If you ask me, you know, why does a stress response in, in humans shut down? Blood forming stem cells? I'd say I have no clue, but I can tell you how. I can tell you exactly the molecules. I can tell you the, the molecules that are shut down. I can tell you who's moving. But why? Why is not a science question? Why is a, why is a metaphysical question?

• 50:28Dr. Peter Attia?

  So let's talk about the how, especially as it pertains potentially to the most important question, which is, well, before I go there, I want to, I want to ask you a question that might set the stage for this. So we have a remarkable immune system. You've already alluded to it a number of times through the lens of immune based therapies. And while we didn't go into great detail, we-

• 50:55Speaker 01

  We have a remarkable immune system.

• 50:56Dr. Peter Attia?

  Yeah, so we have this incredible system and we've danced around the success of this class of drug called checkpoint inhibitors, which come along and remove the brakes on the immune system and unleash the immune system on the cancer, suggesting that our immune cells at least have the potential to recognize cancer as non-self. And in fact, when I had Steve Rosenberg on the podcast a couple of years ago, he shared some unbelievable data, blew my mind, which was that 80, eight zero percent of solid organ tumors had novel neo antigens that could be recognized by self. Now, think about that for a moment.

• 51:41Dr. Peter Attia?

  If you're the average person trying to make sense of this, what that means is 80% of the cancers that are most lethal, the ones we think of, breast, colon, lung, pancreas. These are the really bad cancers. 80% of these are immune cells. Our T cells know that that is bad and it's not self. Then the question is, why can't they mount on their own enough of a response to do the job? Sometimes they can, that's very rare. We now have a drug that can take a subset of those. And this is the checkpoint. But we're still sort of wandering in the desert with cancers that are non-self

• 52:24Dr. Peter Attia?

  and an immune system that just can't make it happen. So let, I want to spend some time talking about T cell biology. And what, what do we think it's going to take? Is it, is it simply the age of the T cells? And is it the case that if you're 10 years old, your T cells are doing this automatically? That's why 10 year olds rarely get cancer. But by the time you're 70, they've just, they've, they've been around the block too many times.

• 52:49Speaker 01

  So the answer is all of the likely, all of those things. But let's talk about new antigens for a second because we need to, we need to really think about this. So Steve Rosenberg, who I know very well, was a pioneer in the field. And years ago, Steve Rosenberg and I had a very public argument on stage at a very prominent cancer conference. And he said, well, there are new antigens in cancer. And I said, but where are they coming from? And he said, well, some of them are coming from mutations. And I said, well, come on, they're like 30 mutations, 50, 100?

• 53:25Dr. Peter Attia?

  100, yep, call it 100. And that doesn't explain at all.

• 53:28Speaker 01

  It doesn't explain anything. Now there's beautiful work from Tyler Jack's lab. And just, I would say it's something from my lab that says that that's not the real neo antigen. The real neo antigens are coming because when cancer cells start deregulating, dysregulating, the way genes are, their genetic apparatus is decoded. They make mistakes. They go wacko. And all sorts of cryptic antigens, cryptic pieces of genes that should not have been expressed, made into proteins, are now coming out and becoming made and making proteins.

• 54:10Speaker 01

  We, Tyler's done, Tyler, Tyler's lab has done, at MIT, has done an incredible job at decoding what this is. It's an incredible story. I would encourage people to read about it. But we now know what those are. We can map them. That's the first part of the problem. So you know, as you know, there are two parts of the problem. Now, one part of the problem is, what are the new antigens that are coming? And number, the number two is, why aren't T cells recognizing them? The second part of the problem is more interesting, which are equally interesting. The T cells don't recognize them because of all the reasons that we've talked about. There's not one checkpoint. There are dozens of checkpoints in cells. And it's, what's a checkpoint?

• 54:56Speaker 01

  A checkpoint is a gene or a flag that a normal cell floats on its surface, saying, I'm normal, leave me alone to a T cell. And that's why we don't have desperate, terrifying autoimmunity. When we know that patients, people who have mutations in some of these checkpoints are consumed by T, that T cells eat them alive. We have enough T cells in our body to eat ourselves alive. Think of a disease like, you know, a T cell autoimmune disease like diabetes type one.

• 55:39Speaker 01

  It eats the pancreas alive. Think of a B cell, again, another immune cell disease, like lupus. It eats our body alive. Think of scleroderma, think about patients. That patient is eaten alive by their own autoimmune cells. But you and I are not, why not? And that's because all of our cells are carrying not one flag, not two flag, but dozens of flags saying to a B cell and T cell, I'm normal, don't eat me. Don't kill me, don't create an autoimmune response against me. So cancer cells, of course, figure this out by themselves. And I'm anthropomorphizing and-

• 56:22Dr. Peter Attia?

  Right, but that's okay. It's a safe spot for that.

• 56:25Speaker 01

  It's an evolutionary process, right? The cancer cells that survive are the cancer cells that are able to put up these flags. So that is the non-anthropomorphic variant of what I'm just saying. Cancer cells that survive create flags that enable them to tell the T cells and B cells not to attack them. And there's not one, there's not two, but a dozen such response elements. And these response elements are ultimately responsible for the fact that even though cancers have now, we now know, not one, not two, but dozens of neo antigens,

• 57:07Speaker 01

  that they're still not attacked by the immune system.

• 57:12Dr. Peter Attia?

  And so do you think that along the lines of the inflammation angle, which I want to spend more time talking about, do you think there's a world in which T cell generation, regeneration, I'm sorry. Just as people are starting to talk about, how do we regenerate cartilage? How do we regenerate corneas, things of that nature? Are we going to get to the place where we have serious considerations of medications, drugs, therapies that say, look, if an 80 year old could be armed with the 20 year old version of their immune system, their mortality is going to plummet. Because not only are they going to be able to combat cancer, but also infections, right? I mean, think about, yeah, yeah.

• 57:56Dr. Peter Attia?

  So how, how much is that sci fi? And how much is that something that, that, that we might see in our lifetime?

• 58:02Speaker 01

  Well, now we come to AI. One of the most interesting talks I heard recently was from someone who, at Harvard, who was looking at, looking through CAT scans of patients and asking the question about wellness, longevity, disease, cancer, et cetera, using AI. And asking the question, was there anything in the scan of their bodies that was correlative, correlative, not causative, that correlated with any of these markers? And they found one marker.

• 58:47Speaker 01

  And it was the presence or absence of an organ called the thymus. So the thymus, T, the thymus is the reason T cells are called T cells. Because the thymus is the, you can imagine it in metaphorical ways as the baby nursery or the kindergarten where T cells grow up. And people across thousands of people, across thousands of disease states, people who had an intact thymus. In this study, it's been well published, well noted.

• 59:28Speaker 01

  People who had an intact thymus tended to have less diseases such as autoimmune disease and cancer. People who lost their thymus as they grew older, because the thymus naturally involutes and dies, tended to have more. Now, this is a correlative study. It's not a causal study. You can propose, right now, you can think of 10,000 ways that you can probe this, but it's super interesting. Because all of a sudden, it says, oh, maybe, just like Lipitor for cardiovascular disease or hypertension for cardiovascular disease, maybe I have a marker.

• 1:00:12Speaker 01

  Maybe the marker is the size of the thymus or the presence of the thymus. The real test, of course, is, starting with animals, take an older animal whose thymus has gone away, put a new thymus in, and see if you can restore their capacity. These are difficult but important studies, but you're on the right track. Could we make a T-cell booster? What better T-cell booster to make than re-implant the kindergarten where T-cells grow up and learn to become T-cells? And this study very clearly points to the idea that that's one of the places to start.

• 1:00:49Dr. Peter Attia?

  You know, there was a paper that came out, I don't think it was quite 10 years ago, but probably around then. And it was, and I say this with no disrespect to the authors or anything, it was a bit of a clumsy paper aimed at thymic regeneration, and it was a little bit of a kitchen sink approach, right? They gave these patients growth hormone and Metformin and a whole cocktail of things. And on imaging, they showed, hey, look, in the patients who got this, and by the way, it was even worse because I think it was an open-label study, so there wasn't even a randomization. But they said, look, the thymus grew. And this sort of idea of thymic regeneration became very popular. I haven't actually followed it closely enough to say, hey, has the field moved to a place where there are legitimate inquiries?

• 1:01:33Dr. Peter Attia?

  Because I don't even recall the rationale for Metformin growth hormone and DHEA or whatever they were giving. Have you followed this space at all? And are there molecular attempts at this?

• 1:01:45Speaker 01

  I have, I have. You know, again, the good news is, we're going from a human, generally speaking, the kind of study that I like is what I call a closed circular study. You start with a human epidemiological observation. And it's an observation that goes back to my old philosophy. Publish observations, you don't need to publish explanations. The observation is, humans who retained their thymus tended to have fewer various diseases.

• 1:02:25Speaker 01

  This was picked up by AI reading of multiple tens of thousands of CAT scans. Great. Now, take that into an animal model in which you can do an experimental implantation of the thymus. This is possible to do. You can actually open the chest, put a new thymus in, and ask questions, you can ask very detailed questions. It'll take some time, but it will happen. And then slowly work yourself back up to the human and close the loop and find out, you know, what are the thymic growth factors? I'm sure there's some. Otherwise, you know, why would, let's say, your thymus, you and I, let's say, are the

• 1:03:07Speaker 01

  same age, I don't know if you are, but your thymus is gone, my thymus is not gone. Can I find the growth factor that made your thymus involute and mine not involute? Great, I'll replace yours with a growth factor. But, you know, putting in random stuff, Metformin, it's just, that's just a mess. So, look, science is systematic, and we need to follow systems. It's great when we follow systems and when we understand systems. Sometimes we have to make a few leaps of faith. It's okay. Sometimes there's a lot of insight, there's some intuition, blah, blah. It's okay. But ultimately, it's a systematic way of thinking. And there's nothing more to it. It's a systematic way of thinking.

• 1:03:50Speaker 01

  So, yes, the answer is, we'll find the hormones, I'm sure. Look, I'm sure there's a hormone. There's some hormone that sustains your thymus and doesn't sustain mine. Yours is there, mine is gone. I need to keep mine alive. I'll keep mine alive. And then I'll have a new way of preventing many diseases, including cancer.

• 1:04:12Dr. Peter Attia?

  Before we leave the immune system, I want to go back to something you brought up, which has been one of the great successes of the past 15 years, which has been the success of CAR-T therapy, especially around the B-cell lymphomas and leukemias, where, to your point, we were talking about durable cure. We're not talking about extension of median survival. Maybe just spend a little moment explaining what the CAR-T is, like what is a chimeric T-cell, et cetera. But where I really want to go with this, Sid, is, will we ever, or do you believe that there's going to be a future where the same technology that has given us a CAR-T

• 1:04:50Dr. Peter Attia?

  cell to treat CD19 B-cell disease is going to allow us to treat a solid cancer like colon cancer, breast cancer, pancreatic cancer?

• 1:05:01Speaker 01

  Okay, so let's start with what a CAR-T is. A CAR-T is, so remember we said T-cells are able to recognize cancer cells and kill them, provided that the cancer cell doesn't have enough flags on its surface that prevents it from being recognized. Okay, so we get that. That's standard immunotherapy. Ketruda is one example of that. There are other ones. Okay. A CAR-T is a slightly different variant of that. A CAR-T is a variant in which I say, okay, I'm going to override all of those signals.

• 1:05:39Speaker 01

  I'm going to take cells from your body, genetically modify them to recognize cancer cells using a genetic modification system based on a virus. The virus just basically inserts a gene into the T-cells. I'm going to grow those T-cells, either in the body or outside the body, re-inject them in the body or change the T-cells in the body. And now those weaponized, very important word, weaponized T-cells will go and kill your cancer.

• 1:06:18Speaker 01

  This has been a great success in leukemias, B-cell leukemias, and B-cell lymphomas, producing not just small cures but durable cures. Just as a plug for one of the things I do, I created one of the first CAR-T cell companies in India, where we sell the therapy for 1/20th the price that is available in the United States. We've treated almost 150 odd patients, maybe coming up to 200 soon. So, that's what a CAR-T cell is. Now, your question is, why can't we do that for colorectal cancer and other tumors, like brain tumors?

• 1:07:03Speaker 01

  The answer is quite subtle. And if you're a listener to this podcast, I want you to pay very attention, very close attention to the subtlety of the answer, because the answer is extremely subtle. Why could we cure B-cell lymphomas and B-cell leukemias? And why have we struggled to cure brain cancer and others with these CAR-T cells, which are weaponized T-cells, which ignore, by the way, ignore all these red flags from cancer cells, they just go kill them? The answer lies in the fact that no one, and I'm sure that no one in your program

• 1:07:44Speaker 01

  has really talked about it, and very few people talk about. So, the CAR-T cells that kill B-cell leukemias and lymphomas don't just kill B-cell leukemias and lymphomas, they kill all B-cells. I'm going to repeat that fact. They don't kill B-cell leukemias and lymphomas, they kill all B-cells. And it just happens to be the case, for reasons that we don't know, evolutionary reasons and others, that human beings can live with B-cells killed.

• 1:08:28Speaker 01

  The problem, and that's great, for so for B cell leukemias, B cell lymphomas and other cancers.

• 1:08:33Dr. Peter Attia?

  But we can, we can, a woman can live without any mammary tissue.

• 1:08:37Speaker 01

  So for instance.

• 1:08:38Dr. Peter Attia?

  Why can't we just, yeah, let's kill every breast tissue in her body when she has breast cancer.

• 1:08:43Speaker 01

  A woman could live without her ovaries if, I mean, pleasant thought, but a woman could live without her endometrium. Not a pleasant thought, but yes.

• 1:08:52Dr. Peter Attia?

  Yep.

• 1:08:53Speaker 01

  So CAR T cells really should be thought about as lineage, not cancer specific.

• 1:09:00Dr. Peter Attia?

  Yep.

• 1:09:01Speaker 01

  Lineage and tissue specific ways of killing cells. Now, you can't live with, obviously, one wonders, but obviously you can't live without a brain. So you can't create a CAR T cell out to a brain cancer because your brain cancer will almost certainly be almost similar to a normal brain cell. But you can live without an ovary, you can live with an endometrium.

• 1:09:26Dr. Peter Attia?

  You can, you can live without a pancreas if push comes to shove.

• 1:09:29Speaker 01

  Live without a pancreas, you can live without a prostate.

• 1:09:31Dr. Peter Attia?

  Yep.

• 1:09:32Speaker 01

  You can live without, so there are a bunch of tissues that you can live without. We just need to find CAR T cells to be able to kill those cells.

• 1:09:41Dr. Peter Attia?

  And what's limiting us? What, do you believe that there are unique antigens on mammary cells, pancreatic cells?

• 1:09:49Speaker 01

  No belief here, we've studied this to the nth point. And the answer is yes, there are.

• 1:09:56Dr. Peter Attia?

  So then there's no physical reason why we should not have a CAR T cell against breast cancer then?

• 1:10:03Speaker 01

  Uh, breast cancer is a hard example, you've chosen a particularly hard one. Pancreas is a hard one because there's, you know, there's not, there are not very many unique antigens in a pancreas cell that is not present in normal cells. But I'll give you an example that's not so hard, ovary. Ovarian cells, which really ovarian, ovarian cancer cells, which really are fallopian tube cells. We now know that ovarian cancer is not an ovarian cancer, it's really a fallopian tube cancer. Long story, we can talk about it later, but ovarian cancer cells have an antigen, it's very well known. Have more than one antigen and there are multiple attempts at making CAR T cells against them.

• 1:10:47Speaker 01

  One of them is going to be successful.

• 1:10:51Speaker 01

  But example.

• 1:10:51Dr. Peter Attia?

  What, what percentage of pancreatic cancers have KRAS mutations? Aren't most of them?

• 1:10:56Speaker 01

  Most of them have KRAS mutations.

• 1:10:57Dr. Peter Attia?

  And does, does the KRAS mutation produce an antigen that we could target with a CAR T?

• 1:11:03Speaker 01

  Not, not really. It produces an antigen in some patients, but most of KRAS is, is hidden inside. Most of KRAS is not a CAR T target. Now, KRAS, told my KRAS, KRAS is a great target for small molecules that shut off its function. So now we're not talking about the immune system, we're talking about small molecules, locks and keys, keys that go and shut off the lock. Daxon Racib, nasty side effects, you've seen the senator with, you know, those lesions in the face. I'm sorry about those nasty side effects, we'll get over, I think we'll get over most of them. Not, not get over, but as in find new medicines that, that, that no longer have those effects.

• 1:11:48Speaker 01

  But yes, KRAS, I think the way to attack pancreatic cancer is either to find a unique pancreatic antigen that a CAR T can attack. And if it takes all of the pancreas away, great. People with type one diabetes have no pancreas or they have no.

• 1:12:05Dr. Peter Attia?

  Effectively, no, no endocrine, yeah, yeah, no endocrine.

• 1:12:08Speaker 01

  Endocrine pancreas, yes. People with a Whipple surgery.

• 1:12:11Dr. Peter Attia?

  Yeah, they lose enough pancreas, I mean, if you had, plenty of patients have Whipple's with a significant, yeah.

• 1:12:16Speaker 01

  No pancreas. So yes, so we, so yes, if you could eat up every pancreatic cell and people would still live, yes. But we haven't found one yet. That's one direction we could go in. Another direction we could go in and say, listen, we, we can't eat up the whole pancreas, including pancreatic cancer. But we can shut off the gene that drives pancreatic cancer KRAS. Daxon Racib does that, nasty side effects, but maybe we can live with that. And then, and that's another, that's another direction to go.

• 1:12:47Dr. Peter Attia?

  What do you think it is about? Sorry, go ahead.

• 1:12:51Speaker 01

  That's not immunotherapy.

• 1:12:52Dr. Peter Attia?

  Yes, yes, correct. What, what is it you think about pancreatic cancer that makes it so devastating, right? So, you know, there's an argument that's been made, and I'm not sure I agree with it, by the way, but I've heard it made by some, which is any patient who is alive five years after they were diagnosed with an adenocarcinoma of the pancreas, didn't have an adenocarcinoma of the pancreas.

• 1:13:15Speaker 01

  Oh, I thought too.

• 1:13:16Dr. Peter Attia?

  Right, so, so the, so the, the argument that those people are making, which again, I don't personally agree with, and that's probably my bias coming from a surgical program that treated this, was that their argument is there is no such thing as early detection of pancreatic cancer. The moment that cancer is present, it is a fait accompli, it has spread, you are dead. The other argument would be, the whole study and argument would be, no, if you catch this at an early, early, early stage one and you do the appropriate Whipple procedure, a subset of these patients can live. And yes, it's probably only 5% that will be surgically cured of all comers. But if we could detect of those 95% who were caught too late, could we catch them earlier? Where do you sit on this spectrum?

• 1:14:01Speaker 01

  So look, I mean, so I agree with you on this, I think, so, so as you know, the pancreas is a long organ. It looks like a big leaf. It's sitting sort of in your, in your gut. They're fundamentally speaking, there are two kinds of pancreatic cancer head. The ones that in the head, one in the tail. So if you think about it as a leaf, the ones that in the head are closer to the parts of your intestines, the ones that in your tail are further away. The tail ones tend to be detected incidentally. The head ones tend to be detected with pain and jaundice and other things. I think that surgically speaking, if you, if you can find the ones in the tail,

• 1:14:43Speaker 01

  they're less involved, they're less involved with other organs in your, it's an anatomically distinct kind of cancer. So I think surgically speaking, those, some of those patients can actually live longer. And I agree with you, the ones that in the head, the problem is that it's all, there's a lot of anatomy there. Your intestines are going down, your blood vessels are crossing. It's in a place, it's sort of like in the, it's like, you know, it's like a, it's like a traffic accident.

• 1:15:13Dr. Peter Attia?

  It's probably the most complicated real estate in the entire avenue. Below the neck, below the neck, I would say it's the most complicated.

• 1:15:21Speaker 01

  Yeah, there are two, there are two, there are three truly complicated real estates in the body. One is right here, one's right here, and the third one is right there. So real estate wise, you know, it's like the traffic intersection of everything going everywhere. And you have an accident. And that accidents, it's not, that accident ain't going to resolve easily. So yes, you're absolutely right, there's surgical cures of patients with, I've, I have patients who lived 10 years with a tail pancreatic cancer, not in the traffic accident area, far away from it, had a Whipple.

• 1:16:01Dr. Peter Attia?

  And it was incidentally found and?

• 1:16:03Speaker 01

  Incidentally found and, and so, so, so the answer is yes, it depends on the anatomy. Now, by the way, what we don't know, and here's what's important.

• 1:16:15Speaker 01

  So cancer therapy almost always moves in the following way, and you need, again, your listeners need to know about this. We can talk about longevity later or in a different podcast. But listen, cancer therapy almost always begins with therapy directed against diffuse metastatic cancer. So the senator has diffuse metastatic prostate cancer, is on the drug, is living, great. The next step in, in cancer therapy is to take patients, take most of their cancer out surgically

• 1:16:55Speaker 01

  and then give them the therapy after most of the cancer has been treated surgically or with radiation to now, now kill the remaining cancer cells. And that's called adjuvant or neo-adjuvant therapy. Adjuvant because it is an, an accompaniment to the main therapy in which case, which, which in this case was the removal of the bulk of the tumor. The real interesting question is what's Daxon Racib going to do to adjuvant therapy? So a patient comes in, not the senator, the patient comes in, has painless jaundice,

• 1:17:35Speaker 01

  classic example of pancreatic cancers, found to have a big lump goomba in the, in the traffic intersection of all of this, goes through Whipple. Now, most of the visible cancer is out. And now we put them, they have KRAS mutation, we put them on Daxon Racib, then ask the question, are they better or worse off?

• 1:17:58Dr. Peter Attia?

  Is that trial, is that trial being done?

• 1:18:01Speaker 01

  It'll be done if, if it's not.

• 1:18:03Dr. Peter Attia?

  I mean, is it in the works is what I mean, is it?

• 1:18:05Speaker 01

  It is in the works, absolutely.

• 1:18:07Dr. Peter Attia?

  Yep.

• 1:18:08Speaker 01

  In, in thousand ways.

• 1:18:09Dr. Peter Attia?

  And by the way, that's, I mean, that's such an important example of a principle in oncology that has some exceptions, but not many, which is.

• 1:18:20Speaker 01

  Some exceptions, but not many.

• 1:18:21Dr. Peter Attia?

  The burden of the tumor matters. A lower burden of tumor is a higher probability of success. Again, we can think of a few exceptions, papillary thyroid of the cancer doesn't seem to matter. These handful of really remarkable checkpoint inhibitors often don't matter. But for the most part, fewer tumor cells is a better outcome and it's a greater.

• 1:18:42Speaker 01

  And, and, and this is, this is where, again, our friend Berberstein says, says it very succinctly. He says that there are three zeros between 1 million and 1 billion. And that means if you, if you have 1 billion cancer cells and you take them out and there is only 1 million left, that means that there's one in a thousand, you've reduced the chances of one in a thousand that you'll have a cancer cell that's resistant to your therapy by 1,000.

• 1:19:14Dr. Peter Attia?

  Huge.

• 1:19:15Speaker 01

  Like by 0.001 degrees, whatever you want to call it.

• 1:19:21Dr. Peter Attia?

  Yeah, yeah.

• 1:19:23Dr. Peter Attia?

  You touched on something at the outset, Sid, that I am not seeing enough hoopla about this, and that is the staggering and upsetting rise of colorectal cancer in young people. Now, I've taken an unbelievable amount of shit for this personally over the past 10 years, which is driving towards earlier and earlier initial colonoscopy. And it's been very pleasant to see that the formal recommendations have now moved from 50 to 45. But if you do the math, you'll realize there are still many people dying of colorectal cancer under the age of 45. And therefore, I believe that really, we should start screening even average-risk adults at 40, and obviously, earlier if they have any of the known hereditary drivers.

• 1:20:08Dr. Peter Attia?

  I know why questions are a fool's errand at times, but as an epidemiologist, if I ask you to put on your epidemiology hat, what are some of the possible explanations for why this particularly lethal cancer, it is the third-leading cause of cancer death, why are we seeing this go up? Is it antibiotic use, gut health, obesity? You know, where do you think the culprit is?

• 1:20:34Speaker 01

  So if I was to be totally honest, I would say I don't know the answer. If I was to be a little bit more speculative, I would say it has to do, our colorectal milieu is rapidly changing, and has rapidly changed in the last few decades.

• 1:20:54Dr. Peter Attia?

  Uh huh.

• 1:20:55Speaker 01

  We are ingesting more and more forever chemicals, and there is strong evidence from animal models that some of these forever chemicals, including the ones that are ingested in food, are very pro-inflammatory. So it brings us back to the inflammation theory of cancer. We have strong evidence that these are multiplied by changes in the microbiology of the gut, the gut microbiome, which is being disrupted by all sorts of things, antibiotics and other foods included.

• 1:21:34Speaker 01

  And this is, I'm sorry, this is, again, maybe for your audience, uncomfortable territory, but Burkitt, Dennis Burkitt, who went to Africa, the person who discovered Burkitt's lymphoma, went to Africa in the 1950s, 60s, I don't remember when, but from Oxford. And he said that he virtually found no evidence of colorectal cancer, especially in young men and women, because the diet was so fiber-rich that virtually everyone was essentially evacuating their colorectal...

• 1:22:16Dr. Peter Attia?

  Contents.

• 1:22:18Speaker 01

  Content, twice a day. In the United States, we've reached a place where we're doing that once every two days or three days. So my recommendation for people who want to avoid colorectal cancer is triple or double your fiber intake, obviously, reduce exposure to these forever chemicals, and based on no evidence whatsoever, use probiotics to, and probiotics are cheap, I don't mean go buy like very fancy, I just mean have live yogurt.

• 1:22:54Dr. Peter Attia?

  Yogurt, yeah.

• 1:22:55Speaker 01

  Yeah, at least once a week so that you can replace your probiotics.

• 1:23:00Dr. Peter Attia?

  So we've touched a little bit on AI, and I know that it's something that we are both thinking a lot about. I want to talk about it through the lens of maybe drug discovery. So you've already given a great example of how AI can do things on a CT scan read that no human can do. And of course, there are lots of reasons for why CT scans are a beautiful environment for AI to shine. But let's talk a little bit on the drug side. Now, AlphaFold, the company that has garnered a lot of much-deserved credit for using AI to be able to predict the sequences of amino acids, which has allowed them to more rapidly develop drugs. This is a very exciting area.

• 1:23:44Dr. Peter Attia?

  So if we would say this is one area in which AI is going to fundamentally change drug discovery, you could say, okay, another area would be AI could help us propose better hypotheses and/or design better experiments. That would be fantastic.

• 1:24:00Speaker 01

  Different idea.

• 1:24:01Dr. Peter Attia?

  Different idea. And then a third idea, and this is the one that I think personally is the biggest unlock, is having real simulated biology that would dramatically shorten the preclinical period, but more importantly, increase the probability of success as we go from preclinical to clinical. And then potentially, a fourth layer would be extracting better insights from the actual clinical trials to speed things up. So are there other areas you're thinking about this in? And then which of these do you think is the biggest unlock?

• 1:24:34Speaker 01

  I think all of them are big unlocks. I don't think any of them is any less unlock than the other. I think we need the entire ecosystem to unlock, because every one of these is a potential unlock. I'll just give you a couple more unlocks. I'll give you one example in the beginning, which is using AI as an epidemiological scanning tool. So that's how we, that's how researchers found the Thymus correlation, right? AI for the recruitment of clinical trials, we have talked about that. AI for the monitoring of clinical trials, we have talked about that. So it's AI all the way.

• 1:25:14Speaker 01

  My personal arena has been AI in drug discovery. So as you very well know, every medicine, every drug, aspirin, Lipitor, you know, Prozac, works by binding to something. It's a key and a lock, lock and a key. The protein that it binds to is the lock, and the drug is the key. It opens or shuts down some function of the protein. Lock and key is a little bit misleading, because the proteins are actually moving in

• 1:25:56Speaker 01

  space, they're wriggling around, so it's a wriggling lock. And so the key has to be a little bit of a wriggle of a key that goes in, but basically, it's all, aspirin is a key, I know the lock, Lipitor is a key, we know the lock, Prozac is a key, we know the lock, and so forth. All right. So in the past, we had two ways of looking for keys. Either we could design them from scratch, so we could look at the protein and say, what is likely to look like a key? And we needed an enormous amount of knowledge of chemistry and chemical biology to do that.

• 1:26:38Speaker 01

  This is why, you know, the smartest chemists in the world were required to create these keys to the lock. And another way to do this is to take, is to do it a little bit more like a search function. So let's make a library of a billion keys and try to see which one fits. Now, both of those, the first one I'll call synthetic molecular design, generative molecular design, and the second one I'll call search-and-fit molecular design, both of them are very amenable to AI and computation. So search-and-fit is a little bit harder, because it's, the number that I quoted to

• 1:27:23Speaker 01

  you, a billion, is not a billion, it's actually 10 to the power of 20.

• 1:27:27Dr. Peter Attia?

  Which is not, that's technically not computational, is it?

• 1:27:31Speaker 01

  That is technically beyond the level of any computational...

• 1:27:35Dr. Peter Attia?

  So there must be an inference that allows this to happen.

• 1:27:38Speaker 01

  That's right. You have to do some inference that allows it to happen. That's right. So you have to have an inferential way of taking, so in other words, let's boil it down to simple language, you start with some keys, and you begin to infer the properties of the key based on what fits and doesn't fit. It's turned out that that is computationally too expensive right now, and it probably require, I mean, this is my guess, it will require quantum computers able to do that, that level of inferential reasoning, because you probably need to fit at least a billion keys to learn

• 1:28:20Speaker 01

  enough about the kind of key that you need to really open the lock.

• 1:28:25Dr. Peter Attia?

  Which is amazing, because it's really, it's more than a billion billion, so that's a huge shortcut.

• 1:28:33Speaker 01

  It's more than a billion billion.

• 1:28:36Dr. Peter Attia?

  But that's still an enormous undertaking.

• 1:28:38Speaker 01

  Yeah.

• 1:28:39Dr. Peter Attia?

  Yeah.

• 1:28:40Speaker 01

  The second way, which is the usual way that, you know, that we are doing drug discovery, is to look at the inside of the lock.

• 1:28:50Speaker 01

  And ask the question, what kind of key will fit into this lock?

• 1:28:56Speaker 01

  How do I design a key? And synthetic molecular chemists working in laboratories, in pharmaceutical companies, et cetera, they have rules. They know that if, you know, if there's a, if there's a crevice here, I'm going to put a certain kind of molecule there. If there's a hollow surface there, I want to put a certain kind of molecule there, et cetera, et cetera. So this is called, this is generally speaking, it's generative chemistry. Generative because you're making it from scratch. You're not just searching and fitting. But you, you need to know the rules of chemistry and physics. This is not biology anymore.

• 1:29:39Speaker 01

  This is pure chemistry and actually really is pure physics. The good news is that you can teach an AI all those rules. And that's what we've done at Manus. We've taught AI all the rules of synthetic molecular chemists and said, let's take one synthetic molecular chemist and make them into 50,000. Because that's what AI does. AI can scale. And if you have one, you can make 50,000.

• 1:30:12Speaker 01

  And so the answer to the question is, we, that is what we do. We take, we, we look at the shape, the geometry, the electrostatics, the, all the elements that form the pocket where you want to put your key. And we design a key from scratch using basic molecular principles. And if you can do that, you can essentially recreate, you can make the smartest generative molecular chemist that ever lived.

• 1:30:45Speaker 01

  And the last plug I'll make for this is that this is the best, to me, the best use case, proximal use case of good AI in the world. This is not a chatbot. It is not a image making bot. It, it is making medicines for human diseases.

• 1:31:06Dr. Peter Attia?

  How difficult do you think it will be to teach AI the rules of biology to thereby simulate actual experiments? I mean, you, you very briefly touched on how much more complicated biology is than physics or chemistry. The rules are not as neat. So is this?

• 1:31:29Speaker 01

  There are barely any rules.

• 1:31:30Dr. Peter Attia?

  Yeah. So is this, is this actually something we can aspire to?

• 1:31:35Speaker 01

  Yeah, I, I think it will come. I'm a little, look, I'm personally skeptical of how useful it's going to be. Because, look, the biology of a kidney cell, a kidney cell has a very particular biology. Its job is to filter out salts.

• 1:31:55Dr. Peter Attia?

  Right, it's quite well known. Like, we actually, it's very discreet.

• 1:31:59Speaker 01

  A cell in your brain has no resemblance.

• 1:32:02Dr. Peter Attia?

  Right.

• 1:32:03Speaker 01

  It has some resemblance, of course. Metabolitics is a saying, blah, blah. But its job is completely different. Its job is to transmit information, sequester information, storage, whatever it might be. Right? A cell in your skin is a completely different kind of cell. So I'm a little skeptical of.

• 1:32:22Dr. Peter Attia?

  And it's also, just to add one more layer there, Sid, sorry to interrupt. It's, it's that there are certain cells in the body, like a muscle cell, where it's, there's a very mechanical and relatively straightforward functional determination of what it can do. Whereas the neuron, just to use that example again, completely different. Like, what's happening in the neuron is not as mechanical as what's happening in the myocyte or what's happening in the nephron, where you can actually just see, oh, this ion moves through this channel against this gradient. And when this gradient switches, it does this.

• 1:32:54Speaker 01

  Yeah, so, so, so listen, I think there's some, there's some use to building biological models of cells. Do I think it's going to be easy? No. Do I think it's going to be, until you get down to every, you know, cell by cell level? Is it going to be, is it going to work? No, I'm a skeptic, but, you know, skeptics are often wrong.

• 1:33:16Dr. Peter Attia?

  Sid, if we're sitting here in 15 years, which I, I hope we are going to be, both you and I personally, sitting here having another discussion in 15 years, looking back and saying, God, I can't believe it was 30 years ago you wrote Emperor of All Maladies.

• 1:33:30Dr. Peter Attia?

  If you had to predict what we're going to say in 15 years that is true about cancer, that is not yet true today, what do you realistically think that might be?

• 1:33:41Speaker 01

  Oh, I think that, you know, we've covered a lot of it. New antigens, new theories of how cancers arise because of inflammatory states or other states, the role of obesity, the role, I mean, all of this will become clear, you know.

• 1:33:58Dr. Peter Attia?

  Where do you think it will translate to the most life saved? Do you think it will be that, do you think there's a chance in 15 years?

• 1:34:08Speaker 01

  The answer is always going to be prevention. So the answer is always going to be prevention. Now, the, the question, that's a real question, is can we do general prevention? Is prevention some kind of like habit change, behavioral change, lifestyle change? Or is it chemoprevention?

• 1:34:26Dr. Peter Attia?

  I was just about to say, will there be a drug? Just as I can give you Lipitor today, long before you have a heart attack, and I can give it to you with an ACE inhibitor if your blood pressure is high, these two molecules will prevent you from having a heart attack. It's chemoprevention. Do you actually think there will be a day when we have molecules that will prevent cancer?

• 1:34:50Speaker 01

  Yes, there will be chemoprevention. I just, I, it is not clear to me that the chemoprevention is going to be, it's not clear to me that chemoprevention is going to be as simple. So remember, Lipitor blocks, decreases your LDL levels. And losartan or whatever ACE inhibitor or ARB inhibits your capacity to have high blood pressure by acting on your kidneys hormonal system. It's not clear to me that it's going to be sort of a, a relationship that's like that.

• 1:35:29Dr. Peter Attia?

  Although what you described with inflammation, there's, there's actually, there's actually an analogy in cardiovascular disease. As I'm sure you know, we are now starting to check for chip in patients.

• 1:35:40Speaker 01

  Yes.

• 1:35:40Dr. Peter Attia?

  And while our therapies are still limited, we have colchicine. Now, it's a crude drug, but there's evidence that if you have, you know, if you're.

• 1:35:50Speaker 01

  We have that as an otocine, by the way.

• 1:35:52Dr. Peter Attia?

  Yes, I'm saying in the, on the cardiovascular side, the, but, but I think that there's, this is an opportunity in cardiovascular medicine to go after residual risk, where you identify clonal hematopoiesis in a patient that's posing risk for CVD. We treat that preemptively. And that's really our first immune based therapy for heart disease. So there's a model, I think, that I would be very excited if we're doing that in 15 years for oncology.

• 1:36:18Speaker 01

  Yeah, I mean, you know, as I said, we have, and we have some tools. We have the GLP-1s, for instance.

• 1:36:22Dr. Peter Attia?

  Yep.

• 1:36:23Speaker 01

  In obesity and potentially in, in inflammation. So that's a trial that I would like to watch very carefully.

• 1:36:30Dr. Peter Attia?

  I hope, I hope someone listening to us today, by the way, has taken, has, has become motivated by that idea.

• 1:36:36Speaker 01

  Yeah. And, you know, you can use, you don't have to go all the way. You can use breast and endometrial cancer as your sort of two simple, not simple, but two.

• 1:36:46Dr. Peter Attia?

  Models, yeah.

• 1:36:48Speaker 01

  Models, yeah. There are a variety of anti-inflammatories, of which we know some. But again, you know, Peter, I know you care about things like longevity and, and I do too. You're not the only person who cares about longevity, obviously. It may turn out that the answer is orthogonal. It may turn out that the answer is that, and I mean, no, to some extent, this is, we already know the answer to this question, that, again, I'm going to use my worst words carefully here. The prevention of pathological disease.

• 1:37:28Speaker 01

  Cancer, heart disease, the two biggest killers, is not the answer to the prolongation of longevity. So I'm gonna use, I'm gonna say that sentence again. I'm gonna say it very slowly. And I'm happy to have be pushed back on it. The current model of longevity is the prevention of diseases that kill us.

• 1:37:57Speaker 01

  Cancer and cardiovascular, or one current model, not the only current model. But one current model of longevity is the prevention, or the elimination, or the treatment, or the cure of diseases that kill us, of which obviously the two big ones are cardiovascular disease and cancer. But the orthogonal way to look at longevity is to say, I'm not, I'm actually not interested in the diseases, cancer and heart disease, the two most common killers. I'm actually interested in a physiological state that promotes the elimination or the decrease of not just those diseases, but all diseases,

• 1:38:41Speaker 01

  including diseases of degeneration, osteoarthritis, immune failure, bone marrow failure, in, inflammatory, chronic, unopposed inflammation, etc. That's a question which is a deep, deep, deep question. And when I say orthogonal, I mean, maybe if we could reduce, if we could change the physiological state of the body, reduce the inflammatory state, reduce the chronic insulinemic tone. And there's a big maybe there, because otherwise everyone's gonna come and attack me and tell me I'm a crap pot.

• 1:39:26Speaker 01

  But maybe it is that the reduction of the chronic inflammatory insulinemic tone and the chronic tone that comes from thymic reduction. I mean, all the things we talked about before. A wellness instead of illness. Maybe that's the path to longevity.

• 1:39:51Dr. Peter Attia?

  You know, Sid, I think about this all the time and

• 1:39:54Speaker 01

  I know you think about this more than I do.

• 1:39:56Dr. Peter Attia?

  No, no, no, but so I'll, yeah, I'll share my thoughts. So I, I agree with, with the broad statement, for sure. My concern is that different diseases behave differently. So when it comes to atherosclerotic cardiovascular disease, which is indeed the number one killer, not just in the US, but globally, there is actually a world in which we can turn that into an orphan disease. Because the causal drivers are well known and we have treatments for all of them.

• 1:40:24Speaker 01

  You could take, you know, you could take aspirin, Libitor, and, you know, BCSK9, you can take like 17 drugs now.

• 1:40:29Dr. Peter Attia?

  That's right. You, so if you don't smoke, if you take whatever drugs are necessary to stay insulin sensitive, if you obliterate your APOB and LDL-C down into the physiologic levels you were born with, and if you ever develop hypertension, you immediately nip it in the bud with a drug, you're, you can't get heart disease, you just can't. The, the pathophysiology inside the artery wall can't happen. So you're gonna die of something, but it won't be the number one cause of death. I don't have that degree of confidence that there's anything we could do that will eliminate all cancers. So even if we were completely insulin sensitive and we never smoked, and et cetera, et cetera, et cetera,

• 1:41:11Dr. Peter Attia?

  we still have enough genes, we still have random mutations. We still need to rely heavily on early detection and treatment.

• 1:41:22Speaker 01

  All fair, all fair, except, let me give you the only counterfactual to that, which is that people who are super, supergenerians.

• 1:41:34Dr. Peter Attia?

  Yes.

• 1:41:35Speaker 01

  People who, you know, more than

• 1:41:36Dr. Peter Attia?

  Hundred and ten, yep, hundred and ten.

• 1:41:39Speaker 01

  They don't die of cancer. What they're dying of is failure of skin regeneration. Their skin falls off. They're dying of bones being broken. Basically, that they're dying of regenerative failure.

• 1:41:55Dr. Peter Attia?

  But they also, they, believe it or not, they still die of atherosclerosis and they still die, they still die of infections, like their, their immune cells are breaking down, yeah.

• 1:42:04Speaker 01

  Infection is immune failure.

• 1:42:05Dr. Peter Attia?

  Yes, yes, yes, yes.

• 1:42:07Speaker 01

  So, so, but, but what they're not dying of, I mean, assume, assume for a second that they took, you know, every anti-atherosclerotic drug, which they don't, by the way, because they're in Greece or some island in Porfu or some, you know, somewhere else, God knows. But what they're not dying of is cancer. They're dying of bone breaks and skin failure and immune failure and blood failure and, you know, all of these other things. That's the only, that's the important counterfactual I'll present to you, which is to say that there are two worlds. It's almost like there are two worlds.

• 1:42:48Speaker 01

  There's one world in which humans die at age 70, 80, 90 of

• 1:42:56Dr. Peter Attia?

  The usual suspects, yeah.

• 1:42:57Speaker 01

  The usual suspects, you know, the three major usual suspects. Neurological disease, cancer, heart disease, in opposite order. Yeah, whatever. And there's another world in which, once you're not dying of those diseases, you can sail into your hundreds, not sail, get into your hundreds. And there, your killers are not those diseases. There, your killers are immune failure, blood system failure, bone breakage, basically regenerative failure. You know, I've been writing a lot about, thinking a lot about Eli Metchnikoff,

• 1:43:37Speaker 01

  who, the Russian, Parisian scientist who discovered the innate immune system. And Metchnikoff, in the 1890s, get this, in the 1890s, had a theory, he was the first person to, to propose that we study death systematically. He, he created the, the word thanatology, the study of death, which of course, the opposite of which is the study of longevity. Metchnikoff argued that, that if you could remove the proximal causes, the pathological causes of death, cancer, heart disease, neurological disease, and of course

• 1:44:21Dr. Peter Attia?

  Accidents and infections, yep.

• 1:44:23Speaker 01

  Accident, infections, et cetera, et cetera. That human beings could live to 100, 102, and they would, at some point of time, would lie, would naturally want to die, just like trees at a certain age, hundreds of years, finish their sap and die. It's a, it was a very radical idea in its time. And I often come back to this thought, thinking, maybe that's true. Maybe that's where, maybe that's where we are. Maybe in eventually, we need to think about, instead of thinking about, oh, let's pick off the buds one by one,

• 1:45:08Speaker 01

  atherosclerosis, cancer, et cetera. Or maybe we keep picking off the buds, it's okay.

• 1:45:13Dr. Peter Attia?

  Right, but we need something that goes after the foundation of aging.

• 1:45:17Speaker 01

  We need to go for some, that's the point.

• 1:45:19Dr. Peter Attia?

  Yeah. And And so how, what is your degree of optimism that, because if you, if you, what is the, what is the sort of AI buzz say? That everybody's saying, look, AI is gonna cure this. We're going to be immortal. We just have to not die for the next 10 or 15 years and we're gonna become immortal. And I'm struggling to come up with a steel man for that argument.

• 1:45:41Speaker 01

  No, no, no, no, no. You know, I think, as I said, regenerative failure is a real phenomenon. And treating regenerative failure is not easy. It's gonna be another, that is a huge new frontier in biology. We haven't even faced that frontier in biology. Why do, what is, you know, what is regenerative failure of cartilage? I don't know. But what is regenerative failure of the brain? I don't know. What is regenerative failure of the immune system? Okay, fine, there's no thymus. How can I make a new one? I don't know. So the new frontiers of longevity

• 1:46:26Speaker 01

  will have to deal with not just sort of, oh, you know, let's change our diet and make ourselves, I don't know, somehow dietary perfections or inject ourselves with some random peptides and make ourselves, by the way, everyone knows this, but let me just remind you, there are 20 amino acids per individual molecule. So the combinatorics of injecting yourself with pep, with a random group of peptides, the chances you'll find the right peptide at the right concentration are basically zero, like zero, not, not, it's like, there's no, the mathematics, this is a mathematical truth.

• 1:47:12Dr. Peter Attia?

  Well, it goes, it goes back to what you said about the billion, billionth chant, like a billion, billion chances, it, it, yeah.

• 1:47:18Speaker 01

  But, but on the other hand, if you find, if you were to find the right peptide, I'd be, I'd be rooting for you, but, not you, but rooting for the person who found the right peptide, but great. Listen, the, the problem is that, yes, I think there is a hack, as the Silicon Valley people wanna call it, to longevity.

• 1:47:41Speaker 01

  The hack, but the hack is not just a simple hack. It's not gonna be peptides. It's going to be finding out systematically how to address these regenerative failures

• 1:47:55Speaker 01

  and separate it out from the diseases that kill you at 70 and 80. Let's separate those out.

• 1:48:01Dr. Peter Attia?

  Yeah, we need, we need both of these happening in parallel, for sure.

• 1:48:05Speaker 01

  Open peril, right? So you remove the diseases, and you have a good example. Atherosclerosis is a good example, right? You remove atherosclerotic, atherosclerotic heart disease using all the mechanisms, all the medicines that we have now, including behavioral change, most importantly, behavioral change. And then you're left with the question of regenerative failure. And that's not a hack. That is a powerful systematic study of how you will remove the regenerative failure of people who are in their 70s, 80s, 90s, including the regenerative failure of the brain, which we know the least about.

• 1:48:48Speaker 01

  And yes, then I can conceive of physical longevity. Now, there's a whole other world in which you can talk about virtual longevity.

• 1:48:58Dr. Peter Attia?

  Sure, sure, yeah.

• 1:48:59Speaker 01

  That's a different, you know, that's a, you know, matrix, red pill, blue pill.

• 1:49:03Dr. Peter Attia?

  Yeah, beyond my pay grade.

• 1:49:04Speaker 01

  It's beyond my pay grade, but, but, but, but it's true. Fair enough. You can, you can imagine there is a red pill, blue pill, matrix longevity universe that you no longer, you no longer need your physical body, or maybe robotics takes over most of it. God knows, maybe you're a brain in a box or whatever. There are a thousand, let's just put those aside for a second. I'm just talking about the physical body. And I think that those are not hacks. These are, they need systematic. And we're beginning to find out, AI is helping us find out. I give you one example, but there are many.

• 1:49:40Dr. Peter Attia?

  But this is not really a priority of the NIH. I mean, the NIH is not putting the resources into studying the hallmarks of aging and geoscience. Because to your point earlier, Sid, if you want to start answering these fundamental questions, you must do them systematically, right? And you started with a human observation. It's a very important human observation. Now we need to go back and do the animal models that begin to look at the ways that one could actually perturb that system. And then, of course, you bring that full circle back into humans. But this is very big science. This is a Manhattan Project of science.

• 1:50:18Speaker 01

  I would make, I would argue that it nearly lies outside the current NIH mandate. And we need a new NIH, if we were to do this, which we should or could, it needs a new NIH mandate. The problem with geoscience is, remember, again, history is very important here. What changed, what really changed cardiovascular science? It was the fact that we found biomarkers for.

• 1:50:49Dr. Peter Attia?

  They were proxies for disease. You can measure blood pressure, you can measure cholesterol.

• 1:50:53Speaker 01

  You can measure blood pressure, you can measure cholesterol. And very soon, we said, we don't need to wait for heart attacks. If there's a drug that reduces blood pressure, if a drug that reduces cholesterol, we will make that drug available. And in post hoc studies, we found that those medicines actually reduce heart attacks.

• 1:51:11Dr. Peter Attia?

  Yep.

• 1:51:12Speaker 01

  You don't have that for cancer. And let's just have a question.

• 1:51:16Dr. Peter Attia?

  You don't have it for aging.

• 1:51:17Speaker 01

  Longevity.

• 1:51:18Dr. Peter Attia?

  Right.

• 1:51:18Speaker 01

  Yeah. So you, you know, there's talk of biological flocks, there's talk. So, so here's my question back to people who study longevity science, an important science, very important science. Find me a reliable biomarker. The problem with finding me a reliable biomarker is going to, is that the biomarker study itself will take 15, 20, 30 years. Cause you can't do it retrospectively. You could do it sort of retrospectively. You could say, what is there in the blood of people who live at 100?

• 1:51:50Dr. Peter Attia?

  Yeah, and we can start with, I mean, and I've talked about this with others on the podcast. I mean, we could go back and look at the interventions testing program, which is that great NIH program that looks at all the molecules. You could, you could just begin by looking in the metabolome and the proteome of all the ITP winners versus losers, and we could at least get some clues. But yes, just finding the biomarker is big science, is very big science.

• 1:52:16Speaker 01

  Very big science, it's very big science, and it's, it's reliable science. The only problem with it, or the question with it that I would argue is that we can't screw it up. Because.

• 1:52:28Dr. Peter Attia?

  Right, it sets the trajectory of where we're going.

• 1:52:30Speaker 01

  It sets the trajectory indefinitely. So we need to find it, confirm it, find it. And once we found it, again, remember lipitor, remember cholesterol, remember hypertension, you can do dozens of studies to think about a systematity. But until that's found, we're sort of stuck.

• 1:52:55Dr. Peter Attia?

  You know, it's funny, just a couple of weeks ago, I was talking to a friend of mine, who I'm sure you know, David Sabatini, good friend of Lou's.

• 1:53:01Speaker 01

  Yes, and a friend of mine.

• 1:53:03Dr. Peter Attia?

  And, and so David was lamenting this. He said, look, what we really need is a Manhattan Project around this. And his view is it's not going to be the NIH stepping up. It's going to be a group of philanthropists that decide that we need to put money. But, but his point, which I think is absolutely spot on, is the effort must have a significant engine in the basic science. It cannot go straight to drug discovery, which is the temptation. When these things are started as for-profit companies, you have to return to shareholders quickly. You've got to go straight to drug discovery and whack a mole. Whereas David's view is, and I think he is correct, you have to have a continuum, and you must have basic science.

• 1:53:47Speaker 01

  He's absolutely correct. And not only that, he's absolutely correct, because you know, again, the, the loop is quite clear. You start with human observation, you go backwards, you, you understand the, the basics. And, and David's absolutely correct. And you know, you know, he's been studying this for years with Lou, with me, with others. There's no short, unfortunately, there's no shortcut. And this is not a drug discovery.

• 1:54:11Dr. Peter Attia?

  That's right.

• 1:54:11Speaker 01

  This is a cholesterol discovery project. This is a hypertension discovery project.

• 1:54:17Dr. Peter Attia?

  Yeah.

• 1:54:17Speaker 01

  And unless we discover cholesterol, hypertension, et cetera, for aging, we're, we're going to be lost. And it requires a 30-year Manhattan Project, maybe 15 years if we're good with AI. Maybe you can shorten that down. And the NIH has no mandate to, right now, maybe a new NIH will, but the current NIH doesn't have a mandate for doing this.

• 1:54:40Dr. Peter Attia?

  I don't, I don't think the NIH ever will. And I, I, I, I think, yeah, I, I, I think there's many reasons why this is not going to be within the purview of NIH. Unfortunately, it should be, but it won't be. And, and therefore, I think, I think you, me, Lou, David, and the bunch of us are long overdue for a dinner to brainstorm some ideas here.

• 1:55:00Speaker 01

  Well, we're happy to have the dinner. And you know, as I said, if there are people who are truly interested in this without the temptation of, you know.

• 1:55:09Dr. Peter Attia?

  We need a drug, we need a drug within six years.

• 1:55:11Speaker 01

  Yeah.

• 1:55:12Dr. Peter Attia?

  Yep.

• 1:55:13Speaker 01

  If there are people, then, then we should, we, we should really launch this, launch it systematically. You know, there is a natural incidence of aging, as you know. They could, they, they, they could, if they, if they wanted to, they could change some of their focus. And there is a focus on well aging. The problem is the NIH's mandate is illness, it's not wellness.

• 1:55:36Dr. Peter Attia?

  Yeah.

• 1:55:36Speaker 01

  It's not, it's, you know, and that is a great thing. We've done great things with it. And it has produced incredible things from vaccines to, you know, liver tour. Great, that's wonderful. It's not the current mandate.

• 1:55:54Dr. Peter Attia?

  Well, Sid, it sounds like I need to, to, to get up to Boston or New York. And we know, we all need to, we need to grab dinner.

• 1:56:01Speaker 01

  Well, as you know, I mean, this metabolic trial.

• 1:56:05Dr. Peter Attia?

  Yeah, you want to just, I don't know how much you can talk about it. Can you give us, is there anything you can give us?

• 1:56:09Speaker 01

  Well, it's a public company now, so it's all good. But listen, you know, the idea was initially proposed by you to Lou and Luke Handley and to me. And then Luke Handley and I sat down for dinner in a restaurant in the Upper East Side, and on the back of a napkin sketched out a potential strategy, which is basically the idea that cancer cells must depend on particular metabolic inputs, which make them different from normal cells. I mean, know that from Otto Warburg, Warburg's work in the 1900s. The cancer cell, the metabolism of a cancer cell is not the metabolism of a normal cell. And every time you say something is different about a cancer cell than a normal cell,

• 1:56:54Speaker 01

  that makes it possible.

• 1:56:55Dr. Peter Attia?

  It's an opportunity.

• 1:56:56Speaker 01

  It's an opportunity. So in this case, we use that opportunity to make a new, new kinds of drugs that would particularly target cancer metabolism and less so normal metabolism. And that led to a company called Fiyeth, Fyeth Therapeutics. It went public maybe two weeks ago, four weeks, God knows when. But it's in the middle of trials and early trials are very promising. And we'll see, we'll have to see, you know. It's a public company, so I'm actually no longer privy to the internal information. I'm a founder, but Lou is a founder. We, we no longer know anything about the internal information of the company. But the last we heard, the last public disclosures that we heard,

• 1:57:41Speaker 01

  that the, that the idea that targeting cancer metabolism in endometrial and breast cancer was working. So we're happy about that.

• 1:57:50Dr. Peter Attia?

  Well, we will continue to follow that story.

• 1:57:52Speaker 01

  And if it's a success, we, we owe you a dinner in, in Manhattan.

• 1:57:56Dr. Peter Attia?

  Yeah, I remember that, that dinner very well. It was sushi and it was, it was a great sushi dinner. Are you working on another book? You mentioned your writing.

• 1:58:05Speaker 01

  Yeah, I'm working, well, this is why I talk about a lot of this. I'm working on a book on death. And dying and longevity. But not this kind of usual, oh, you know, let's get to, it's the kind of stuff that we talk about.

• 1:58:17Dr. Peter Attia?

  Yeah.

• 1:58:18Speaker 01

  How do we really systematically think about longevity, systematically think about death?

• 1:58:24Dr. Peter Attia?

  What, what is your process for writing? You know, we've, I, I, I'm just going to have to embarrass you a little bit, because it's possible there are people listening to this podcast who haven't read any of your books. I've read all of them multiple times. And I, I'm not just saying this, Sid, I think you are not only a generational talent, you are the single greatest writer I have ever read when it comes to the discipline that I find myself in. And I, and I really mean that, Sid, you, and I think I've told you this before. When I was struggling to write my book, I would curse you constantly and think, god damn it, he does it so well. My book is going to be garbage. I'll never be able to do what he does. And I can't, but that's okay.

• 1:59:07Dr. Peter Attia?

  And I don't want to suggest that you're just gifted and it doesn't come down to how hard you work. But, but my guess is it's a bit of both. I think you have a way with words and you obviously work very hard at it. So tell me a little bit about the process by which you're, you're writing this book.

• 1:59:22Speaker 01

  Look, you know.

• 1:59:25Speaker 01

  It's a, it's a, the first part of the process, and this is what I generally tell people who ask me this question, it's gonna sound like a generic answer, it's not generic, it's real. I think it's very important before starting to put the first word on the page is to spend a lot of time, I call it dream time, people can have different, different words for it, thinking about what the book will sound like, who's driving the narrative? Because there has to be a who, where is it placed? Where, where does it go? Where's the geography? What time is it in? What mood does it convey?

• 2:00:07Speaker 01

  Who's the reader and why is he or she being moved by it? What's the, what's the structure? What's the anatomy? Do we, is it compartmentalized? Or what do the chapters seem like? What do the big sections look like? And I think that before you put the first word down for a book, you should spend months, weeks, years, thinking about all of that. Because that's what's the basis, that's the center of a book. And once you've gotten that piece straight, it turns out that writing a book, I mean,

• 2:00:49Speaker 01

  it's complicated, you know, you put a lot of explanation, blah, blah, blah, blah. But then the book just kind of moves along much more quickly. So in other words, you know, musicians often say this, and you have to listen to the musicians, because of course, there's a lot of closeness between prosody and music. Musicians often say, you need to know the mood of the piece you're playing before you play the piece, long before you play the piece. It's the mood of the piece that's important. The, the notes are just a mechanism to drive the mood of the, of, of the. By the same logic, you need to know the mood of the book. Yes. And the skeleton, once you have the skeleton, you can hang meat on the skeleton,

• 2:01:32Speaker 01

  you can hang pages on words, et cetera, et cetera. So my, my, my advice process, whatever it might be, whatever you're going to, don't write the first word before knowing anything about all of this. Once you know all of this, you can write the first word to the last word for 600 pages, 700 pages, it'll just, it'll just come to you.

• 2:01:56Dr. Peter Attia?

  So your writing, the actual period of pen to paper is, is, is, is short? It sounds like relative.

• 2:02:02Speaker 01

  My writing is, my writing is actually short. And my editing is not.

• 2:02:07Dr. Peter Attia?

  Yeah.

• 2:02:08Speaker 01

  I edit, I edit very great, I, I give time, I have great editors, Nan Graham, has been my editor from day one, she's an incredible editor, one of the story editors, you know, she's edited Pinchon and Roy and Stephen King and God knows what. She's a great editor, we work together. Editing is not a slow, is not a fast, slow process. Writing a book is a fast process.

• 2:02:32Dr. Peter Attia?

  So lots of thinking, speeding through the writing, slow editing.

• 2:02:38Speaker 01

  Yes.

• 2:02:39Dr. Peter Attia?

  Yeah, fast on the straightaway, slow on the curves.

• 2:02:41Speaker 01

  Yep. Hmm. That's what I think about it, yes.

• 2:02:45Dr. Peter Attia?

  Sid, it's always a pleasure.

• 2:02:47Speaker 01

  Always a pleasure, thanks for having me.

• 2:02:49Dr. Peter Attia?

  Thank you so much for everything. This has always been a great discussion.

• 2:02:52Speaker 01

  Great, my pleasure, and good luck, and I owe you a dinner.

• 2:02:56Dr. Peter Attia?

  Talk soon. Thank you for listening to this week's episode of The Drive. Head over to peterattiamd.com/shownotes if you want to dig deeper into this episode. You can also find me on YouTube, Instagram and Twitter, all with the handle peteratiaMD. You can also leave us a review on Apple Podcasts or whatever podcast player you use. This podcast is for general informational purposes only and does not constitute the practice of medicine, nursing, or other professional healthcare services, including the giving of medical advice. No doctor-patient relationship is formed. The use of this information and the materials linked to this podcast is at the user's own risk.

• 2:03:39Dr. Peter Attia?

  The content on this podcast is not intended to be a substitute for professional medical advice, diagnosis, or treatment. Users should not disregard or delay in obtaining medical advice from any medical condition they have, and they should seek the assistance of their healthcare professionals for any such conditions. Finally, I take all conflicts of interest very seriously. For all of my disclosures and the companies I invest in or advise, please visit peterattiamd.com/about, where I keep an up-to-date and active list of all disclosures.