Podcast appearances and mentions of tony wyss coray

The Chief Scientific Advisor at Novo Nordisk, Lotte Bjerre Knudsen, was the key force who pushed hard to develop GLP-1 drugs for treating obesity and subsequently for Alzheimer's. She was recently recognized by the 2024 Lasker Medical Research Award, and the 2024 AAAS Bhaumik Breakthrough of the Year Award. That recognition is richly deserved, since it is unclear if the GLP-1 drug path to obesity treatment, and all of the associated benefits, would have been seen at this time without her influence. That's especially true given the mystery for why people with Type 2 diabetes (for which these drugs were used for many years) did not exhibit much in the way of weight loss. We discussed that and the future of these drugs, including their potential to prevent neurodegenerative diseases. And about dressing up in pink!The Ground Truths podcasts are also available on Apple and Spotify.Our entire conversation can also be seen by video at YouTube along with all of the Ground Truths podcasts. If you like the video format, please subscribe to this channel. Even if you prefer video, please take a look at the transcript with graphics and useful links to citations.A Video Clip below on the barriers of a woman scientist to push Novo Nordisk to develop GLP-1 for obesity. “I was always just been a nerdy little scientist who kind of found home here in this company for 35 years.”—Lotte Bjerre Knudsen, 60 MinutesTranscript with Links to audio and external referencesEric Topol (00:06):Well, hello, it's Eric Topol with Ground Truths, and I have with me a special guest. She's the Chief Science Officer of Novo Nordisk and it's Lotte Bjerre Knudsen, and we're delighted to have her. She's a recent recipient of the Lasker Award, which I think is considered like the pre-Nobel Award here in the United States. And I was involved with her in terms of researching who was the principal person who brought the GLP-1 drugs to the forefront for obesity, and it turned out to be Lotte. So welcome, Lotte.Lotte Bjerre Knudsen (00:48):Thank you very much. And also very, very happy to be here. I'm not the Chief Science Officer for Novo Nordisk, I'm the Chief Scientific Advisor of working for the Chief Science Officer of Novo Nordisk, but maybe too many people, not so different, right?From Laundry Detergents to GLP-1 DrugsEric Topol (01:06):Yes. Thank you, I actually meant to say advisor, but yes, I'm glad you cleared that up. I know from speaking to some of your colleagues, I actually spoke to Robin yesterday that you are looked to very highly, the most highly regarded person in science there, so not surprisingly. What I want to do is first talk about the glucagon-like peptide-1 (GLP-1) that got its legs back in, I guess 1984. So we're going way back. And what's also interesting is that you go way back at Novo Nordisk to 35 years in 1989. And so, there had been this work with this extraordinary hormone and neurotransmitter with a very short half-life that you knew about. But when you first started in Novo Nordisk, you weren't working on this. As I understand it, you're working on laundry detergent enzymes. How did you make this pivot from the laundry enzymes to getting into the GLP-1 world?Lotte Bjerre Knudsen (02:16):Yeah, thank you for that question. I'm from the technical University of Denmark, so I'm trained in biotechnology, and we're a small country, so not that many companies to work for. And I always had my mind set on, I wanted to work for Novo as it was called back then, and it just happened to be in the industrial enzyme part that I got my foot in first. And then I had a very interesting boss at the time. Unfortunately, he's not alive anymore, but he was both a medical doctor as well as a chemist. So he was actually put in charge of actually, let's see if we can do something new in diabetes. And then since he hired me and I had not been there that long, I simply tagged along as the youngest scientist on the team, and then suddenly I became a diabetes researcher. Around the same time, I think you remember that all of pharma was interested in obesity in the early 90s, everyone wanted to do diabetes as well as obesity, but they were separate teams and they all wanted to do small molecules, but it just happens to be so that the best idea we could find at that time was actually GLP-1, because we actually had clinical data relatively early that GLP-1 was a really good candidate as a treatment for diabetes because of the glucose sensitivity of the actions.(03:43):So you'd have efficient lowering of glucose through a dual mechanism with increasing insulin, lowering glucagon, and then it was safe because there wasn't this hypoglycemia you get from insulin. But then I had other colleagues who were working on obesity, and I was just kind of listening, right, what's going on there? And then also a colleague that I had, we had, I don't know if you remember the old Hagedorn Research Institute, but Novo actually had kind of like an academic research institute that was affiliated with us. And there was this group that were working on this glucagon tumor model that produced high levels of glucagon, GLP-1 and PYY. And these rats, they starved themselves to death. And I knew about that from 1994. So that actually inspired my thinking. So when Stephen Bloom's paper came out in January of 1996, and he was the first one to call GLP-1 a neurotransmitter, I think, but I was already way into actually screening these kind of molecules that later then became liraglutide.No One Else Thought About This [Obesity](04:54):And then I thought, why on earth should we not actually do both things at the same time? If we have an idea that can both work in diabetes in a much safer way than in insulin, and then also at the same time work in obesity. But the reality is that no one else thought about this, or if they thought about it, they didn't really think that it would a good idea. But I think I had the luxury of being in a biotech company, so everyone was working with peptides and proteins. So I don't think I got the same challenge that the other people in the other pharma's got when they all wanted small molecules.Eric Topol (05:36):Well, also just to set the foundation here, which you alluded to, there had been so many attempts to come up with a drug that would work, not just of course in diabetes where there are many classes of drugs, but moreover, to treat the condition of obesity. Actually, I was involved with one of them, Rimonabant and did the large trial, which as you know, led to having to stop the drug, discontinue it because it was associated with suicidal ideation and actual some suicide. So there had been such a long history of checkered inability to come up with a drug. But what was striking is the challenge, and this is one of the first important questions about, when you had the extended half-life of the first GLP-1 drug, that instead of having to take multiple times a day, you could actually, with liraglutide get to a point where you were starting to get to an extended half-life. This is now going back to 1997 with approval in 2010, still 14 years ago. But when you came up with this drug, because this was certainly one of your great contributions, this drug was just a step along the way in this kind of iterative process, wouldn't you say? It wasn't the long half-life and the potency that eventually got us to where we are today. Is that true?Lotte Bjerre Knudsen (07:15):Yeah, it was a stepwise process. And what's super interesting about this class of medicines is that they're actually so different. If you talk about a class of medicine where small molecules, they can be different, but they're usually more alike than they're different. And when it comes to this class with these medium-sized peptides, people tried a whole bunch of different things. So they're actually really, really different. Some are simple peptides. So the idea that I came up with was to use this fatty acid isolation principle, and that's then a subclass in the class. And then the first, once weekly, for example, was an antibody-based molecule liraglutide. So they're much, much, much larger molecule compared to the small peptides. So they're very different. And neither the simple peptides nor the really big antibody derived molecules, they don't give a lot of weight loss. So we actually get more weight loss with these kinds of molecules, which is also why you can now see that it has actually kind of inspired a whole industry to kind of try and go and make similar kinds of molecules.Eric Topol (08:27):Well, inspired a whole industry is an understatement. It's become the most extraordinary class of drugs, I think in medical history, having been a student of various, I mean obviously statins have been a major contribution, but this seems to have transcended that already. We're going to talk about more about where things are headed, but this fatty acid acetylation was a major step forward in extending the half-life of the drug, whereby today you can give semaglutide once a week. And this, I think, of course, there are many ways that you might've been able to extend the half-life, but you were starting with a hormone, a natural hormone neurotransmitter that had such an exquisitely short half-life of basically second or minutes rather than that you could give for a week. So I know there were many different ways you could have protected or extended the half-life one way or another, but this seemed to be a breakthrough of many along the chain of breakthroughs. But the question I have is when you were giving this to the diabetics, which was the precedent, that was really what these drugs were first intended, they didn't lose that much weight, and they never, still today when it's looked at for obese non-diabetics versus diabetics, there's a gap in weight loss. Why is that at the exact same dose, with the exact same peptide that the weight loss differs for people with type 2 diabetes as compared to those who have pure obesity?The Mystery of Why People With Type 2 Diabetes Don't Lose Weight Like Those With Obesity Lotte Bjerre Knudsen (10:09):Yeah, I can't give you a molecular answer to that, right. But I think the notion, I think it's the same for example with metformin, even though it gives less weight loss because that has also been tried in both people with diabetes and people without diabetes. So I think it's just for somehow people with diabetes are more resistant to weight loss. I think it's a really good question that I'm hoping maybe we could get through, for example, with proteomics and actually comparing people with diabetes and people without diabetes and looking at people who have the similar kind of weight loss. That could be really interesting. But I really don't have a good molecular answer for you, but it's just a really, really strong fact. But it also leads me to wanting to say it's interesting, because if that had been our motivation to actually say, oh, there's weight loss in diabetes, let's pursue it in people with obesity, I don't think we would've done that because the weight loss in people with diabetes wasn't that impressive. So it was very important for our chain of thought and decision early on that we actually knew that GLP-1 had these separate effects and that they could work in the brain and have a separate effect on well-known pathways in the brain. And that was more our motivation to actually continue to invest in obesity.Eric Topol (11:42):Yeah, no, I think this is when we did the research on the committee for the American Association for Advancement of Science (AAAS) award, the Mani L. Bhaumik Award, that you were recognized for the breakthrough of the year, this year. We tried to scour all the work and we actually had to hit Danish translations and all sorts of other papers they reviewed. And we learned through that process working on this committee that you were the one to be the champion of pushing this towards obesity, and it would've easily been missed because as we've been discussing, the weight loss in people with diabetes was small, but you push for it. And this was an extraordinarily important push because what it has resulted in, of course, has been spectacular. And obviously as we're going to get into much more than just obesity and obesity related conditions. But before we get to those other conditions, and as you've been known in the medical community as “the mother of GLP-1”, you were dubbed that term. The GLP-1 receptor is expressed in many parts of the body. Maybe you could just tell us about the distribution because this, I think is tied into these central nervous system effects that are not just related to the gut hormone type of axis.GLP-1 Receptors and the BrainLotte Bjerre Knudsen (13:17):So I spent a lot of time on that together with my amazing colleague, Charles Pyke, who's an histology expert because it turned out to be so very important. In general, when you're trying to make new medicines, understanding the mechanism, sometimes people say, yeah, who cares? But actually, it should matter, I think because where it becomes really important can be an understanding what they do not do. We've had to do a lot of proving the negatives for GLP-1. We went through these issues with thyroid cancer, pancreatitis, pancreas cancer. In all of that work, it was actually really important that we could show where the GLP-1 receptor was not expressed. So in the pancreas, we know that it's primarily on the insulin producing cells, and then we also have them in the intestine where they're probably involved in regulating inflammation and really creating a much healthier gut.(14:15):And then we have a lot of receptors in the brain. They're typically expressed on neurons, but they're also on astrocytes, they're also on smooth muscle cells. We have them on the heart and the sinus node. That's why there's a small increase in heart rate. We have them in the kidney, on again some smooth muscle cells that are renin positive. So there we can start thinking blood pressure and other things. So it turns out that you can go around the body and there are all of these specific GLP-1 receptor population, that you can see how they tie into the pharmacology. But obviously in physiology, they're not as important as they have turned out to be in pharmacology when we suddenly come with 24 hours a day exposure for a day or a week or for as long as the administration interval is. So, but specifically for obesity, I think it's in the vein, it's hard to, you should always be careful.(15:18):That's something I've learned to never say never. Of course, there could be a contribution from the peripheral nervous system as well to the effects in obesity. But I do think there are so many important and well described neuronal populations that have the GLP-1 receptor and which are accessible from the periphery. So just to mention, maybe one of the most, well-known is a POMC/CART neuron in the hypothalamus. They have the GLP-1 receptor, they're activated, but there also is an inhibitory tone on the AgRP and NPY neurons, and it fits very well with that. We know that people report that they feel more sated, they feel less hungry. But then there are also effects in the hindbrain and in some of the reward centers also have GLP-1 receptors. And we know that also now, we have really good actually clinical studies that show that there is a change in food choice and people can control their food intake better. So I think that fits very well with effects on the reward system. So it's a whole myriad, or maybe you could say that GLP-1 orchestrates a number of different neuronal populations to have these overall effects that reduce energy intake.Eric Topol (16:42):Yeah, it's pretty striking. It's almost like we're all walking around with GLP-1 deficiency, that if we had this present at higher levels around the clock, and of course eventually we'll see things that are well beyond obesity, how well this has an impact. Now, there was an extraordinary review in Cell Metabolism on the brain and GLP-1, and not just the brain, but the essential nervous system, the neurovascular, it's called the “GLP-1 programs and neurovascular landscape.”(17:20):And in this review, it got into the brain effects that were well beyond, I think what are generally appreciated. Not only the protection of the integrity of the blood-brain barrier, this whole neuroglial vascular unit, the myelin sheath protection, reducing inflammation within the brain, improving the glymphatic flow, which is of course critical for clearing waste and promoting cerebral vascular remodeling and more, so the brain effects here is what it seems to be. You mentioned the reward circuit, of course, but the brain effects here seem to be diverse, quite a bit of breath and extraordinary. And as we've seen in the clinic now with the work that's been done, we're seeing things about addiction, even gambling, alcohol, drugs, I mean neuropsychiatric impact, it's pretty profound. Maybe you could comment about that.On to Alzheimer's and Parkinson's DiseasesLotte Bjerre Knudsen (18:23):Yeah. I haven't read that paper yet, but I just saw it earlier. And I have been following this for about actually more than 10 years because when I was kind of over the big work of actually getting the approval for diabetes and obesity. I thought I had a little bit of capacity to actually look at Alzheimer's and Parkinson's disease because I just thought there's such an insane unmet need and what if GLP-1 could actually make a difference? And the first big paper that talked about this was actually in Nature Medicine in 2003, and it was originally, I think I should credit Nigel Greig. Greig, he's from NIH or from NIA, I can't remember, right. But he was actually the first one, I think to say if GLP-1 has all of these important effects in the pancreas and to protect cells, and there are all these GLP-1 receptors in the brain, maybe it also protects neurons.(19:25):So that was the first hypothesis. And the paper on Nature Medicine in 2003 describes how the GLP-1 receptor in the hippocampus is involved in cognition. And then we did a couple of studies in different animal models, and I was, to be honest, really confused. But then there was a new paper in Nature Medicine in 2018 that started to focus in on neuroinflammation. And by that time, I knew much more about inflammation and knew GLP-1 actually lower CRP by about 50% in the different trials. So I was really tuned into the potential importance of that in cardiovascular and kidney disease. But I was like, oh, what if that's also something that is important in the brain? Then it made more sense to me to try and build some evidence for that. So that was how we actually started looking at a hypothesis for Alzheimer's and Parkinson's.(20:21):And we now have a really large phase three study ongoing, but of course, it's a hypothesis, right? And no one has yet, I think, proven that GLP-1 has really important effects on these indications, but we are testing it in 4,000 people with Alzheimer's disease. So our hypothesis is around neuroinflammation, but defined in a way where you could say it's both peripheral inflammation and the effect it has on the vasculature, it's the effect on the blood-brain barrier. It's the astrocytes and the microglia, and there are probably also some T cells that have the GLP-1 receptor that could be important. And then couple that up also with some of the new information from neurons, because there are two papers to think in the last year that has highlighted neurons either in the hindbrain or a little bit further on. Both of them are probably hindbrain populations that actually seem to be really important in regulating both peripheral as well as central information.(21:27):So what if neurons are actually also an overlooked mechanism here, and both of these neuronal populations have the GLP-1 receptor and are accessible from the periphery, even though the child super paper in Nature doesn't mention that, but they do have the GLP-1 receptor. So there are all these different mechanisms that GLP-1 can have an impact on the broad definition maybe of neuroinflammation. And maybe the way one should start thinking about it is to say it's not an anti-inflammatory agent, but maybe it induces homeostasis in these systems. I think that could maybe be a good way to think about it, because I think saying that GLP-1 is anti-inflammatory, I think that that's wrong because that's more for agents that have a really strong effect on one particular inflammatory pathway.Eric Topol (22:22):That's a very important point you're making because I think we conceive of these drugs as anti-inflammatory agents from these more diverse actions that we've just been reviewing. But I like this restoring homeostasis. It's an interesting way to put it. This brings us, you mentioned about the Parkinson's, and when I reviewed the three randomized Parkinson's trials, they're all small, but it appears to be the first disease modifying drug ever in Parkinson's. Of course, these were done with different drugs that were older drugs. We haven't seen the ones that yet to be with semaglutide or other agents. And I wondered if you pushed, just like you did for obesity within Novo Nordisk, you pushed to go into obesity. Did you also force to push for Alzheimer's?Lotte Bjerre Knudsen (23:19):Yes. So that is also me who had to argue for that. I'm happy to do these things. I was born brave. I am happy to do these things.Eric Topol (23:31):That's wonderful. Without you, we would be way behind, and it took decades to get to this point. But look where we are now, especially with all the rigorous trials, the large clinical trials. You're into one right now of some 20,000 participants to see whether not just people with prior heart disease, but people without known heart disease to see whether or not this will have an effect. And there's so much data now, of course, already a completed trial with reduction of heart attacks and strokes. But now to extend this to people who are not such high risk, but these large trials, we keep learning more. Like for example, the reduction of inflammatory markers is occurring even before the weight loss that starts to manifest. So we learned a lot from the trials that are just even beyond some of the major primary outcomes. Would you agree about that?Lotte Bjerre Knudsen (24:34):So I'm not sure we can say that it comes before the weight loss because the energy intake reduction happens instantly. The glycemic response happens instantly. And all of these improvements will of course also have an effect to dampen inflammation. We do not have data that supports that it comes before because we haven't sampled that much in the beginning.Eric Topol (25:04):Okay.Lotte Bjerre Knudsen (25:05):I wouldn't be able to say that, and I don't think there are any, well, it's hard to keep up that the entire literature on GLP-1 these days, but I don't think anyone has actually shown that there is a separation because it's super hard to separate when things are occurring at the same time.Eric Topol (25:24):Yeah, I'm just citing the heart disease trial where in the New England Journal that point was made. But I think your point also that there was already a change in energy intake immediately is apropos for sure. Now, when we get into this new paper of yours, the proteomics, can you tell us about that because that's really exciting. We're in a high throughput proteomics era right now that we can analyze thousands of plasma proteins in any given individual. What are you learning about proteomics with the GLP-1 drug?The GLP-1 Drug Impact on ProteomicsLotte Bjerre Knudsen (26:07):Yeah, yeah. So I'm also the super excited about omics, right? Because I have worked in a wonderful organization of people who can do these large scale clinical trials, and we used to not collect a lot of samples for future use, but we've done that for some years now. So now we have this amazing collection of samples we can learn from and actually both inform the patients and the physicians, but also inform future research. So we have been doing that in our semaglutide trials, and we've just published the proteomics data from the step one and step two trials. So the phase 3a trials that supported the approval of semaglutide for the treatment of obesity. So one of them in people with obesity and one in people with obesity and diabetes, and those data are now published in Nature Medicine. [3 January 2025]. And we were learning a lot of things because you can compare the proteome effects to what has been done in the decode cohort.(27:11):So they have all these disease signature. So that's one thing that you can for sure see, and you can see a lot of things there with hints towards addiction. And then also you can take more predefined signatures also to look into what actually might be driving the cardiovascular risk. So I think there are so many things that you can learn from this, and of course it can also inform when you look at what's actually mediating the effect and probably something around inflammation is important. We have already also shown a more standard mediation analysis that shows that actually the most explainable factor for the effect on MACE [major adverse cardiovascular events] in the select trial is inflammation. It doesn't explain everything, but it actually looks like it's more important than BMI and weight loss. So that's really interesting how much we can learn from there. We're making the data are available at the summary statistic level so people can go and play with them ourselves.(28:23):And I think as we have more different kinds of medicines available in obesity, it's also a way to kind of compare how these different medicines work. And as we get more and more better at maybe also characterizing people with obesity, because I think that's a great thing that's going to happen now is there's going to be more funding for obesity research. Because I think that's what the attention that we are seeing right now is also giving. Then we can better start to understand. We always, we've been saying that people probably have different kinds of obesity, but we don't really know. So now we can actually start to understand that much better and maybe also understand how these different classes of medicines will work if we have the proteome data from different trials.Eric Topol (29:10):No, I'm absolutely fascinated about the proteomics. I call it a quiet revolution because many people don't know about it. [My recent post on this topic here.](29:18):The ability to assess thousands of proteins in each individual, and it's giving us new insights about cause and effect as you alluded to, the relationship with as you said, MACE (major adverse cardiovascular events) and the actions of this drug class. I mean, there's just so much we can learn here from the proteomics. Another thing that's fascinating about the GLP-1 is its effect on epigenetic clocks. And recently at one of the meetings it was presented, this is Steven Horvath that we had on Ground Truths not long ago. He talked about at this talk that for the first time to see that you could basically slow the epigenetic clock with a GLP-1. Is there any further information about that?Lotte Bjerre Knudsen (30:16):Yeah, no. We've never had enough of a sample size to actually be able to look at it, so unfortunately, no. But there is something else, right, because there is this group at the Stanford, Tony Wyss-Coray or something.Eric Topol (30:33):Yes, Tony Wyss-Coray.Lotte Bjerre Knudsen (30:35):Now he published a paper, is it two years ago? Where he did it using proteomics. He defined an anti-aging signature for various different organs.Lotte Bjerre Knudsen (30:46):We are in the process of trying to see if we could take those signatures and apply them on to our data.Eric Topol (30:55):Well, what's interesting is we're pretty close friends, and he, not only that paper you mentioned on organ clocks, which is a phenomenal contribution, but he has a paper coming out soon in Nature Medicine, the preprint is up, and what he showed was that the brain and the immune system was the main organ clocks that were associated with longevity. And so, it takes another step further and it's looking at 11,000 plasma proteins. So it's really interesting how this field is evolving because the omics, as you put it, whether it's proteomics, and now we're learning also about the epigenome and what brings us to the potential that this class of drugs would have an impact on health span in all people, not just those who are obese. Would you project that's going to be possible in the years ahead?Lotte Bjerre Knudsen (32:02):I don't know about health span, but because certainly there's been so many studies with metformin and there's been a lot of wonderful data showing an effect on the epigenetic clocks, but not really an effect on lifespan because that metformin is so widely used. If that was the case, it would be easy to dig those data out of different registries. But certainly a healthier aging is the most obvious one because when you have one class of medicine that actually has so many different effects. Right now we are looking at them at a one by one case, but we really should be looking at them so you are getting the benefits on the heart and the vasculature on the brain and the kidneys and the diabetes and the knees. You're getting all of that at the same time, and that certainly should lead to much, much healthier lives. And then of course, we just need to get people to eat healthier. Also, maybe we should talk a little bit about the food industry. I heard you did that in some of your podcast, right?Eric Topol (33:17):Yes. That is the big food, if you will. It's a big problem, a very big problem, and the ultra-processed foods. And so, lifestyle is not good and trying to compensate for that with a drug intervention strategy is like chasing your tail. So you're absolutely right about that. I mean, I guess what I'm getting into here is that whereas today we keep seeing the effects, whether it's the liver, the kidney, the heart, obesity, and people with diabetes. But for example, in the Alzheimer's trial, do you have to be obese to be enrolled in the Alzheimer's trial, or is it just people who are at risk for developingAlzheimer's?Lotte Bjerre Knudsen (34:01):Yeah, no, you do not have to be obese. It's a standard Alzheimer's trial.GLP-1 PillsEric Topol (34:07):So this will be one of the really important trials to get a readout in people who are not having an obesity background. Now, the future, of course, gets us to oral GLP-1 drugs, which obviously you have there at Novo Nordisk. And it seems to me once that happens, if it can simulate the effects we see with the injectables, that would be another big step forward. What do you think about that?Lotte Bjerre Knudsen (34:39):Yeah. Isn't it interesting, what we've learned is that people actually don't mind the injections, right? Also, because I think it's simple, once a week injection and the needles are so small, obviously there are people who really have needle phobia, but take those aside, it's relatively few. I would argue if you close your eyes and somebody else used this needle on you, you would not be able to feel where it was inserted, right? They're so small. So it becomes maybe a personal preference. Would you like to have once a day or maybe twice a day tablets, or are you fine with once a week injection? And I think there probably will be quite a few once they've tried it. And now so many have tried it and they actually, maybe it gives us a simple lifestyle. You don't have to do it every day, right? You can just have a weekly reminder.Eric Topol (35:46):Yeah, no, I think that's really interesting what you're bringing up. I never thought we would evolve to a point where injectables were becoming some common, and I even have some physician colleagues that are taking three different injectable drugs.Lotte Bjerre Knudsen (36:00):That's also just mentioned Richard DiMarchi, who I shared the Breakthrough Prize with, and also Svetlana Mojsov, who I was one of the other two recipients for the Lasker prize because they both been at Rockefeller, and they both have worked a lot with peptides, and they both say the same thing. They were told so many times, this is not medicines, these kinds of molecules just they're not medicines. Forget about it. It turns out people were wrong. And peptides can be medicines, and they can even be produced also in a sustainable manner with fermentation, which is not a bad way of producing medicines. And people actually don't mind. Maybe some people actually even like it because it's once a week and then it's done.Confronting BarriersEric Topol (36:58):Yeah, no, that's a very important point. And the quest for the oral, which have more issues with bioavailability versus the peptides that are having such pronounced impact is really interesting to ponder. Well, before we wrap up, it's very clear the impact you've had has been profound, not just obviously at Novo Nordisk, but for the world of advancing health and medicine. And you've mentioned some of the key other people who have made seminal contributions, but I think you stand out because when we went deep into who took this field forward into obesity and who might also wind up being credited for Alzheimer's, it was you. And as a woman in science, especially in an era that you've been at Novo now for three and a half decades, there weren't many women in science leaders. And for one to be, as you said, you're brave for the good old boys to listen to the woman in science. Tell us about that challenge. Was this ever an issue in your career? Because obviously we want to have this whole landscape change. It is in the midst of change, but it's certainly still a ways to go. So maybe you can give us insight about that.Lotte Bjerre Knudsen (38:27):Yeah. Well, it for sure was a thing. It was a very male dominated world, and in a way, it might have prevented other people from doing it. But then, as I said, I was born brave for some reason. I'm not really sure why. It actually motivated me to kind of like, yeah, I'm going to show them. I'm going to show them. So it never really got to me that people, not everyone was nice to say. There was the first 10 years of my career, I think they were quite lonely, but then I was really inspired. I was so happy to be allowed to work on this. I thought it was super fun. And I did find people who wanted to play with me. And I also have to say that the CSO back then, Mads Krogsgaard Thomsen, he always supported me. So maybe I didn't get everything I wanted, but I always got what I needed in order to progress.(39:29):So on the women's side, and I think that yes, and there's still a change to be made, and I'm actually a little bit on behalf of my generation, maybe not too proud of the change we made because we didn't do a lot of change. It was all the women coming from the arts and the culture. They were the ones who actually make the big change here like 5 or 10 years ago. So I've also started to be more open about sharing my journey and advocating for women in science. So that's why I show up in pink to some of these award sessions just to be a little bit different and to maybe also just show that you don't have to be a certain type in order to fit into a certain job. But there is still a change to be made where people should be better at listening to what a person say and what ideas they say.(40:28):And they should be mindful about not always labeling women as passionate. When people call me passionate, I say like, no, thank you. I'm actually not too happy about the mother of either, because men always are being told. They're being told that they're brave and ambitious and courageous and strategic, whereas we we're, oh, you're so passionate. No, thank you. I'm also brave and strategic and ambitious and all of that. So we simply put different vocabulary on. I don't think people don't do it on purpose. I think we need to be better at actually giving people at work the same kind of vocabulary for their contributions. And I think that would mean that we get listened to in the same way. And that would be important. And then I also have to say that science, whether it comes from men or women, doesn't really matter.(41:32):Successful science is always the work of many. And I hope that some of you will actually listen to my last speech because that's what I speak about, how it's always the work of the many. And also, how if you want to do something novel, then you actually have to do it at a time when no one else is doing it, and you should believe in your ideas. So believe in it, listen to the critique, but believe in it, and then come back with new arguments or give up if you can't come up with any new arguments, right?Eric Topol (42:05):Well, we'll definitely put a link to the Lasker Awards speech that you gave. And I just want to say that the parallels here, for example, with Kati Karikó , my friend who had the Nobel Award for mRNA, she spent three decades trying to get people to listen to her and never got a grant from the NIH or other places [our conversation here]. And it was a really tough battle. And as you already touched on Svetlana Mojsov, who did some of the seminal work at Rockefeller to isolate the portion of GLP-1, that really was the key part peptide, and it was overlooked for years. And so, it's a tough fight, but you're paving the way here. And I think the contributions you've made are just so extraordinary. And I hope that over the years we will continue to see this momentum because people like what you've done, deserve this extraordinary recognition. I'm glad to see. And the Lasker Award is really capping off some of that great recognition that is so well deserved. We've covered a lot of ground today, and I want to make sure if I missed anything that you wanted to get into before we wrap up.Lotte Bjerre Knudsen (43:30):I think we've been around all the exciting biology of GLP-1, both in diabetes, obesity, cardiovascular, kidney, potential in Alzheimer's and addiction. We'll see, we need the clinical data and we've put out a message to inspire people to do new science. There's still a lot of unmet need out there. There's a lot of diseases that don't have good treatments. Even in the diseases we've talked about there's a lot of money for diabetes. There are no disease modifying therapies for diabetes. It's not really changing the course of the disease. So there's a lot of things that needs great scientists.Eric Topol (44:17):And I guess just in finishing the discovery of this class of drugs and what it's led to, tells us something about that, there's so much more to learn that is, this has taken on perhaps the greatest obstacle in medicine, which was could you safely treat obesity and have a marked effect. Which decades, many decades were devoted to that and gotten nowhere. It's like a breakthrough in another way is that here you have an ability to triumph over such a frustrating target, just like we've seen with Alzheimer's, of course, which may actually intersect with Alzheimer's, with a graveyard of failed drugs. And the ones that it were approved so far in certain countries, like the US are so questionable as to the safety and efficacy. But it gives us an inspiration about what is natural that can be built on the basic science that can lead to with people like you who push within the right direction, give the right nudges and get the support you need, who knows what else is out there that we're going to be discovering in the years ahead. It's a broad type of lesson for us.Lotte Bjerre Knudsen (45:38):Yeah, there is another hormone that's also in phase three clinical development, right? The amylin hormone. We've had pramlintide on the market for years, but we have this long-acting version that is in phase three clinical development. That could be the same kind of story because there's also additional biology on that one.Eric Topol (45:58):Yeah, this is what grabs me Lotte, because these gut hormone, we've known about them, and there's several more out there, of course. And look what they're having. They're not just gut hormones, like you said, they're neurotransmitters and they're body-wide receptors waiting to be activated, so it's wild. It's just wild. And I'm so glad to have had this conversation with you. Now, congratulations on all that you've done, and I know the Nature Medicine paper that just came out is going to be just one of many more to come in your career. So what a joy to have the chance to visit with you, and we'll be following the work that you and your colleagues are doing with great interest.Lotte Bjerre Knudsen (46:45):And thank you very much, and thank you for your wonderful podcast. They're really great to listen to on the go. 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Great news for the nearly-extinct monarch butterflies, which will pass through the area as they migrate back to Mexico. Also, to find out how blood affects aging, scientists can surgically connect two animals and let blood circulate between them.After California's Park Fire, A Second Bloom of MilkweedDon Hankins examines a bright yellow-green patch in the meadow. The land all around is charred by fire. But here, there's a sort of miracle at work. Native milkweed has sprung up and bloomed for the second time this year. This is not something these plants, Asclepias eriocarpa, also known as Indian milkweed, are known to do.They bloomed in late spring and early summer and had already done so this year when the Park Fire roared through. But the fire seemed to happen at just the right time to coax a second flowering, one that is likely to line up with the return migration of the monarch butterflies south to overwinter in Mexico. Monarchs rely on these flowers to complete their life cycle. For researcher Don Hankins, this is a surprise delight.“We may be coming back into some knowledge here that hasn't been practiced in a long time,” said Don Hankins, a professor at Chico State, who teaches classes in geography with a focus on fire. He is also a California Plains Miwok traditional cultural practitioner.Read the rest at sciencefriday.com.Inside The ‘Creepy' Procedure That Taps Into Young BloodWhile fictional vampires suck the blood of the young to live forever, some researchers have found that certain elements in young blood actually can improve the health of the old. This is possible through a spooky procedure called parabiosis, in which the circulatory systems of two animals are joined, letting the blood flow from one into the other.By connecting old mice and young mice through parabiosis, researchers have observed how different molecules in the blood impact symptoms of aging. While some outcomes have excited experts, enthusiastic biohackers attempting to defy their own aging might have jumped the gun. There's a long way to go before we understand how elements of young blood might be harnessed to treat aging humans.Emma Gometz, SciFri's digital producer of engagement, talks to Dr. Tony Wyss-Coray, a neurology professor at Stanford University who has used parabiosis (which he once described as “creepy”) to help reveal how components of our blood affect our cognition as we age. They discuss parabiosis, vampires, and how far the field has to go before humans can benefit.Transcripts for each segment will be available after the show airs on sciencefriday.com. Subscribe to this podcast. Plus, to stay updated on all things science, sign up for Science Friday's newsletters.

Recently, a series of papers were published in Nature and Nature journals illuminating the physiologic effects of exercise from an NIH initiative called MoTrPAC. To understand the wealth of new findings, I spoke with Professor Euan Ashley, who, along with Matt Wheeler, heads up the bioinformatics center.Earlier this week, Stanford announced Evan Ashley will be the new Chair of the Department of Medicine. He has done groundbreaking work in human genomics, including rapid whole genome sequencing for critically ill patients and applying the technology for people with unknown diseases. A few years ago he published The Genome Odyssey book. As you'll see from our conversation, he has also done extensive work on the science of exercise.Video snippet from our conversation. Full videos of all Ground Truths podcasts can be seen on YouTube here. The audios are also available on Apple and Spotify.Transcript with audio and external linksEric Topol (00:06):Well, hello, it's Eric Topol with Ground Truths, and I'm really delighted today to welcome my friend, Euan Ashley. He is the Roger and Joelle Burnell Chair of Genomics and Precision Health at Stanford. He's done pioneering work in genomics, but today we're going to talk about something very different, which he also is working in exercise. Exercise the cover of a Nature paper in May regarding this MoTrPAC, which we're going to talk about this big initiative to understand the benefits of exercise. But before I hand it over to Euan, and I just want to mention his description of the paper that he posted to summarize started with, “Exercise may be the single most potent medical intervention ever known.” So Euan welcome.Euan Ashley (01:01):Yeah, well, great. It's wonderful to be here, Eric, and so nice to see you.Eric Topol (01:06):Yeah. Well, we have a lot to talk about because exercise is a fascinating topic. And I guess maybe we'd start with the MoTrPAC, which is an interesting acronym that you all came up with. Maybe tell us a bit about that with the 800 rats and the 2,400 people and the 17,000 molecules, there's a lot there.Euan Ashley (01:24):Right, right. Yeah. Well, first of all, of course, before you do any scientific study, especially with a large number of people in a consortium, you need a good acronym. So that was where we started with the idea was to focus on the molecular transducers of physical activity. As you pointed out there at the beginning, we really don't have a more potent medical intervention, especially for prevention of disease. I mean, it's just such a powerful thing that we have, and yet we don't really understand how it works. And so, the MoTrPAC Consortium was designed to really work together, bring groups of people across the US together who all have some interest in exercise and some ability to measure molecules and really put together the world's largest study of exercise to try and start answering some of the questions about where the potency of this intervention come from.Eric Topol (02:20):So the first crop of papers, and there were several of them that came out all on the same day in Nature publications, was about the rats. The people part is incubating, but can you give us a skinny on, there was a lot there, but maybe you could just summarize what you thought were the main findings.Key MoTrPAC FindingsEuan Ashley (02:43):Yeah, of course, of course. And the MoTrPAC Consortium, I'll say first of all, yeah, large group is probably I think 36 principal investigators funded by the Common Fund. And so, it brings together large numbers of people, some of whom who spend most of their time thinking about let's say animal exercise. Some have spent a lot of time thinking about humans in exercise and many of whom think about measuring technologies. And as you say, these first group of papers were focused on the rat study, but actually the study goes much more broadly than that. But of course, there are some advantages to the animal protocols. We can look at tissue and we'll talk about that in a moment. But the humans, of course, are where we're most interested in the end. And we do have tissues coming from humans blood and adipose tissue and skeletal muscle, but those are obviously the only organs we can really access.(03:31):So there's a rat study, which is this one we'll talk about, and that's aerobic exercise and training. There's human studies that include aerobic exercise, strengths studies as well. There's a study in kids, pediatric study and then also a study of people who are very fit because here we're focusing on the change from sedentary to fit. And so that gives us the key exercise signal. So this first crop of papers was really our first look, cross-tissue, cross multi-omics, so multiple different modalities of measurement. And I think, yeah, we were like about nine and a half thousand assays, 19 tissues, 25 different measurement platforms, and then four training points for these rats. So let's talk about the rats for a minute. What do they do? So they normally live at night. They're active at night. In this study, we reverse that so that we can actually do the studies during the day.(04:25):So we reverse their at night cycle and they do their treadmill exercise over the course of several weeks. They start with about 20 minutes, and they do more every day. There's a control group of rats that just get placed on the treadmill and then don't do any exercise. And so, this is a controlled study as well. And over the course of time, we work more, it's about eight weeks in total and then two days after each of those bouts of exercise. So it's not an acute study, we measure to see where we are. So we also have this time trajectory of exercise. So what did we find? I mean, I think the first thing I would say, we talked about just how potent exercise is. It's very, very clear from looking at all these tissues that when you exercise regularly, you are just a different person, or in this case a different rat.(05:15):Like literally every tissue is changed dramatically and some in quite surprising ways. So I give you a couple of the things that surprised me or that I thought were most interesting. The first thing was this question of how does exercise actually work? Because exercise is a stress. You go out and you pound the pavement or you're on the bike or whatever, and then your body recovers. And so, there's been this idea, it's referred to as hormesis, this idea that some of the benefit of exercise might come from this recurrent stress. So your body learns how to deal with stress. And so given that we were very interested that this heat shock response was so prominent across multiple tissues. So heat shock proteins are molecular chaperones and they take care of protein folding to make sure it's appropriately done and they prevent protein aggregation. And when proteins need degraded because they're damaged, the heat shock system jumps in.(06:10):So perhaps not surprising, but pretty interesting that the heat shock proteins were very prominent part of the stress response to exercise. And remember, this is not acute exercise, so these are benefits that are built up over time, so that was one. A surprising one to me, the adrenal gland. So we're used to thinking of adrenaline as an epinephrine, as a stress hormone, but actually we saw dramatic changes in the adrenal gland and we don't necessarily think too much. You think about the exercising muscles, you think about the heart, we think about the lungs, when we think about exercise, you don't necessarily think that you're changing your adrenal gland, but it was one of the most changed tissues. The immune system was a common upregulated system. We saw that. And in fact, some of the tissues in which the immune genes were most changed were somewhat surprising.(07:02):So the small intestine, for example, was a place where there was a highest enrichment of immune mediated pathways. And then some tissues changed pretty early, like the small intestine changed after just one or two weeks of training other tissues like the brown adipose tissue. It was more like seven or eight weeks of training before we saw the real changes in there. So just one or two little things that struck out, but I think this really the first molecular map of exercise. So we're looking across the whole system across multiple modalities of measurement across multiple tissues.Simulating StressEric Topol (07:34):So as far as understanding the benefits of exercise, does this tell us that it really does simulate stress that it's conditioning the body to deal with stress as reflected by the various points you just summarized?Euan Ashley (07:51):Yeah, I think that is exactly right. I mean, part of what we were trying to understand was in what way are you changed after you do exercise regularly? And I think if we think about things that are positive, then the ability to deal with stress at a cellular level, quite literally repair mechanisms seems to be a big part of it. The other aspect that was interesting is that when you're measuring this many analytes, you can also compare that with disease. And so, we understand that exercises is preventive benefit against disease. So in some cases, and this was work highlighted by my colleague Maléne Lindholm in the mitochondrial paper that came along with the main paper and she looked with a team across all mitochondrial changes across all of the tissues of the cell. So these are the workhorses of the individual cells that like the batteries inside the cells of the mitochondria.(08:54):And we saw big changes across, it's not surprisingly, but it's the energy source for cells, big changes across many tissues. But interestingly for two specific really important diseases, a liver disease in one case and type 2 diabetes on the other, it was very clear that the training upregulated a network that was exactly the opposite of that of the disease. And so, it really was intervening in a way that was very specifically opposite to the way we know disease mechanisms go. So it does seem like, I mean people talk about an exercise pill. I think this shows that that is just not going to be possible. There may be ways we could mimic some elements of exercise, but there's no pill. This is a multisystem, multi-tissue, multidimensional response to exercise.Eric Topol (09:44):Yeah, I think it's really important. That was one of the questions I was going to ask you is whether this would ever be simulated by a drug. And I think you already answered that, and the fact that it's so comprehensively sweeping across every organ and all these different signals, tens thousand plus signals across them, it's really striking. We never really understood the benefits of exercise and not that it's all resolved by any means. Some of the things that were interesting too was the sex specific findings. Maybe you want to comment about that because we don't spend enough time thinking about how sex does have a big effect on physiology.Sex-Specific FindingsEuan Ashley (10:24):Yeah, I mean that's a really good point and one that I think was really underlined for us at every corner, every turn of the analysis here. So really no matter which measurement modality, no matter which tissue, no matter which point of training, if we just asked these computer models to sort of separate the data according to the prominent signals without giving it a clue of what to do, the so-called unsupervised models, then sex basically came out every single time. So I think you say you're absolutely right that we so often overlook the difference. For years we've said, oh, it's too expensive to do animal studies in both sexes, so we'll just pick one. And males were picked more often. But there are plenty of studies that were just females, and I mean that clearly is wrong, and we are really, sometimes it appeared like we're almost dealing with two different species.(11:18):They were so different. But I think we can also learn from what those differences were. Interestingly, some of them were most profound in adipose tissue, so in fat, and that was the case both at rest, sedentary and amplified by exercise. So we saw big difference between females and males in relation to the kinds of signals that were prominent in the white adipose tissue. So this fat storage tissue, for example, in sedentary females, insulin signaling and the trigger to make fat and store fat was very prominent. But whereas in the males, even before any exercise, the fat signals were more related to metabolism, and we could have wild speculation about in evolutionary terms why that might be. Obviously, males and females have different biological many differences in their biology and obviously thinking about hormone systems and specifically pregnancy of course. And so, we could probably come up with some theories. In reality, all we know now are these observations were found and they're pretty interesting and they show us that we really always need to think separately about both sexes and look at both independently.Eric Topol (12:39):Well, and the other thing that you already pointed out, but I just want to underscore, you can't do this stuff in people. You can't just do fat biopsies and whatnot. So I mean, the fact that you can do this multi-omic, multi-organ type assessment is just really an extraordinary opportunity for learning. And while we're on the white fat story just briefly, we would rather have a lot more brown fat, but as we age, and I assume it's the same in rats, they don't have much as they get older brown fat. Does exercise help us get more brown fat or are we just stuck with the white adipose tissue?Brown vs White FatEuan Ashley (13:21):Yeah, well, it certainly allows us to have less of a white adipose tissue, and I think it's potential that our brown adipose tissue maybe more functional, and for those who are listening who are not familiar, I mean these really are different colors that relate to the actual color of the tissue, but the color is different because the brown adipose tissue contains lots of mitochondria and lipid droplets, and the brown adipose is there to help essentially generate heat. It has a very different function in a way, but even white adipose tissue that we think of as just being about storing energy, people think of fat as a very metabolically neutral or inert tissue, but in reality it's not. It's signaling. It's constantly, it's a tissue that's as alive as any other and not just a storage for excess energy, but exercise definitely appears to alter both in this sexually dimorphic way as we noted already and clearly both in a positive health way where I think the makeup of the brown tissue is different. The white tissue, there is less of it obviously with exercise, which is something that is well known, but not new here for the first time. But still important to have seen that even in the rats.Eric Topol (14:49):And there's even, we talked a moment go about drugs, but there are some molecules that are thought to be able to help convert white to brown fat that are understudy and we'll see if they get anywhere that's interesting. But also, you talked about aerobic exercise and with us both being cardiologists, and I know throughout my earlier part of my career, we only talked about aerobic exercise. There was no such thing as strength training, and we even discouraged that or we never talked about it. Now we know how important strength training is and not just strength and resistance training, but balance and posture and all these other things. I assume you can't study that in the rats.Euan Ashley (15:32):Well, it's not impossible. This study of course is about endurance, but as you say, and there are some models, I mean I've even seen models in trying to trigger flies to do strength training.Eric Topol (15:46):Wow, I didn't know that.Intensity of ExerciseEuan Ashley (15:46):That somewhere, yeah, we'll have something, there are various methods of making animals hang off things, and this was treadmill. So it's a fairly routine and standard I think part of a rat's life to run. So this was not so different. As we mentioned at the beginning in the human study, we do have a strength portion and the endurance portion, which I think is very important because as you say, the benefits of exercise are found really across both of those. And indeed, as you say, flexibility and other often neglected element of physical activity. But yeah, those benefits are there for both aerobic exercise and endurance. And in fact, they are perhaps even higher for higher intensity exercise. Although I think we don't necessarily recommend everybody do higher intensity exercise. I don't think it's necessary to get most of the benefits of exercise, but there is some additional benefit.(16:42):One of my favorite facts, I think I first saw it probably on a presentation a few years ago, but I looked up the original and recalculated it. But if you look at this very big study of half a million people and look at their physical activity over the course of years and correlate it with their likelihood of being alive or being dead, then it was clear that one minute of exercise bought you five minutes of extra life. And I just thought that was just a really interesting way of putting it essentially. And actually it's a little more, if you did high intensity exercise, one minute would give you seven or eight minutes of extra life. So I tell this to my patients when they come in and tell me they don't have enough time to exercise. I said, oh, well, one minute of exercise. I'm not very popular when I tell them that, but anyway.Eric Topol (17:30):You think it's true. Do you think it's based on good data?Euan Ashley (17:34):Well, the data is large, I mean half a million people. I think we've also seen it currently since the early fifties when we were first doing the London bus conductor study that Jerry Morris did that you will know well, where he compared bus conductors on the London to the bus drivers and found a significantly reduced cardiovascular mortality among the conductors because they were on their feet all day up and down stairs and the driver otherwise in the same environment the drivers were sitting. So I think we have a wealth of epidemiologic correlative evidence that exercise leads to a greater length of life, greater longevity, maybe more than for anything else. The causal evidence is less of course, but we do have causal evidence too. There are enough randomized trials and now increasingly some genetic causal evidence that helps us understand that this is really a causal link and that we actually can change our outcome if we do additional exercise.Mental Health BenefitEric Topol (18:32):Oh, and I don't question at all what you said about the enhancing healthy aging health span and even possibly lifespan. I just wondered about the one to five ratio if we could assert that. I mean that's really interesting and it's a good motivating factor because as you well know by that WHO criteria, one out of four people aren't even close to the modest exercise recommendation. So we got ways to go to get people to spruce up exercise. Now speaking of people, I do want to come back to MoTrPAC and the people plan, but I do want to before that get your sense about a couple of really fascinating studies. So earlier this year there was a study of every exercise study that's been looking at mental health along with SSRIs that name drugs that are used for mental health. And it was a pretty fascinating study. I think I'm just going to pull it up. They looked at everything that this is for depression, walking, jogging, yoga, strength training, SSRIs. And what was fascinating is that dancing, walking, jogging, it made the drugs look like a joke. They didn't seem to work at all. So this was 218 studies with over 14,000 people. And so, I don't know that enough people recognize this fact that this Prozac nation and all this stuff about the SSRIs, but exercise seems to do wonders for people who are depressed, anxious, stressed. What do you think about that?Euan Ashley (20:26):Yeah, I mean it's exactly right. I mean I think that it's very clear from the data and as you mentioned, you and I tend to focus first on the cardiovascular benefit, which is very significant, potentially 50% reduction in risk, but there are similar sorts of numbers when you look at mental health and exercise as an intervention for mental health has been very well studied and has these really dramatic benefits. And I think even if we go in the more general population and think about the fact people talk about a runner's high or an exercise high, and many, many of us, myself included, feel that. And a few years ago, I started exercising every morning and now if I don't do that, I really feel like I'm missing something, there's something in the chemistry of my brain is not quite right. And so, I think that benefit for those who have mental health issues is also very much felt and is real at the brain chemical signaling level and with this few adverse effects as exercise has, I do think we need to think of it earlier and more prominently for almost every disease.Eric Topol (21:40):Yeah, you're I think alluding to the opioids that are released with exercise and addiction to exercise, which is what ideally if everybody could be addicted to exercise, that might help a lot of things. As you mentioned in your post that I started with, “its benefits in prevention outstrip any known drugs: 50% reduction in the cardiovascular disease, 50% reduction in risk of many cancers, positive effects on mental health that we just discussed, pulmonary health, GI health, bone health, muscle function. You name it.” So you said it really well there, and that was just one recent report that substantiated the mental health. I want to also mention another report that's fascinating on cancer that is a publication again recently was looking at both mice and people with pancreatic cancer. And what was fascinating about it is the more exercise of the mice and in the people, the more survival that is from pancreatic cancer, which as we both know and all the listeners will know, is that one of the worst cancers of humankind. So the affecting cancer is fascinating. Now can you dial up your immune system response with exercise?Euan Ashley (23:02):Yeah, I think you can. And I think we were at some level expecting to see it because it's certainly a known thing, but I think again, this is able, our ability to measure it in this study is just much deeper than we've ever had in any study before. And so, I think when we think about mechanisms that might relate to reduced risk of cancer, as you say, we think first of the immune system and that signal was there in many places. As we mentioned at the very beginning, sometimes to me in some slightly surprising places like the small intestine, we don't think of that necessarily as the seat of immune activation, but I think what we were doing, what we were seeing is those signals really across all the tissues and ultimately the immune system is a distributed system. It senses in multiple places and then obviously has implementation.(23:53):Now exactly in what way we've turned up our T or B cells, for example, to be able to attack those cancers or support the therapy that's been given. I don't think we understand that yet. But actually, you bring up another great point, which is part of MoTrPAC was to create this molecular map and analyze it and put the first analysis out there. So that's what we've done, but just as big and maybe even a bigger reason is that to release the data and to make it accessible for everyone and anyone in the world as of the moment this paper came out can go to our data portal at https://motrpac-data.org/ and download the data and then use that in their own work. They can do their own analysis just of this data, but also what we're hoping is that they'll start to use the data, let's say as control data for a cancer study or for a diabetes study or for others. So we really hope it'll fuel many, many more studies over many years from now.Eric Topol (24:52):Yeah, I mean that open science approach to applaud that it's so vital and amplifies what's good to come out of this really important initiative. Now you mentioned the opioids and proteins that are secreted with exercise, exerkines is a term that's used and also I guess these extracellular vesicles (EVs) not electric vehicles. Can you tell us about exerkines and EVs and are they part of the story?Euan Ashley (25:25):Yeah, and actually in the human study there's a specific exosome analysis that will be reported there. Yeah, I think that when we think about this multi-system nature of exercise, and one of the fascinating things was to be able to have these omics in multiple tissues and think about how those tissues were signaling to each other. So obviously there are some tissues that are more fundamental to the exercise response. We think of those as the skeletal muscles. They literally the effectors of our ability to exercise. And I think we think of the heart and lungs in particular in the blood system of course, but we were seeing changes everywhere and it's one of the reasons we were seeing changes everywhere is that there are molecules that are essentially secreted into the circulation or locally by these exercising muscles, exerkines that have a number of positive benefits.(26:21):And it is possible if there's some mechanism towards mimicking some of what exercise does with a drug, then that's a good place to go look for it. And I think that this will also fuel those thoughts. I think we both, we'd agree that there isn't going to be one pill that will do all the magic of exercise, but I think there are probably things we will learn from the study where we say, well, this was a very positive benefit and it seems to be mediated by this particular molecule, and that's something that could potentially lead towards a more targeted drug. I think we'll definitely get into that and understanding just we're systems people are, again, I think we think in physiology, so when we see the tissues like connecting and communicating with each other, I think that just makes a lot of sense from a systems perspective.Eric Topol (27:10):Now getting onto the forthcoming work that's going to come out with the 2,400 people and the different groups that you mentioned, I wonder if it'll include things like biologic aging with DNA methylation, will it have immunomes to characterize the differences in the immune system? What kind of things might we expect? Obviously, you can't get tissue, but for blood samples and things like DNA methylation, can we get some more illumination on what's going on?Euan Ashley (27:41):Yeah, I think we can. And of course, ultimately the human is the organism we're most interested in. Interestingly, I'll say interestingly as well, we can get some tissue and huge credit to both the investigators who are doing this and most credit of all to the individuals who agreed to join the study because they actually agreed not just to give blood samples, but actually to give skeletal muscle samples. So a biopsy of the skeletal muscle and a biopsy of the fat pad. So we will actually have two other tissues in the humans, not this obviously vast range that we talked about with the rat study, but we'll have those two other tissues and we'll also then have the rat data, which is the other great thing. So we'll have this foundational insight that we can then bring to the human study with the humans as we mentioned before as well, we'll have not just endurance but strength trained, we'll have it in kids as well, and we'll have these higher intensity exercise.(28:36):I think we will be able to connect with this, as you mentioned, longevity literature or the health span literature where we can start to think about DNA methylation. We do have genomes of course, on all of the individuals. It won't be a study powered because it's thousands individuals, these kinds of numbers. It won't be powered to give us genetic predictors. If you think about the studies had to be hundreds of thousands of people and even more now in order to give us, let's say common variant predictive. So we won't be able to do that, but there's lots of connections we'll be able to make by being much closer to the effector systems, which is to say the proteins and the metabolites and those signals we're already seeing are very significant. And so, I do think that there'll be a lot of new signals that we'll see that are specific to humans that will connect into other bodies of work, for example, the longevity, and we'll see those in blood and I hope that we'll be able to connect also the skeletal and adipose tissue data as well.Eric Topol (29:37):One of the things that would be wonderful to connect if you can, our mutual friend and your colleague at Stanford, Tony Wyss-Coray has these organ clocks that have been validated now in the UK Biobank, and then you can see what's happening with the wealth of plasma proteins that have been validated across each organ. So without having to do tissue, you might get some real insights about organ clock. So I mean, I'm really looking forward to the people part of this. When do you think the next wave of output's going to come from MoTrPAC?Euan Ashley (30:11):Well, I think that another element of the study is that we have ancillary studies, so investigators who said, I want to be able to use MoTrPAC data and use some of the infrastructure, but I'm looking for funding for my parallel study. So some of those ancillary studies will start to come out over time, which I think will be interesting and will be a very good place to see the breadth of activity that has been triggered by this one investment. The human study is coming along. We're actually just now plotting the last two or three years of the consortium. Time has really gone by pretty fast, and we've had to scale back just a little bit on the total numbers of humans, but it should still be, I think probably the largest multi-omics study of humans that there has been. And I think if we were going to plan one of those, then planning it to study around exercise definitely, definitely makes sense. So there is some data that was, of course Covid happened in the middle of this, so that was a major challenge with hitting the original numbers. But there's some data from the humans who were recruited before Covid hit that will be coming out and hopefully in the relatively near future. And then the big study may still be a year or two away to get it finished. But after that, as we say, we hope that the data and the science will continue for I hope decades beyond just the collection of this repository.Eric Topol (31:41):That's great. You mentioned Covid and I did want to ask you about the folks with Long Covid who are suffering from fatigue and exercise intolerance and what do you think about this kind of vicious cycle? Because if they could exercise, it could help them get into a better state, but because of not being able to, it's just a negative feedback loop. Any thoughts about that?Exercise and the Immune SystemEuan Ashley (32:13):I mean, it's such a good point and it's one of course that we talk to many of our patients where they, for whatever reason, sometimes it's because they are struggling with weight or they're struggling with other mobility challenges, and now we have this very large population who are struggling with fatigue. As you mentioned, it's a group that we were somewhat familiar with because of flu and because EBV and other, I mean long syndromes were something we were familiar with. They were just kind of rare, and so there wasn't really much work done on trying to understand them. Now as you've, I think articulated better than anyone, we have this entire population of people because of the scale of Covid who have these symptoms that are recognizable for the first time and including on your podcast, you have had folks on that have discussed it. Some of the insights that have happened from actually applying science, I wish there was an answer that was buried here in MoTrPAC and maybe there is, there will certainly have data from before and after the pandemic and maybe there may be some insights that we can bring to that.(33:20):I certainly think we have a lot of insights on the interaction between infection and the immune system. We talked about the potential for the immune system to be ramped up in that potentially being one of the mechanisms through which this might help cancer. There's also the idea of, and we've seen this with the effect of vaccination on Long Covid, which perhaps surprisingly does seem to have a significant benefit for at least a group of people. The assumption there is that we're ramping up the immune system and it's having that extra effect on whether it's actually pools of hidden antigens that are hidden from the immune system or whether it's some other element of the kind of ensemble attack of the immune system that is related to the symptoms. But either way, I think we feel that having a more ramped up immune system is likely to be beneficial, but at a very real human level, the point you made is the hard one. If you're really fatigued and you just feel you can't exercise, then these benefits are just out of reach and you're in this negative feedback cycle and breaking that cycle is hard. I think we try to suggest people do it very gradually because you can get a lot of benefit from just a little exercise and that's something, so that's some way, and then hopefully people can build up slowly over time, but it's a really big challenge.Eric Topol (34:43):I hope we can crack the case on that because I know that's something holding these folks back and there's just millions of them out there. Now let's talk about the healthy folks that you see in clinic. What do you advise them about exercise besides the fact that one minute we'll give them five minutes, but do you advise them to have X amount of aerobic and X amount of resistance and in the general person, what would you tell them patients?Euan Ashley (35:13):Yeah, yeah, I do. So I suggest habit is everything. So I suggest to people that they exercise every day or take one day of rest because I think there is some benefit with the stress response and having a rest day. So I suggest five or six days a week if possible, trying to get into a habit of doing it. So pick a time that works for you. It could be first thing in the morning, could be last thing at night. The jury's out on when the best time to exercise is. What it's very, very clear is that getting the exercise done is what counts. Accumulating time is also what counts. I mean, if you're not someone who wants to pull on running kit and go out running, that's fine, but accumulating steps, accumulating physical activity and moving is key. So not having people overshoot being too ambitious, but if they're really motivated to do something, then I would say five or six times a week a combination of both aerobic and endurance exercise and strength.(36:07):Usually I suggest two to one in favor of aerobic exercise, but it's also possible I think to alternate and do more 50/50. I think the key is that both are featured and then I think a bit neglected because to be honest, our data on it is just not as good, but flexibility is really critical and particularly in the senior population and for a group who sit all day long, I think for those two groups in particular, flexibility is really under-recognized as a major component. Even in my cardiology clinic, I've helped several patients just get over their back pain by teaching them some back stretching exercises. And so, I think that's neglected. So I suggest all three of those and really it's whatever works for the individual. I think the key is to find, it might be working in a group format, it might be going to a gym, it might just be taking regular walks. The key is to get moving and not sit. Get moving and do it regularly and get into the habit.Individualized Exercise?Eric Topol (37:09):Yeah, and actually on that point about potential individualization in the future, I noticed that you and some people that worked in your lab and others, Svexa is a company you started for exercise. Can you tell us about that?Euan Ashley (37:26):Yeah, this was a PhD student who was in my lab many years ago and was doing his PhD joint between the Karolinska Institute in Sweden. And of course, the country of Sweden has a long history of exercise physiology, science, and as he came out, we realized that there was the potential for optimization of training for individuals, whether they're recreational athletes or elite athletes in the Olympics. And he was interested in taking this and running with it, which he did. So the company originally Silicon Valley exercise analytics, but shortened now to Svexa builds, builds products to help people basically individualize their training. And we work, say with recreational athletes on an individual basis, we work with a lot of Olympic athletes in multiple countries and the technology building the sort of magic sauce that many of these coaches even up to and including Olympic coaches have into a format that can be spread and amplified to many more people is one of the themes.(38:29):And when we think about professional athletes and the company works with a number of well-known brand name teams that are in soccer leagues and in national football league here in the US and really across professional sport, what we're thinking of there is optimizing performance. Of course, all the teams want to win, but reducing injury is the other key part because the management of load, these are professional athletes, they're getting up every day in training and they're trying to optimize their training and their coaches are trying to do that. And it's been a fairly data free zone over the years, but meanwhile, we actually have learned a lot about how to measure individuals and how to measure what training works, and if you think about a team that might be paying 20 million a year for their star player, if that player gets injured, that's a pretty expensive thing. And so, investing a little bit in understanding the training load, helping the coaches understand the data, and then adapting that to each individual in the team so that their chance of injury is lower. That's really a lot of what the company spends its time thinking about.Eric Topol (39:36):Now, do you use sensors like lactate and glucose and AI of their body and how do you figure this stuff out?Euan Ashley (39:45):Yeah, all of that is possible. It's interesting, some sports have a kind of culture of measurement. For example, lactate measurements, which as your listeners will know, is it requires a small blood sample usually from the finger or from the ear lobe. Some sports like swimming have done that for years. But other sports, it's just not been so much in the culture. So I would say that from the company perspective, we work with whatever data is available and we'll make recommendations if people want to think about wearable devices. Of course, the digital era is around us, and you can get a lot from just a standard watch in terms of heart rate, heart rate variability in terms of accelerometry and movement. You can do a lot with just that, but there's lots more. Many of these teams have GPS signals so they know how far an athlete moves in a given game, how fast they move, how much time they spend at tool speed versus medium speed.(40:37):So we can use all of that. And as you say, yes, AI for sure is a large part of what we do and a couple of different ways actually. One is just for the analysis of the data, but another is this idea of scaling expertise. This is something in the AI community. I know you talked about a lot where you could take the expertise of let's say a physician with a very specialized practice or an Olympic coach for a marathon runner and basically make a language model that contains that expertise and then allow many people, thousands of people potentially to benefit from that expertise that we'd otherwise be sort of locked up with next available appointment is 18 months down the road, but if your AI can potentially reflect a lot of what you have, a lot of your expertise, not all of it, we hope, but probably a lot of it, then that expertise could potentially be offered much more broadly. And if it's to help people exercise more and more effectively, it's going to be a lot of good that I think can come from that.Eric Topol (41:33):Yeah. No, it's really interesting. I think there's unlimited opportunities there. It's like Moneyball to the 10th power. It's like all this data that's in sports that gets me, I guess to the last question I had for you, and that is the elite athlete or athlete hard. These are people that are working out endurance just to the max, these extremists, and they're prone to heart issues like atrial fibrillation. Why is that? What's going on with these people that they exercise too much? Is it just the lack of moderation, extremism or what's going on?Euan Ashley (42:10):Yeah, well, so it's interesting that of course you mentioned atrial fibrillation. I think that really is the only downside of exercise, even fairly extreme exercise that I've ever been, I think that we've ever had really good data for. And I would say that over the years, and I've been one way or another touching the exercise science world for 20 years and more now and certainly have been asked very often, surely these people are doing themselves harm. And the reality is, although every now and again there's a study that shows some harm or they measure troponin, they measure something in the blood and someone says, oh, they must be doing themselves harm. It's been very hard to find it. The reality is atrial fibrillation though really is, especially for those ultra endurance athletes, that's for real. And that is, we don't know that it's associated with a mortality impact necessarily, but it's definitely annoying and it slows down.Endurance Athletes and Atrial Fibrillation(43:03):We have athletes who come in and say they're cycling up a hill and suddenly they drop their power drops and they realize they've gone into atrial fibrillation. I used to play basketball with someone who would go into atrial fibrillation, so I would know when to try and get past him once he went into atrial fibrillation. But that's a real thing, and I think one of your questions was why I think I have a lot of close friends who are ultra endurance runners. They're among some of the most chilled and happiest people I know. I think those benefits of exercise are what they're enjoying, and I think there's a literature on addiction to exercise. So there is a small number of people who get addicted to that feeling and addicted to the chemical matter in their brain and can't stop, and they really do get to the point of doing themselves harm.(43:53):Fortunately, I think that's a pretty small number. And overall, although there are many consequences of chronic long-term exercise, almost all of them seem to be positive. The other one that you and I are probably very familiar with is the calcium scans that we see now much more often, it's common for people who've exercised a lot to have more calcium in their hearts. Now they have a lower risk of that. They have lower risk of heart attacks in general, one or two studies muddied the waters just a little. But in general, it's very clear they have very positive health benefits and yet they have more calcium. So they are an exception. We've seen in our sports cardiology clinic here at Stanford, several athletes every month, several will come in with this finding and we are explaining to them, this doesn't mean they have the same risk as someone who hasn't exercised at that level who would have that calcium score. It does seem to be very different, and it may be that there's a stabilization of those plaques in the arteries. I don't think we understand the biology that well, but we understand the epidemiology quite well, which is that their risk really is still low.Eric Topol (44:59):Yeah, no, it's interesting that there's still some uncertainties there and MoTrPAC may help guide us or at elucidate some of them. I guess it does bring up one other thing I got to get to with you because we didn't really get to the question of moderate to higher intensity, not to the level of the ultra exercises, but if you just do steps or do you sweat like hell, where do you draw the line? Or is that really part a function of age and ability? When you recommend exercise, because obviously you're rational and there's others out there that are exercising three or four hours a day and they're going to extreme craziness, but just in a reasonable thing, do you think just telling people who are 70 that walking is good enough or do you try to encourage them to push it?Euan Ashley (45:59):Yeah, I do encourage people to push it a bit because I think there's clear evidence that higher intensity, some degree of higher intensity exercise really does provide more benefit. But I think my main message first is because for most people, the potential of moderate versus high is in the distance and in the future for most people, we need to get them off the couch and get them on their feet. So my emphasis is that you can go a long way with just a little movement, even a little standing. And then I think if they're really getting into the habit and really doing some exercise then, and if they don't have a prior history of let's say, heart attack or other medical issues that might make high intensity exercise risky, if they don't have those, then I absolutely do get to the point where I recommend some amount of higher intensity exercise, because I think there is some evidence that it has a little extra benefit.Eric Topol (46:51):Oh, that's great. Well, this is the most in-depth conversation I've ever had with anybody on exercise, so Euan I really appreciate it. I mean, I knew you from all your work in genomics of course, and we've had some overlap from time to time, but the exercise stuff is fantastic. Did I miss anything?Euan Ashley (47:09):No, I don't think so. Just underline again to anyone who's listening if they're interested to play with this data, it's very much out there. It's a tool for the world, and they can go to https://motrpac-data.org/ and even you can do some analysis without downloading any data either. If you just have a favorite gene or a favorite protein, you can type that in and take a look at some of the tools we have there. But yeah, really appreciate the conversation and very fun to chat about what has been a really, really fun project.Eric Topol (47:39):Well, thank you and all the folks at MoTrPAC, all the hard work and of course the funding that got it going to give it that runway of several years. So we'll look forward to more. I hope to convene with you again when some of the other studies come out, and thanks so much.*****************************************************Thanks for listening, reading or watching!The Ground Truths newsletters and podcasts are all free, open-access, without ads.Please share this post/podcast with your friends and network if you found it informativeVoluntary paid subscriptions all go to support Scripps Research. Many thanks for that—they greatly helped fund our summer internship programs for 2023 and 2024.Thanks to my producer Jessica Nguyen and Sinjun Balabanoff for audio and video support at Scripps Research.Note: you can select preferences to receive emails about newsletters, podcasts, or all I don't want to bother you with an email for content that you're not interested in. Get full access to Ground Truths at erictopol.substack.com/subscribe

In this podcast, Thomas Czech, Distinguished Professor at the University of Colorado, Boulder, with a lineage of remarkable contributions on RNA, ribozyme, and telomeres, discuss why RNA is so incredibly versatile.Video snippet from our conversation. Full videos of all Ground Truths podcasts can be seen on YouTube here. The audios are also available on Apple and Spotify.Transcript with links to the audio and external linksEric Topol (00:07):Well, hello, this is Eric Topol from Ground Truths, and it's really a delight for me to welcome Tom Cech who just wrote a book, the Catalyst, and who is a Nobel laureate for his work in RNA. And is at the University of Colorado Boulder as an extraordinary chemist and welcome Tom.Tom Cech (00:32):Eric, I'm really pleased to be here.The RNA GuyEric Topol (00:35):Well, I just thoroughly enjoyed your book, and I wanted to start out, if I could, with a quote, which gets us right off the story here, and let me just get to it here. You say, “the DNA guy would need to become an RNA guy. Though I didn't realize it at the time, jumping ship would turn out to be the most momentous decision in my life.” Can you elaborate a bit on that?Tom Cech (01:09):As a graduate student at Berkeley, I was studying DNA and chromosomes. I thought that DNA was king and really somewhat belittled the people in the lab next door who were working on RNA, I thought it was real sort of second fiddle material. Of course, when RNA is acting just as a message, which is an important function, a critical function in all life on earth, but still, it's a function that's subservient to DNA. It's just copying the message that's already written in the playbook of DNA. But little did I know that the wonders of RNA were going to excite me and really the whole world in unimaginable ways.Eric Topol (02:00):Well, they sure have, and you've lit up the world well before you had your Nobel Prize in 1989 was Sid Altman with ribozyme. And I think one of the things that struck me, which are so compelling in the book as I think people might know, it's divided in two sections. The first is much more on the biology, and the second is much more on the applications and how it's changing the world. We'll get into it particularly in medicine, but the interesting differentiation from DNA, which is the one trick pony, as you said, all it does is store stuff. And then the incredible versatility of RNA as you discovered as a catalyst, that challenging dogma, that proteins are supposed to be the only enzymes. And here you found RNA was one, but also so much more with respect to genome editing and what we're going to get into here. So I thought what we might get into is the fact that you kind of went into the scum of the pond with this organism, which by the way, you make a great case for the importance of basic science towards the end of the book. But can you tell us about how you, and then of course, many others got into the Tetrahymena thermophila, which I don't know that much about that organism.Tom Cech (03:34):Yeah, it's related to Tetrahymena is related to paramecium, which is probably more commonly known because it's an even larger single celled animal. And therefore, in an inexpensive grade school microscope, kids can look through and see these ciliated protozoa swimming around on a glass slide. But I first learned about them when I was a postdoc at MIT and I would drive down to Joe Gall's lab at Yale University where Liz Blackburn was a postdoc at the time, and they were all studying Tetrahymena. It has the remarkable feature that it has 10,000 identical copies of a particular gene and for a higher organism, one that has its DNA in the nucleus and does its protein synthesis in the cytoplasm. Typically, each gene's present in two copies, one from mom, one from dad. And if you're a biochemist, which I am having lots of stuff is a real advantage. So 10,000 copies of a particular gene pumping out RNA copies all the time was a huge experimental advantage. And that's what I started working on when I started my own lab at Boulder.Eric Topol (04:59):Well, and that's where, I guess the title of the book, the Catalyst ultimately, that grew into your discovery, right?Tom Cech (05:08):Well, at one level, yes, but I also think that the catalyst in a more general conversational sense means just facilitating life in this case. So RNA does much more than just serve as a biocatalyst or a message, and we'll get into that with genome editing and with telomerase as well.The Big Bang and 11 Nobel Prizes on RNA since 2000Eric Topol (05:32):Yes, and I should note that as you did early in the book, that there's been an 11 Nobel prize awardees since 2000 for RNA work. And in fact, we just had Venki who I know you know very well as our last podcast. And prior to that, Kati Karikó, Jennifer Doudna who worked in your lab, and the long list of people working RNA in the younger crowd like David Liu and Fyodor Urnov and just so many others, we need to have an RNA series because it's just exploding. And that one makes me take you back for a moment to 2007. And when I was reading the book, it came back to me about the Economist cover. You may recall almost exactly 17 years ago. It was called the Biology's Big Bang – Unravelling the secrets of RNA. And in that, there was a notable quote from that article. Let me just get to that. And it says, “it is probably no exaggeration to say that biology is now undergoing its neutron moment.”(06:52):This is 17 years ago. “For more than half a century the fundamental story of living things has been a tale of the interplay between genes, in the form of DNA, and proteins, which is genes encode and which do the donkey work of keeping living organisms living. The past couple of years, 17 years ago, however, has seen the rise and rise of a third type of molecule, called RNA.” Okay, so that was 2007. It's pretty extraordinary. And now of course we're talking about the century of biology. So can you kind of put these last 17 years in perspective and where we're headed?Tom Cech (07:34):Well, Eric, of course, this didn't all happen in one moment. It wasn't just one big bang. And the scientific community has been really entranced with the wonders of RNA since the 1960s when everyone was trying to figure out how messenger RNA stored the genetic code. But the general public has been really kept in the dark about this, I think. And as scientists, were partially to blame for not reaching out and sharing what we have found with them in a way that's more understandable. The DNA, the general public's very comfortable with, it's the stuff of our heredity. We know about genetic diseases, about tracing our ancestry, about solving crimes with DNA evidence. We even say things like it's in my DNA to mean that it's really fundamental to us. But I think that RNA has been sort of kept in the closet, and now with the mRNA vaccines against Covid-19, at least everyone's heard of RNA. And I think that that sort of allowed me to put my foot in the door and say, hey, if you were curious about the mRNA vaccines, I have some more stories for you that you might be really interested in.RNA vs RNAEric Topol (09:02):Yeah, well, we'll get to that. Maybe we should get to that now because it is so striking the RNA versus RNA chapter in your book, and basically the story of how this RNA virus SARS-CoV-2 led to a pandemic and it was fought largely through the first at scale mRNA nanoparticle vaccine package. Now, that takes us back to some seminal work of being able to find, giving an mRNA to a person without inciting massive amount of inflammation and the substitution of pseudouridine or uridine in order to do that. Does that really get rid of all the inflammation? Because obviously, as you know, there's been some negativism about mRNA vaccines for that and also for the potential of not having as much immune cell long term activation. Maybe you could speak to that.Tom Cech (10:03):Sure. So the discovery by Kati Karikó and Drew Weissman of the pseudouridine substitution certainly went a long way towards damping down the immune response, the inflammatory response that one naturally gets with an RNA injection. And the reason for that is that our bodies are tuned to be on the lookout for foreign RNA because so many viruses don't even mess with DNA at all. They just have a genome made of RNA. And so, RNA replicating itself is a danger sign. It means that our immune system should be on the lookout for this. And so, in the case of the vaccination, it's really very useful to dampen this down. A lot of people thought that this might make the mRNA vaccines strange or foreign or sort of a drug rather than a natural substance. But in fact, modified nucleotides, nucleotides being the building blocks of RNA, so these modified building blocks such as pseudoU, are in fact found in natural RNAs more in some than in others. And there are about 200 modified versions of the RNA building blocks found in cells. So it's really not an unusual modification or something that's all that foreign, but it was very useful for the vaccines. Now your other question Eric had to do with the, what was your other question, Eric?Eric Topol (11:51):No, when you use mRNA, which is such an extraordinary way to get the spike protein in a controlled way, exposed without the virus to people, and it saved millions of lives throughout the pandemic. But the other question is compared to other vaccine constructs, there's a question of does it give us long term protective immunity, particularly with T cells, both CD8 cytotoxic, maybe also CD4, as I know immunology is not your main area of interest, but that's been a rub that's been put out there, that it isn't just a weaning of immunity from the virus, but also perhaps that the vaccines themselves are not as good for that purpose. Any thoughts on that?Tom Cech (12:43):Well, so my main thought on that is that this is a property of the virus more than of the vaccine. And respiratory viruses are notoriously hard to get long-term immunity. I mean, look at the flu virus. We have to have annual flu shots. If this were like measles, which is a very different kind of virus, one flu shot would protect you against at least that strain of flu for the rest of your life. So I think the bad rap here is not the vaccine's fault nearly as much as it's the nature of respiratory viruses.RNA And Aging Eric Topol (13:27):No, that's extremely helpful. Now, let me switch to an area that's really fascinating, and you've worked quite a bit on the telomerase story because this is, as you know, being pursued quite a bit, has thought, not just because telomeres might indicate something about biologic aging, but maybe they could help us get to an anti-aging remedy or whatever you want to call it. I'm not sure if you call it a treatment, but tell us about this important enzyme, the role of the RNA building telomeres. And maybe you could also connect that with what a lot of people might not be familiar with, at least from years ago when they learned about it, the Hayflick limit.Tom Cech (14:22):Yes. Well, Liz Blackburn and Carol Greider got the Nobel Prize for the discovery of telomerase along with Jack Szostak who did important initial work on that system. And what it does is, is it uses an RNA as a template to extend the ends of human chromosomes, and this allows the cell to keep dividing without end. It gives the cell immortality. Now, when I say immortality, people get very excited, but I'm talking about immortality at the cellular level, not for the whole organism. And in the absence of a mechanism to build out the ends of our chromosomes, the telomeres being the end of the chromosome are incompletely replicated with each cell division. And so, they shrink over time, and when they get critically short, they signal the cell to stop dividing. This is what is called the Hayflick limit, first discovered by Leonard Hayflick in Philadelphia.(15:43):And he, through his careful observations on cells, growing human cells growing in Petri dishes, saw that they could divide about 50 times and then they wouldn't die. They would just enter a state called senescence. They would change shape, they would change their metabolism, but they would importantly quit dividing. And so, we now see this as a useful feature of human biology that this protects us from getting cancer because one of the hallmarks of cancer is immortality of the tumor cells. And so, if you're wishing for your telomeres to be long and your cells to keep dividing, you have to a little bit be careful what you wish for because this is one foot in the door for cancer formation.Eric Topol (16:45):Yeah, I mean, the point is that it seems like the body and the cell is smart to put these cells into the senescent state so they can't divide anymore. And one of the points you made in the book that I think is worth noting is that 90% of cancers have the telomerase, how do you say it?Tom Cech (17:07):Telomerase.Eric Topol (17:08):Yeah, reactivate.Tom Cech (17:09):Right.Eric Topol (17:10):That's not a good sign.Tom Cech (17:12):Right. And there are efforts to try to target telomerase enzyme for therapeutic purposes, although again, it's tricky because we do have stem cells in our bodies, which are the exception to the Hayflick limit rule. They do still have telomerase, they still have to keep dividing, maybe not as rapidly as a cancer cell, but they still keep dividing. And this is critical for the replenishment of certain worn out tissues in our such as skin cells, such as many of our blood cells, which may live only 30 days before they poop out. That's a scientific term for needing to be replenished, right?Eric Topol (18:07):Yeah. Well, that gets me to the everybody's, now I got the buzz about anti-aging, and whether it's senolytics to get rid of these senescent cells or whether it's to rejuvenate the stem cells that are exhausted or work on telomeres, all of these seem to connect with a potential or higher risk of cancer. I wonder what your thoughts are as we go forward using these various biologic constructs to be able to influence the whole organism, the whole human body aging process.Tom Cech (18:47):Yes. My view, and others may disagree is that aging is not an affliction. It's not a disease. It's not something that we should try to cure, but what we should work on is having a healthy life into our senior years. And perhaps you and I are two examples of people who are at that stage of our life. And what we would really like is to achieve, is to be able to be active and useful to society and to our families for a long period of time. So using the information about telomerase, for example, to help our stem cells stay healthy until we are, until we're ready to cash it in. And for that matter on the other side of the coin, to try to inhibit the telomerase in cancer because cancer, as we all know, is a disease of aging, right? There are young people who get cancer, but if you look at the statistics, it's really heavily weighted towards people who've been around a long time because mutations accumulate and other damage to cells that would normally protect against cancer accumulates. And so, we have to target both the degradation of our stem cells, but also the occurrence of cancer, particularly in the more senior population. And knowing more about RNA is really helpful in that regard.RNA DrugsEric Topol (20:29):Yeah. Well, one of the things that comes across throughout the book is versatility of RNA. In fact, you only I think, mentioned somewhere around 12 or 14 of these different RNAs that have a million different shapes, and there's so many other names of different types of RNAs. It's really quite extraordinary. But one of the big classes of RNAs has really hit it. In fact, this week there are two new interfering RNAs that are having extraordinary effects reported in the New England Journal on all the lipids, abnormal triglycerides and LDL cholesterol, APOC3. And can you talk to us about this interfering the small interfering RNAs and how they become, you've mentioned in the book over 400 RNAs are in the clinic now.Tom Cech (21:21):Yeah, so the 400 of course is beyond just the siRNAs, but these, again, a wonderful story about how fundamental science done just to understand how nature works without any particular expectation of a medical spinoff, often can have the most phenomenal and transformative effects on medicine. And this is one of those examples. It came from a roundworm, which is about the size of an eyelash, which a scientist named Sydney Brenner in England had suggested would be a great experimental organism because the entire animal has only about a thousand cells, and it's transparent so we can look at, see where the cells are, we can watch the worm develop. And what Andy Fire and Craig Mello found in this experimental worm was that double-stranded RNA, you think about DNA is being double-stranded and RNA as being single stranded. But in this case, it was an unusual case where the RNA was forming a double helix, and these little pieces of double helical RNA could turn off the expression of genes in the worm.(22:54):And that seemed remarkable and powerful. But as often happens in biology, at least for those of us who believe in evolution, what goes for the worm goes for the human as well. So a number of scientists quickly found that the same process was going on in the human body as a natural way of regulating the expression of our genes, which means how much of a particular gene product is actually going to be made in a particular cell. But not only was it a natural process, but you could introduce chemically synthesized double helical RNAs. There are only 23 base pairs, 23 units of RNA long, so they're pretty easy to chemically synthesize. And that once these are introduced into a human, the machinery that's already there grabs hold of them and can be used to turn off the expression of a disease causing RNA or the gene makes a messenger RNA, and then this double-stranded RNA can suppress its action. So this has become the main company that is known for doing this is Alnylam in Boston, Cambridge. And they have made quite a few successful products based on this technology.Eric Topol (24:33):Oh, absolutely. Not just for amyloidosis, but as I mentioned these, they even have a drug that's being tested now, as you know that you could take once or twice a year to manage your blood pressure. Wouldn't that be something instead of a pill every day? And then of course, all these others that are not just from Alnylam, but other companies I wasn't even familiar with for managing lipids, which is taking us well beyond statins and these, so-called PCSK9 monoclonal antibodies, so it's really blossoming. Now, the other group of RNA drugs are antisense drugs, and it seemed like they took forever to warm up, and then finally they hit. And can you distinguish the antisense versus the siRNA therapeutics?Tom Cech (25:21):Yes, in a real general sense, there's some similarity as well as some differences, but the antisense, what are called oligonucleotides, whoa, that's a big word, but oligo just means a few, right? And nucleotides is just the building blocks of nucleic acid. So you have a string of a few of these. And again, it's the power of RNA that it is so good at specifically base pairing only with matching sequences. So if you want to match with a G in a target messenger RNA, you put a C in the antisense because G pairs with C, if you want to put an A, if want to match with an A, you put a U in the antisense because A and U form a base pair U is the RNA equivalent of T and DNA, but they have the same coding capacity. So any school kid can write out on a notepad or on their laptop what the sequence would have to be of an antisense RNA to specifically pair with a particular mRNA.(26:43):And this has been, there's a company in your neck of the woods in the San Diego area. It started out with the name Isis that turned out to be the wrong Egyptian God to name your company after, so they're now known as Ionis. Hopefully that name will be around for a while. But they've been very successful in modifying these antisense RNAs or nucleic acids so that they are stable in the body long enough so that they can pair with and thereby inhibit the expression of particular target RNAs. So it has both similarities and differences from the siRNAs, but the common denominator is RNA is great stuff.RNA and Genome EditingEric Topol (27:39):Well, you have taken that to in catalyst, the catalyst, you've proven that without a doubt and you and so many other extraordinary scientists over the years, cumulatively. Now, another way to interfere with genes is editing. And of course, you have a whole chapter devoted to not just well CRISPR, but the whole genome editing field. And by the way, I should note that I forgot because I had read the Codebreaker and we recently spoke Jennifer Doudna and I, that she was in your lab as a postdoc and you made some wonderful comments about her. I don't know if you want to reflect about having Jennifer, did you know that she was going to do some great things in her career?Tom Cech (28:24):Oh, there was no question about it, Eric. She had been a star graduate student at Harvard, had published a series of breathtaking papers in magazines such as Science and Nature already as a graduate student. She won a Markey fellowship to come to Colorado. She chose a very ambitious project trying to determine the molecular structures of folded RNA molecules. We only had one example at the time, and that was the transfer RNA, which is involved in protein synthesis. And here she was trying these catalytic RNAs, which we had discovered, which were much larger than tRNA and was making great progress, which she finished off as an assistant professor at Yale. So what the general public may not know was that in scientific, in the scientific realm, she was already highly appreciated and much awarded before she even heard anything about CRISPR.Eric Topol (29:38):Right. No, it was a great line you have describing her, “she had an uncanny talent for designing just the right experiment to test any hypothesis, and she possessed more energy and drive than any scientist I'd ever met.” That's pretty powerful. Now getting into CRISPR, the one thing, it's amazing in just a decade to see basically the discovery of this natural system to then be approved by FDA for sickle cell disease and beta thalassemia. However, the way it exists today, it's very primitive. It's not actually fixing the gene that's responsible, it's doing a workaround plan. It's got double strand breaks in the DNA. And obviously there's better ways of editing, which are going to obviously involve RNA epigenetic editing, if you will as well. What is your sense about the future of genome editing?Tom Cech (30:36):Yeah, absolutely, Eric. It is primitive right now. These initial therapies are way too expensive as well to make them broadly applicable to the entire, even in a relatively wealthy country like the United States, we need to drive the cost down. We need to get them to work, we need to get the process of introducing them into the CRISPR machinery into the human body to be less tedious and less time consuming. But you've got to start somewhere. And considering that the Charpentier and Doudna Nobel Prize winning discovery was in 2012, which is only a dozen years ago, this is remarkable progress. More typically, it takes 30 years from a basic science discovery to get a medical product with about a 1% chance of it ever happening. And so, this is clearly a robust RNA driven machine. And so, I think the future is bright. We can talk about that some more, but I don't want to leave RNA out of this conversation, Eric. So what's cool about CRISPR is its incredible specificity. Think of the human genome as a million pages of text file on your computer, a million page PDF, and now CRISPR can find one sentence out of that million pages that matches, and that's because it's using RNA, again, the power of RNA to form AU and GC base pairs to locate just one site in our whole DNA, sit down there and direct this Cas9 enzyme to cut the DNA at that site and start the repair process that actually does the gene editing.Eric Topol (32:41):Yeah, it's pretty remarkable. And the fact that it can be so precise and it's going to get even more precise over time in terms of the repair efforts that are needed to get it back to an ideal state. Now, the other thing I wanted to get into with you a bit is on the ribosome, because that applies to antibiotics and as you call it, the mothership. And I love this metaphor that you had about the ribosome, and in the book, “the ribosome is your turntable, the mRNA is the vinyl LP record, and the protein is the music you hear when you lower the needle.” Tell us more about the ribosome and the role of antibiotics.Tom Cech (33:35):So do you think today's young people will understand that metaphor?Eric Topol (33:40):Oh, they probably will. They're making a comeback. These records are making a comeback.Tom Cech (33:44):Okay. Yes, so this is a good analogy in that the ribosome is so versatile it's able to play any music that you feed at the right messenger RNA to make the music being the protein. So you can have in the human body, we have tens of thousands of different messenger RNAs. Each one threads through the same ribosome and spills out the production of whatever protein matches that mRNA. And so that's pretty remarkable. And what Harry Noller at UC Santa Cruz and later the crystallographers Venki Ramakrishnan, Tom Steitz, Ada Yonath proved really through their studies was that this is an RNA machine. It was hard to figure that out because the ribosome has three RNAs and it has dozens of proteins as well. So for a long time people thought it must be one of those proteins that was the heart and soul of the record player, so to speak.RNA and Antibiotics(34:57):And it turned out that it was the RNA. And so, when therefore these scientists, including Venki who you just talked to, looked at where these antibiotics docked on the ribosome, they found that they were blocking the key functional parts of the RNA. So it was really, the antibiotics knew what they were doing long before we knew what they were doing. They were talking to and obstructing the action of the ribosomal RNA. Why is this a good thing for us? Because bacterial ribosomes are just enough different from human ribosomes that there are drugs that will dock to the bacterial ribosomal RNA, throw a monkey wrench into the machine, prevent it from working, but the human ribosomes go on pretty much unfazed.Eric Topol (36:00):Yeah, no, the backbone of our antibiotics relies on this. So I think people need to understand about the two subunits, the large and the small and this mothership, and you illuminate that so really well in the book. That also brings me to phage bacteria phage, and we haven't seen that really enter the clinic in a significant way, but there seems to be a great opportunity. What's your view about that?Tom Cech (36:30):This is an idea that goes way back because since bacteria have their own viruses which do not infect human cells, why not repurpose those into little therapeutic entities that could kill, for example, what would we want to kill? Well, maybe tuberculosis has been very resistant to drugs, right? There are drug resistant strains of TB, yes, of TB, tuberculosis, and especially in immunocompromised individuals, this bug runs rampant. And so, I don't know the status of that. It's been challenging, and this is the way that biomedicine works, is that for every 10 good ideas, and I would say phage therapy for bacterial disease is a good idea. For every 10 such ideas, one of them ends up being practical. And the other nine, maybe somebody else will come along and find a way to make it work, but it hasn't been a big breakthrough yet.RNA, Aptamers and ProteinsEric Topol (37:54):Yeah, no, it's really interesting. And we'll see. It may still be in store. What about aptamers? Tell us a little bit more about those, because they have been getting used a lot in sorting out the important plasma proteins as therapies. What are aptamers and what do you see as the future in that regard?Tom Cech (38:17):Right. Well, in fact, aptamers are a big deal in Boulder because Larry Gold in town was one of the discoverers has a company making aptamers to recognize proteins. Jack Szostak now at University of Chicago has played a big role. And also at your own institution, Jerry Joyce, your president is a big aptamer guy. And you can evolution, normally we think about it as happening out in the environment, but it turns out you can also make it work in the laboratory. You can make it work much faster in the laboratory because you can set up test tube experiments where molecules are being challenged to perform a particular task, like for example, binding to a protein to inactivate it. And if you make a large community of RNA molecules randomly, 99.999% of them aren't going to know how to do this. What are the odds? Very low.(39:30):But just by luck, there will be an occasional molecule of RNA that folds up into a shape that actually fits into the proteins active sighting throws a monkey wrench into the works. Okay, so now that's one in a billion. How are you going to find that guy? Well, this is where the polymerase chain reaction, the same one we use for the COVID-19 tests for infection comes into play. Because if you can now isolate this needle in a haystack and use PCR to amplify it and make a whole handful of it, now you've got a whole handful of molecules which are much better at binding this protein than the starting molecule. And now you can go through this cycle several times to enrich for these, maybe mutagen it a little bit more to give it a little more diversity. We all know diversity is good, so you put a little more diversity into the population and now you find some guy that's really good at recognizing some disease causing protein. So this is the, so-called aptamer story, and they have been used therapeutically with some success, but diagnostically certainly they are extremely useful. And it's another area where we've had success and the future could hold even more success.Eric Topol (41:06):I think what you're bringing up is so important because the ability to screen that tens of thousands of plasma proteins in a person and coming up with as Tony Wyss-Coray did with the organ clocks, and this is using the SomaLogic technology, and so much is going on now to get us not just the polygenic risk scores, but also these proteomic scores to compliment that at our orthogonal, if you will, to understand risk of people for diseases so we can prevent them, which is fulfilling a dream we've never actually achieved so far.Tom Cech (41:44):Eric, just for full disclosure, I'm on the scientific advisory board of SomaLogic in Boulder. I should disclose that.Eric Topol (41:50):Well, that was smart. They needed to have you, so thank you for mentioning that. Now, before I wrap up, well, another area that is a favorite of mine is citizen science. And you mentioned in the book a project because the million shapes of RNA and how it can fold with all hairpin terms turns and double stranded and whatever you name it, that there was this project eteRNA that was using citizen scientists to characterize and understand folding of RNA. Can you tell us about that?RNA Folding and Citizen ScienceTom Cech (42:27):So my friend Rhiju Das, who's a professor at Stanford University, sort of adopted what had been done with protein folding by one of his former mentors, David Baker in Seattle, and had repurposed this for RNA folding. So the idea is to come up with a goal, a target for the community. Can you design an RNA that will fold up to look like a four pointed cross or a five pointed star? And it turned out that, so they made it into a contest and they had tens of thousands of people playing these games and coming up with some remarkable solutions. But then they got a little bit more practical, said, okay, that was fun, but can we have the community design something like a mRNA for the SARS-CoV-2 spike protein to make maybe a more stable vaccine? And quite remarkably, the community of many of whom are just gamers who really don't know much about what RNA does, were able to find some solutions. They weren't enormous breakthroughs, but they got a several fold, several hundred percent increase in stability of the RNA by making it fold more tightly. So I just find it to be a fascinating approach to science. Somebody of my generation would never think of this, but I think for today's generation, it's great when citizens can become involved in research at that level.Eric Topol (44:19):Oh, I think it's extraordinary. And of course, there are other projects folded and others that have exemplified this ability for people with no background in science to contribute in a meaningful way, and they really enjoy, it's like solving a puzzle. The last point is kind of the beginning, the origin of life, and you make a pretty strong case, Tom, that it was RNA. You don't say it definitively, but maybe you can say it here.RNA and the Origin of LifeTom Cech (44:50):Well, Eric, the origin of life happening almost 4 billion years ago on our primitive planet is sort of a historical question. I mean, if you really want to know what happened then, well, we don't have any video surveillance of those moments. So scientists hate to ever say never, but it's hard to sort of believe how we would ever know for sure. So what Leslie Orgel at the Salk Institute next to you taught me when I was a starting assistant professor is even though we'll never know for sure, if we can recapitulate in the laboratory plausible events that could have happened, and if they make sense chemically and biologically, then that's pretty satisfying, even if we can never be absolutely sure. That's what a number of scientists have done in this field is to show that RNA is sort of a, that all the chemistry sort of points to RNA as being something that could have been made under prebiotic conditions and could have folded up into a way that could solve the greatest of all chicken and egg problems, which came first, the informational molecule to pass down to the next generation or the active molecule that could copy that information.(46:32):So now that we know that RNA has both of those abilities, maybe at the beginning there was just this RNA world RNA copying itself, and then proteins came along later, and then DNA probably much more recently as a useful but a little bit boring of genetic information, right?Eric Topol (46:59):Yeah. Well, that goes back to that cover of the Economist 17 years ago, the Big Bang, and you got me convinced that this is a pretty strong story and candidate. Now what a fun chance to discuss all this with you in an extraordinary book, Tom. Did I miss anything that you want to bring up?Tom Cech (47:21):Eric, I just wanted to say that I not only appreciate our conversation, but I also appreciate all you are doing to bring science to the non-scientist public. I think people like me who have taught a lot of freshmen in chemistry, general chemistry, sort of think that that's the level that we need to aim at. But I think that those kids have had science in high school year after year. We need to aim at the parents of those college freshmen who are intelligent, who are intellectually curious, but have not had science courses in a long time. And so, I'm really joining with you in trying to avoid jargon as much as possible. Use simple language, use analogies and metaphors, and try to share the excitement of what we're doing in the laboratory with the populace.Eric Topol (48:25):Well, you sure did that it was palpable. And I thought about it when I read the book about how lucky it would be to be a freshman at the University of Boulder and be having you as the professor. My goodness. Well, thank you so much. This has been so much fun, Tom, and I hope everybody's going to get out there and read the Catalyst to get all the things that we didn't even get a chance to dive into. But this has been great and look forward to future interactions with you.Tom Cech (48:53):Take care, Eric.*********************Thanks for listening or reading this edition of Ground Truths.Please share this podcast with your friends and network. That tells me you found it informative and makes the effort in doing these worthwhile.All Ground Truths newsletters and podcast are free. Voluntary paid subscriptions all go to support Scripps Research. 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Professor Venki Ramakrishnan, a Nobel laureate for his work on unraveling the structure of function of the ribosome, has written a new book WHY WE DIE which is outstanding. Among many posts and recognitions for his extraordinary work in molecular biology, Venki has been President of the Royal Society, knighted in 2012, and was made a Member of the Order of Merit in 2022. He is a group leader at the MRC Laboratory of Molecular Biology research institute in Cambridge, UK.A brief video snippet of our conversation below. Full videos of all Ground Truths podcasts can be seen on YouTube here. The audios are available on Apple and Spotify.Transcript with links to audio and external linksEric Topol (00:06):Hello, this is Eric Topol with Ground Truths, and I have a really special guest today, Professor Venki Ramakrishnan from Cambridge who heads up the MRC Laboratory of Molecular Biology, and I think as you know a Nobel laureate for his seminal work on ribosomes. So thank you, welcome.Venki Ramakrishnan (00:29):Thank you. I just want to say that I'm not the head of the lab. I'm simply a staff member here.Eric Topol (00:38):Right. No, I don't want to give you more authority than you have, so that was certainly not implied. But today we're here to talk about this amazing book, Why We Die, which is a very provocative title and it mainly gets into the biology of aging, which Venki is especially well suited to be giving us a guided tour and his interpretations and views. And I read this book with fascination, Venki. I have three pages of typed notes from your book.The Compression of MorbidityEric Topol (01:13):And we could talk obviously for hours, but this is fascinating delving into this hot area, as you know, very hot area of aging. So I thought I'd start off more towards the end of the book where you kind of get philosophical into the ethics. And there this famous concept by James Fries of compression of morbidity that's been circulating for well over two decades. That's really the big question about all this aging effort. So maybe you could give us, do you think there is evidence for compression of morbidity so that you can just extend healthy aging and then you just fall off the cliff?Venki Ramakrishnan (02:00):I think that's the goal of most of the sort of what I call the saner end of the aging research community is to improve our health span. That is the number of years we have healthy lives, not so much to extend lifespan, which is how long we live. And the idea is that you take those years that we now spend in poor health or decrepitude and compress them down to just very short time, so you're healthy almost your entire life, and then suddenly go into a rapid decline and die. Now Fries who actually coined that term compression or morbidity compares this to the One-Hoss Shay after poem by Oliver Wendell Holmes from the 19th century, which is about this horse carriage that was designed so perfectly that all its parts wore out equally. And so, a farmer was riding along in this carriage one minute, and the next minute he found himself on the ground surrounded by a heap of dust, which was the entire carriage that had disintegrated.Venki Ramakrishnan (03:09):So the question I would ask is, if you are healthy and everything about you is healthy, why would you suddenly go into decline? And it's a fair question. And every advance we've made that has kept us healthier in one respect or another. For example, tackling diabetes or tackling heart disease has also extended our lifespan. So people are not living a bigger fraction of their lives healthily now, even though we're living longer. So the result is we're spending the same or even more number of years with one or more health problems in our old age. And you can see that in the explosion of nursing homes and care homes in almost all western countries. And as you know, they were big factors in Covid deaths. So I'm not sure it can be accomplished. I think that if we push forward with health, we're also going to extend our lifespan.Venki Ramakrishnan (04:17):Now the argument against that comes from studies of these, so-called super centenarians and semi super centenarians. These are people who live to be over 105 or 110. And Tom Perls who runs the New England study of centenarians has published findings which show that these supercentenarians live extraordinarily healthy lives for most of their life and undergo rapid decline and then die. So that's almost exactly what we would want. So they have somehow accomplished compression of morbidity. Now, I would say there are two problems with that. One is, I don't know about the data sample size. The number of people who live over 110 is very, very small. The other is they may be benefiting from their own unique genetics. So they may have a particular combination of genetics against a broad genetic background that's unique to each person. So I'm not sure it's a generally translatable thing, and it also may have to do with their particular life history and lifestyle. So I don't know how much of what we learned from these centenarians is going to be applicable to the population as a whole. And otherwise, I don't even know how this would be accomplished. Although some people feel there's a natural limit to our biology, which restricts our lifespan to about 115 or 120 years. Nobody has lived more than 122. And so, as we improve our health, we may come up against that natural limit. And so, you might get a compression of morbidity. I'm skeptical. I think it's an unsolved problem.Eric Topol (06:14):I think I'm with you about this, but there's a lot of conflation of the two concepts. One is to suppress age related diseases, and the other is to actually somehow modulate control the biologic aging process. And we lump it all together as you're getting at, which is one of the things I loved about your book is you really give a balanced view. You present the contrarians and the different perspectives, the perspective about people having age limits potentially much greater than 120, even though as you say, we haven't seen anyone live past 122 since 1997, so it's quite a long time. So this, I think, conflation of what we do today as far as things that will reduce heart disease or diabetes, that's age related diseases, that's very different than controlling the biologic aging process. Now getting into that, one of the things that's particularly alluring right now, my friend here in San Diego, Juan Carlos Belmonte, who went over from Salk, which surprised me to the Altos Labs, as you pointed on in the book.Venki Ramakrishnan (07:38):I'm not surprised. I mean, you have a huge salary and all the resources you want to carry out the same kind of research. I wouldn't blame any of these guys.Rejuvenating Animals With Yamanaka FactorsEric Topol (07:50):No, I understand. I understand. It's kind of like the LIV Golf tournament versus the PGA. It's pretty wild. At any rate, he's a good friend of mine, and I visited with him recently, and as you mentioned, he has over a hundred people working on this partial epigenetic reprogramming. And just so reviewing this for the uninitiated is giving the four Yamanaka transcription factors here to the whole animal or the mouse and rejuvenating old mice, essentially at least those with progeria. And then others have, as you point out in the book, done this with just old mice. So one of the things that strikes me about this, and in talking with him recently is it's going to be pretty hard to give these Yamanaka factors to a person, an intravenous infusion. So what are your thoughts about this rejuvenation of a whole person? What do you think?Venki Ramakrishnan (08:52):If I hadn't seen some of these papers would've been even more skeptical. But the data from, well, Belmonte's work was done initially on progeria mice. These are mice that age prematurely. And then people thought, well, they may not represent natural aging, and what you're doing is simply helping with some abnormal form of aging. But he and other groups have now done it with normal mice and observed similar effects. Now, I would say reprogramming is one way. It's a very exciting and powerful way to almost try to reverse aging because you're trying to take cells back developmentally. You're taking possibly fully differentiated cells back to stem cells and then helping regenerate tissue, which one of the problems as we age is we start losing stem cells. So we have stem cell depletion, so we can no longer replace our tissues as we do when we're younger. And I think anyone who knows who's had a scrape or been hurt in a fall or something knows this because if I fall and scrape my elbow and get a big bruise and my grandson falls, we repair our tissues at very, very different rates. It takes me days or weeks to recover, and my grandson's fine in two or three days. You can hardly see he had a scrape at all. So I think that's the thing that these guys want to do.Venki Ramakrishnan (10:48):And the problem is Yamanaka factors are cancer. Two of them are oncogenic factors, right? If you give Yamanaka factors to cells, you can take them all the way back to what are called pluripotent cells, which are the cells that are capable of forming any tissue in the body. So for example, a fertilized egg or an early embryo cells from the early embryo are pluripotent. They could form anything in the body. Now, if you do that to cells with Yamanaka factors, they often form teratomas, which are these unusual forms of cancer tumors. And so, I think there's a real risk. And so, what these guys say is, well, we'll give these factors transiently, so we'll only take the cells back a little ways and not all the way back to pluripotency. And that way if you start with skin cells, you'll get the progenitor stem cells for skin cells. And the problem with that is when you do it with a population, you're getting a distribution. Some of them will go back just a little, some of them may go back much more. And I don't know how to control all this. So I think it's very exciting research. And of course, if I were one of these guys, I would certainly want to carry on doing that research. But I don't think it's anywhere near ready for primetime in terms of giving it to human beings as a sort of anti-aging therapeutic.Aging and Cancer Shared HallmarksEric Topol (12:31):Yeah. Well, I couldn't agree more on that because this is a company that's raised billions of dollars to go into clinical trials. And the question that comes up here, which is a theme in the book and a theme with the aging process to try to artificially, if you will affect it, is this risk of cancer. And as we know, the hallmarks of aging overlap considerably with the hallmarks of cancer. And this is just one example, as you mentioned, where these transcription factors could result in generating cancer. But as you also point out in the book at many places, methylation changes, DNA, repair, and telomeres.Venki Ramakrishnan (13:21):And telomeres.Venki Ramakrishnan (13:24):All of those are related to cancer as well. And this was first pointed out to me by Titia de Lange, who's a world expert on telomeres at Rockefeller, and she was pointing out to me the intimate connection between cancer and aging and many mechanisms that have evolved to prevent cancer early in life tend to cause aging later in life, including a lot of DNA damage response, which sends cells into senescence and therefore causes aging. Buildup of senescence cells is a problem later in life with aging, but it has a role which is to prevent cancer early in life. And so, I think it's going to be the same problem with stem cell therapy. I think very targeted stem cell therapy, which is involved in replacing certain tissues, the kind of regenerative medicine that stem cells have been trying to address for a very long time, and only now we're beginning to see some of the successes of that. So it's been very slow, even when the goal and target is very specific and well-defined, and there you are using that stem cell to treat a pretty bad disease or some really serious problem. I think with aging, the idea that somebody might take this so they can live an extra 10 years, it's a much higher bar in terms of safety and long-term safety and efficacy. So I don't think that this is going to happen anytime soon, but it's not to say it'll never happen. There is some serious biology underlying it.Eric Topol (15:13):Right. Well, you just touched on this, but of course the other, there's several big areas that are being explored, and one of them is trying to deal with these senescent cells and trying to get rid of them from the body because they can secrete evil humors, if you will. And the problem with that, it seems that these senescent cells are sort of protective. They stop dividing, they're not going to become cancerous, although perhaps they could contribute to that in some way. So like you say, with telomeres and so many things that are trying to be manipulated here, there's this downside risk and it seems like this is what we're going to have to confront this. We have seen Venki with the CAR-T, the T-cell engineering, there's this small risk of engendering cancer while you're trying to deal with the immune system.SenolyticsVenki Ramakrishnan (16:07):Yeah, I think with senescent cells, the early in life senescent cells have an important role in biology. They're essentially signaling to the immune system that there's a site that's subject to viral infection or wounds or things like that. So it's a signal to send other kinds of cells there to come and repair the damage. Now, of course, that evolved to help us early in life. And also many senescent cells were a response to DNA damage. And that's again, a way for the body that if your DNA is damaged, you don't want that cell to be able to divide indefinitely because it could become cancerous. And so, you send it into senescence and get it out of harm's way. So early life, we were able to get rid of these senescent cells, we were able to come to the site and then clean up the damage and eventually destroy the senescent cells themselves.Venki Ramakrishnan (17:08):But as we get older, the response mechanisms also deteriorate with age. Our immune system deteriorates with age, all the natural signaling mechanisms deteriorate with age. And so, we get this buildup of senescent cells. And there people have asked, well, these senescent cells don't just sit there, they secrete inflammatory compounds, which originally was a feature, not a bug, but then it becomes a problem later in life. And so, people have found that if you target senescent cells in older animals, those animals improve their symptoms of aging improved dramatically or significantly anyway. And so, this has led to this whole field called senolytics, which is being able to specifically target senescent cells. Now there the problem is how would you design compounds that are highly specific for senescent cells and don't damage your other cells and don't have other long-term side effects? So again, I think it's a promising area, but a lot of work needs to be done to establish long-term safety and efficacy.Eric Topol (18:23):Right. No, in fact, just today in Nature, there's a feature on killing the zombie cells, and it discusses just what you're pointing out, which is it's not so easy to tag these specifically and target them, even though as you know, there's some early trials and things like diabetic macular edema. And we'll see how that plays out. Now, one of the things that comes up is the young blood story. So in the young blood, whether it's this parabiosis or however you want to get at it, and I guess it even applies to the young microbiome of a gut, but there's this consistent report that there's something special going on there. And of course the reciprocal relationship of giving the old blood to the young mice, whatever, but no one can find the factor, whether it's platelet factor 4, GDF11, or what are your thoughts about this young blood story?Venki Ramakrishnan (19:25):I think there's no question that the experiments work because they were reproduced and they were reproduced over quite a long period, and which is that when you connect an old mouse or rat with a young equivalent, then the old mouse or old rat benefits from the young blood from the younger animal. And conversely, the younger animal suffers from the blood from the older animal. And then people were wondering whether this is simply that the young animal has better detoxification and things like that, or whether it's actually the blood. And they gave it just as transfusion without connecting the animals and showed that it really was the blood. And so, this of course then leads to the question, well, what is it about young blood that's beneficial and what is it about old blood that is bad? But the problem is blood has hundreds of factors. And so, they have to look at which factors are significantly different, and they might be in such small quantities that you might not be able to detect those differences very easily.Venki Ramakrishnan (20:40):And then once you've detected differences, then you have to establish their mechanism of action. And first of all, you have to establish that the factor really is beneficial. Then you have to figure out how it works and what its potential side effects could be. And so again, this is a promising area where there's a lot of research, but it has not prevented people from jumping the gun. So in the United States, and I should say a lot of them in your state, California somehow seems to attract all these immortality types. Well, anyway, a lot of companies set up to take blood from young donors, extract the plasma and then give it to rich old recipients for a fee for a healthy fee. And I think the FDA actually shut down one of them on the grounds that they were not following approved procedure. And then they tried to start up under a different name. And then eventually, I don't know what happened, but at one point the CEO said something I thought was very amusing. He said, well, the problem with clinical trials is that they take too long. I'm afraid that's characteristic of some portion of this sort of anti-aging therapeutics community. There's a very mainstream rigorous side to it, but there's also at the other end of the spectrum, kind of the wild west where people just sell whatever they can. And I think this exploits people's fear of getting old and being disabled or things like that and then dying. And I think the fear seems to be stronger in California where people like their lives and don't want to age.Eric Topol (22:49):You may be right about that. I like your term in the book immortality merchants, and of course we'll get into a bit, I hope the chapter on the crackpots and prophets that you called it was great. But that quote, by the way, which was precious from, I think it was Ambrosia, the name of the company and the CEO, but there's another quote in the book I want to ask you about. Most scientists working on aging agree that dietary restriction can extend both healthy life and overall life in mice and also lead to reductions in cancer, diabetes, and overall mortality in humans. Is that true? Most scientists think that you can really change these age-related diseases.Caloric Restriction and Related PathwaysVenki Ramakrishnan (23:38):I think if you had to pick one area in which there's broad agreement, it is caloric restriction. But I wouldn't say the consensus is complete. And the reason I say that is that most of the comparisons are between animals that can eat as much as they want, called ad libitum diet and mice that are calorically restricted or same with other animals even yeast. You either compared with an extremely rich medium or in a calorically restricted medium. And this is not a great comparison. And people, there's one discrepancy, and that was in monkeys where an NIH study didn't find huge differences, whereas a Wisconsin study found rather dramatic differences between the control group and the calorically restricted group. And so, what was the difference? Well, the difference was that the NIH study, the controlled group didn't have a calorically restricted diet, but still had a pretty reasonable diet.Venki Ramakrishnan (24:50):It wasn't given a unhealthy rich diet of all you can eat. And then they tried to somehow reconcile their findings in a later study. But it leads to the question of whether what you can conclude is that a rich all you can eat diet, in other words, gorging on an all you can eat buffet is definitely bad for you. So that's why you could draw that conclusion rather than saying it's actually the caloric restriction. So I think people need to do a little more careful study. There was also a study on mice which took different strains of mice and showed that in some strains, caloric restriction actually shortened lifespan didn't increase lifespan. Now, much of the aging community says, ah, that's just one study. But nobody's actually shown whether there was anything wrong with that study or even tried to reproduce it. So I think that study still stands.Venki Ramakrishnan (25:51):So I think it's not completely clear, but the fact is that there's some calorie dependence that's widely been observed across species. So between the control group and the experimental group, whatever you may, however, you may define it as there's been some effective calories intake. And the other interesting thing is that one of the pathways affected by caloric restriction is the so-called TOR pathway and one of the inhibitors of the TOR pathways is rapamycin. And rapamycin in studies has also shown some of these beneficial effects against the symptoms of aging and in lifespan. Although rapamycin has the same issue as with many other remedies, it's an immunosuppressive drug and that means it makes you more prone to infection and wound healing and many other things. I believe one of them was there's a question of whether it affects your libido, but nevertheless, that has not prevented rapamycin clinics from opening up, did I say in California? So I do think that there's often serious science, which leads to sort of promising avenues. But then there are of course people who jump the gun and want to go ahead anyway because they figure by the time trials are done, they'll be dead and they'd rather try act now.Eric Topol (27:36):Right. And you make a good, I mean the rapamycin and mTOR pathway, you really developed that quite a bit in the book. It's really quite complex. I mean, this is a pleotropic intervention, whether it's a rapalogs or rapamycin, it's just not so simple at all.Venki Ramakrishnan (27:53):Right. It's not at all simple because the TOR pathway has so many consequences. It affects so many different processes in the cell from including my own field of protein synthesis. It's one of the things it does is shut down global protein synthesis, and that's one of the effects of inhibiting TOR. So, and it turns up autophagy, which is this recycling of defective proteins and entirely defective entire organelles. So I think the TOR pathway is like a hub in a very large network. And so, when you start playing with that, you're going to have multiple consequences.Eric Topol (28:37):Yeah, no. And another thing that you develop so well is about this garbage disposal waste disposal system, which is remarkably elaborate in the cell, whether it's the proteasome for the proteins and the autophagosome for the autophagy with the lysosomes and the mitochondria mitophagy. Do you want to comment about that? Because this is something I think a lot of people don't appreciate, that waste management in the cell is just, it's a big deal.Venki Ramakrishnan (29:10):So we always think of producing things in the cell as being important, making proteins and so on. But the fact is destroying proteins is equally important because sometimes you need proteins for a short time, then they've done their job and you need to get rid of them, or proteins become dysfunctional, they stop working, or even worse, they start clumping together and causing diseases for example you could think of Alzheimer's as a disease, which involves protein tangles. Of course, the relationship between the tangles and the disease is still being worked out, but it's a characteristic of Alzheimer's that you have these protein tangles and the cell has evolved very elaborate mechanisms to constantly turn over defective proteins. Well, for example, it senses when proteins are unfolded and essentially the chain has unraveled and is now sticking to all sorts of things and causing problems. So I think in all of these cases, the cells evolved very elaborate mechanisms to recycle defective products, to have proper turnover of proteins. And in fact, recycling of entire organelles like mitochondria, when they become defective, the whole mitochondria can be recycled. So these systems also break down with aging. And so, as we age, we have more of a tendency to accumulate unfolded proteins or to accumulate defective mitochondria. And it's one of the more serious problems with aging.Eric Topol (30:59):Yeah, there's quite a few of them. Unfortunately, quite a few problems. Each of them are being addressed. So there's many different shots on goal here. And as you also aptly point out, they're interconnected. So many of these things are not just standalone strategies. I do want to get your sense about another popular thing, especially here out in California, are the clocks, epigenetic clocks in particular. And these people are paying a few hundred dollars and getting their biologic age, which what is that? And they're also thinking that I can change my future by getting clocks. Some of these companies offer every few months to get a new clock. This is actually remarkable, and I wonder what your thoughts are about it.Venki Ramakrishnan (31:48):Well, again, this is an example of some serious biology and then people jumping the gun to use it. So the serious biology comes from the fact that we age at different rates individuals. So anyone who's been to a high school reunion knows this. You'll have classmates who are unrecognizable because they've aged so much and others who've hardly changed since you knew them in high school. So of course at my age, that's getting rarer and rarer. But anyway, but you know what I mean. So the thing is that, is there a way that we can ask on an individual level how much has that individual aged? And there are markers that people have identified, some of them are markers on our DNA, which you mentioned in California. Horvath is a very famous scientist who has a clock named after him actually, which has to do with methylation of our DNA and the patterns of methylation affect the pattern of gene expression.Venki Ramakrishnan (33:01):And that pattern changes as we age. And they've shown that those patterns are a better predictor of many of the factors of aging. For example, mortality or symptoms of aging. They're a better predictor of that than chronological age. And then of course there are blood markers, for example, levels of various blood enzymes or blood factors, and there are dozens of these factors. So there are many different tests of many different kinds of markers which look at aging. Now the problem is these all work on a population level and they also work on an individual level for time comparison. That is to say, if you want to ask is some intervention working? You could ask, how fast are these markers changing in this person without the intervention and how fast are they changing with the intervention? So for these kind of carefully controlled experiments, they work, but another case is, for example, glycosylation of proteins, especially proteins of your immune system.Venki Ramakrishnan (34:15):It turns out that adding sugar groups to your immune system changes with age and causes an immune system to misfire. And that's a symptom of aging. It's called inflammaging. So people have used different markers. Now the problem is these markers are not always consistent with each other because you may be perfectly fine in many respects, but by some particular marker you may be considered old just because they're comparing you to a population average. But how would you say one person said, look, we all lose height as we age, but that doesn't mean if you take a short person, you can consider them old. So it's a difference between an individual versus a population, and it's a difference between what happens to an individual by following that individual over time versus just taking an individual and comparing it to some population average. So that's one problem.Organ ClocksVenki Ramakrishnan (35:28):The other problem is that our aging is not homogeneous. So there's a recent paper from I believe Tony Wyss-Coray group, which talks about the age of different organs in the same person. And it turns out that our organs, and this is not just one paper, there are other papers as well. Our organs don't necessarily age at the same rate. So giving a single person, giving a person a single number saying, this is your biological age, it's not clear what that means. And I would say, alright, even if you do it, what are you going to do about it? What can you do about it knowing your biological, the so-called number of a biological age. So I'm not a big fan. I'm a big fan of using these markers as a tool in research to understand what interventions work because otherwise it would take too long. You'd have to wait 20 years to see some large scale symptoms. And certainly, if you want to look at mortality, you'd have to wait possibly even longer. But if you were to be able to follow track these interventions and see that these markers slowed down with intervention, then you could say, well, your interventions having an effect on something related to aging. So I would say these are very useful research tools, but they're not meant to be used at $500 a pop in your age.Venki Ramakrishnan (37:02):But of course that hasn't stopped lots of companies from doing it.Eric Topol (37:07):No, it's just amazing actually. And by the way, we interviewed Tony Wyss-Coray about the organ clock, the paper. I thought it really was quite a great contribution, again, on a research level.Venki Ramakrishnan (37:19):He's a very serious scientist. He actually spoke here at the LMB as well. He gave a very nice talk here.Is Aging A Disease?Eric Topol (37:26):He's the real deal. And I think that's going to help us to have that organ specific type of tracking is another edge here to understand the effects. Well, before we wrap up, I want to ask you a question that you asked in the book. Is aging a disease?Venki Ramakrishnan (37:49):That's again, a controversial subject. So the WHO, and I believe the FDA decided that aging was not a disease on the grounds that it's inevitable and ubiquitous. It happens to everybody and it's inevitable. So how could something that happens to everybody and inevitable be considered a disease? A disease is an abnormal situation. This is a normal situation, but the anti-aging researchers and especially the anti-aging therapeutics people don't like that because if it's not a disease, how can they run a clinical trial? So they want aging to be considered a disease. And their argument is that if you look at almost every condition of old age, every disease of old age like cancer, diabetes, heart disease, dementia, the biggest risk factor in all of these diseases is age. That's the strongest risk factor. And so, they say, well, actually, you could think of these diseases as secondary diseases, the primary disease being age, and then that results in these other diseases.Venki Ramakrishnan (39:07):I am a little skeptical of that idea. I tend to agree with the WHO and the FDA, but I can see both sides of the argument. And as you know, I've laid them both out. My view is that it should be possible to do trials that help with aging regardless of whether you consider aging a disease or not. But that will require the community to agree on what set of markers to use to characterize success. And that's people, for example, Tony Wyss-Coray has his proteome, blood proteome markers, Horvath has his DNA methylation clock. There are a whole bunch of these. And then there are people with glycation or glycosylation of various proteins as markers. These people need to all come together. Maybe we need to organize a nice conference for them in some place like Southern California or Hawaii or somewhere, put them together in a locked room for a week so that they can thrash out a common set of markers and at least agree on what experiments they need to do to even come to that agreement and then use that to evaluate anti-aging therapies. I think that would be a way forward.Eric Topol (40:35):Yeah, I think you're bringing up a really valuable point because at the moment, they're kind of competing with one another, whether it's the glycosylated proteins or the transcriptomics or the epigenetics. And we don't know whether these are additive or what they're really measuring.Venki Ramakrishnan (40:53):Some of them may be highly correlated, and that's okay, but I think they need to know that. And they also need to come up with some criteria of how do we define age in an individual. It's not one number, just like we have many things that characterize our health. Cholesterol is one, blood pressures another, various other lipids. They're all blood enzymes, liver enzymes. All these things are factors in defining our so-called biological health. So I don't think there's some single number that's going to say this is your age. Just like there isn't one single thing that says you're healthy, you're not healthy.DNA RepairEric Topol (41:38):Right, that's well put. Last topic on aging is on about DNA repair, which is an area that you know very well. And one of the quotes in your book, I think is important for people to take in. “Nevertheless, they will make an error once every million or so letters in a genome with a few billion letters. That means several thousand mistakes occur each time a cell divides. So the DNA repair enzyme, as you point out the sentinels of our genome, the better we repair, the better we age.” Can we fix the DNA repair problem?Venki Ramakrishnan (42:20):I think maybe, again, I'm not sure what the consequences would be and how much it would take. There's one curious fact, and that is that there was a paradox called Peto's paradox after the scientist who discovered it, which is why don't big animals get cancer much more frequently than say a mouse? In fact, a mouse gets cancer far more readily than an elephant does, and in reality, the elephant should actually get cancer more because it has many orders of magnitude more cells, and all it takes is for one cell to become cancerous for the animal to get cancer and die. So the chances that one cell would become cancer would be larger if there are many, many more cells. And it turns out that elephants have many copies of DNA repair proteins or DNA damage response proteins, not so much DNA repair, but the response to DNA damage and in particular, a protein called p53. And so, this leads to the question that if you had very good DNA repair or very good DNA damage response, would you then live longer or solve this problem? I'm not entirely sure because it may have other consequences because for example, you don't want to send cells into senescence too easily. So I think these things are all carefully balanced, evolutionarily, depending on what's optimized to optimize fitness for each species.Venki Ramakrishnan (44:13):For a mouse, the equation's different than for a large animal because a mouse can get eaten by predators and so on. So there, it doesn't pay for evolution to spend too much select for too much spending of resources in maintenance and repair, for larger animals the equation is different. So I just don't know enough about what the consequences would be.Eric Topol (44:40):No, it's really interesting to speculate because as you point out in the book, the elephant has 20 copies of p53, and we have two as humans. And the question is that protection from cancer is very intriguing, especially with the concerns that we've been talking about.Venki Ramakrishnan (44:57):And it was also true, I believe they did some analysis of genomics of these whales that live very long, and they found sorts of genes that are probably involved in DNA repair or DNA damage response.Eric Topol (45:14):Well, this is a masterful book. Congratulations, Venki. I thoroughly enjoyed it. It's very stimulating. I know a lot of the people that will listen or read the transcript will be grabbed by it.Crackpots and ProphetsVenki Ramakrishnan (45:28):I think what I've tried to do is give the general reader a real understanding of the biology of aging so that even a complete non-scientist can get an understanding of the processes, which in turn empowers them to take action to do the sort of things that will actually really help. And also it'll guard them against excessive hype, of which there's a lot in this business. And so, I think that was the goal, and to try and present a balanced view of the field. I'm merely trying to be a realist. I'm not being a pessimist about it, but I also think this excessively optimistic hype is actually bad for the field and bad for science and bad for the public as well.Eric Topol (46:16):Well, and you actually were very kind in the chapter you have on crackpots and prophets. You could have been even tougher on some of these guys. You were very relatively diplomatic and gentle, I thought, I don't know if you were holding back.Venki Ramakrishnan (46:28):I had two lawyers looked at it, so.Eric Topol (46:33):I believe it. And now one thing, apart from what we've been talking about because of your extraordinary contribution on the structural delineation of the ribosome back in the early 2000s and 2009 Nobel Prize. Now, the world of AI now with AlphaFold 3 and all these other large language models, would that have changed your efforts? Would that have accelerated things or is it not really?Venki Ramakrishnan (47:09):Well, it would've helped, but you would still need the experimental data to solve something like the ribosome, a large complex like the ribosome. And the other thing that would really change well has changed our world is the advent of cryo-electron microscopy of which Scripps is one of the leading places for it. And that has really changed it so that now nobody would bother to crystallize a ribosome and try to get an X-ray structure out of it. You would just throw it into an EM grid, collect your data and be off to the races. So new ribosome structures are being solved all the time at a fraction, a tiny fraction of the time it took to solve the first one.Eric Topol (48:02):Wow, that's fascinating. This has been a real joy for Venki to discuss your book and your work, and thanks so much for what you're doing to enlighten us and keep the balance. And it may not be as popular as the immortality merchants, but it's really important stuff.Venki Ramakrishnan (48:19):Yeah, no, I hope actually, I found that many of the public want to read about the biology of aging. They're curious. Humans have been curious ever since we knew about mortality, about why some species live so short lives and other species live such a long time and why we actually have to age and die. So there's natural curiosity and then it also empowers the public once they understand the basis of aging, to take action, to live healthy lives and do that. It's an empowering book rather than a recipe book.Venki Ramakrishnan (49:01):I think a lot of the public actually does appreciate that. And of course, scientists will like the sort of more balanced and tone.Eric Topol (49:13):Well, you do it so well. All throughout you have metaphors to help people really understand and the concepts, and I really applaud you for doing this. In fact, a couple of people who we both know, Max and John Brockman, apparently were influential for you to get to do it. So I think it's great that you took it on and all the power to you. So thank you, and I hope that we'll get a chance to visit further as we go forward.******************Headshot photo credits by Kate Joyce and Santa Fe InstituteThe Ground Truths newsletters and podcasts are all free, open-access, without ads.Please share this post/podcast with your friends and network if you found it informativeVoluntary paid subscriptions all go to support Scripps Research. Many thanks for that—they greatly helped fund our summer internship programs for 2023 and 2024.Thanks to my producer Jessica Nguyen and Sinjun Balabanoff tor audio and video support at Scripps Research.Note: you can select preferences to receive emails about newsletters, podcasts, or all I don't want to bother you with an email for content that you're not interested in.A Poll on Anti-Aging Get full access to Ground Truths at erictopol.substack.com/subscribe

In diesem Podcast spreche ich mit Markus Okumus. Zusammen mit dem Neurowissenschaftler Prof. Tony Wyss-Coray gründete er das StartUp Teal Omics Inc., welches in der Lage ist, das biologische Alter unserer Organe zu messen.   In dieser Folge besprechen wir: Wie sich die Messungen von Teal Omics Inc. von der epigenetischen Uhr unterscheidet. Wie wir frühzeitig die Entstehung von Organschäden erkennen. Warum es so wichtig ist die Alterung individueller Gewebe im Körper zu messen. Wie die Technik die heutige Gesundheitssystem entlasten und nach vorne bringen kann. Wo in Moment noch Schwierigkeiten liegen und wie wir sie beheben können. Wie jeder einzelne Mensch in Zukunft von dieser Technik profitieren kann. Wie wir Alzheimer, Parkinson, Herz-Kreislauf-Erkrankungen und viele weitere Krankheiten schon vor der Entstehung erkennen und ihnen entgegenwirken können.   Weitere Informationen zu Markus Okumus und Teal Omics Inc. findest du hier: https://www.linkedin.com/in/markusokumus/ https://linktr.ee/markusokumus https://www.tealomics.com/   Du interessierst dich für Gesunde Langlebigkeit (Longevity) und möchtest ein Leben lang gesund und fit bleiben, dann folge mir auch auf den sozialen Kanälen bei Instagram, TikTok, Facebook oder Youtube. https://www.instagram.com/nina.ruge.official https://www.tiktok.com/@nina.ruge.official https://www.facebook.com/NinaRugeOffiziell https://www.youtube.com/channel/UCOe2d1hLARB60z2hg039l9g   Disclaimer: Ich bin keine Ärztin und meine Inhalte ersetzen keine medizinische Beratung. Bei gesundheitlichen Fragen wende dich bitte an deinen Arzt/deine Ärztin. STY-27

Today: the clocks in your body.We're talking again this week with Tony Wyss-Coray, the director of the Knight Initiative for Brain Resilience here at Wu Tsai Neuro. Last year, we spoke with Tony about the biological nature of the aging process. Scientists can now measure signs of aging in the blood, and can in some cases slow or reverse the aging process in the lab. We discussed how this biological age can be quite different from your chronological age, and why understanding why people age at different rates has become a hot topic for researchers who study aging. Since we last spoke, Professor Wyss-Coray and his lab have published some exciting new work that takes this idea from the level of the whole body down to the level of specific organs and tissues. We can now ask: are your brain, your heart, or your liver aging faster than the rest of you? The implications of this idea could be profound for both neuroscience and medicine more broadly.Listen to the episode to learn more!Further readingWyss-Coray labPhil and Penny Knight Initiative for Brain ResilienceOrgan aging study in Nature:Organ aging signatures in the plasma proteome track health and disease (Nature, 2023)Study coverage:Stanford Medicine-led study finds way to predict which of our organs will fail first (Stanford Medicine)Your Organs Might Be Aging at Different Rates (Scientific American)Tony Wyss-Coray: The Science of Aging (Ground Truths with Eric Topol)Related reading:You can order a test to find out your biological age. Is it worth it? (NPR)What's Your ‘Biological Age'? (New York Times)Episode CreditsThis episode was produced by Michael Osborne at 14th Street Studios, with production assistance by Morgan Honaker. Our logo is by Aimee Garza. The show is hosted by Nicholas Weiler at Stanford's Wu Tsai Neurosciences Institute and the Knight Initiative for Brain Resilience. Thanks for listening! If you're enjoying our show, please take a moment to give us a review on your podcast app of choice and share this episode with your friends. That's how we grow as a show and bring the stories of the frontiers of neuroscience to a wider audience. Thanks for listening! If you're enjoying our show, please take a moment to give us a review on your podcast app of choice and share this episode with your friends. That's how we grow as a show and bring the stories of the frontiers of neuroscience to a wider audience. Learn more about the Wu Tsai Neurosciences Institute at Stanford and follow us on Twitter, Facebook, and LinkedIn.

“A few years ago, I might have chuckled at the naiveté of this question, but now it's not so crazy to think that we will be able to take some sort of medicine to extend our healthy lifespans in the foreseeable future.”—Coleen MurphyTranscript with external linksEric Topol (00:06):Hello, this is Eric Topol from Ground Truths, and I'm just so delighted to have with me Professor Coleen Murphy, who has written this exceptional book, How We Age: The Science of Longevity. It is a phenomenal book and I'm very eager to discuss it with you, Coleen.Coleen Murphy (00:25):Thanks for having me on.Eric Topol (00:27):Oh yeah. Well, just so everyone who doesn't know Professor Murphy, she's at Princeton. She's the Richard Fisher Preceptor in Integrative Genomics, the Lewis-Sigler Institute for Integrative Genomics at Princeton, and director of the Paul Glenn Laboratories for Aging Research. Well, obviously you've been in this field for decades now, even though you're still very young. The classic paper that I can go back to would be in Nature 2003 with the DAF-16 and doubling the lifespan of C. elegans or better known as a roundworm. Would that be the first major entry you had?Coleen Murphy (01:17):Yeah, that was my postdoctoral work with Cynthia Kenyon.Eric Topol (01:20):Right, and you haven't stopped since you've been on a tear and you've put together a book which has a hundred pages of references in a small font. I don't know what the total number is, but it must be a thousand or something.Coleen Murphy (01:35):Actually, it's just under a thousand. That's right.Eric Topol (01:37):That's a good guess.Coleen Murphy (01:38):Good guess. Yeah.Eric Topol (01:39):So, because I too have a great interest in this area, I found just the resource that you've put together as extraordinary in terms of the science and all the work you've put together. What I was hoping to do today is to kind of take us through some of the real exciting pathways because there's a sentence in your book, which I thought was really kind of nailed it, and it actually is aligned with my sense. Obviously don't have the expertise by any means that you do here but it says, “A few years ago, I might have chuckled at the naivety of this question, but now it's not so crazy to think that we will be able to take some sort of medicine to extend our healthy lifespans in the foreseeable future.” That's a pretty strong statement for a person who's deep into the science. First I thought we'd explore healthy aging health span versus lifespan. Can you differentiate that as to your expectations?Coleen Murphy (02:54):So, I think most people would agree that they don't want to live necessary super long. What they really want to do is live a healthy life as long as they can. I think that a lot of people also have this fear that when we talk about extending lifespan, that we're ignoring that part. And I do want to assure everyone that the people in the researchers in the aging field are very much aware of this issue and have, especially in the past decade, I think put a real emphasis on this idea of quality of life and health span. What's reassuring is actually that many of the mechanisms that extend lifespan in all these model organisms also extend health span as well and so I don't think we're going to, they're not diametrically opposed, like we'll get to a healthier quality of life, I think in these efforts to extend lifespan as well.Eric Topol (03:50):Yeah, I think that's important that you're bringing that up, which is there's this overlap, like a Venn diagram where things that do help with longevity should help with health span, and we don't necessarily have to follow as you call them the immoralists, as far as living to 190 or whatever year. Now, one of the pathways that's been of course a big one for years and studied in multiple species has been caloric restriction. I wonder if you could talk to that and obviously there's now mimetics that could simulate that so you wouldn't have to go through some major dietary starvation, if you will. What are your thoughts on that pathway?Coleen Murphy (04:41):Yeah, actually I'm really glad you brought up mimetics because often the conversation starts and ends with you should eat less. I think that is a really hard thing for a lot of people to do. So just for the background, so dietary restriction or caloric restriction, the idea is that you would have to take in up to 30% less than your normal intake in order to start seeing results. When we've done this with laboratory animals of all kinds, this works from yeast all the way up through mice, actually primates, in fact, it does extend lifespan and in most metrics of health span the quality of life, it does improve that as well. On the other hand, I think psychologically it's really tough to not eat enough and I think that's a part that we kind of blindly ignore when we talk about this pathway.Coleen Murphy (05:30):And of course, if we gave any of those animals the choice of whether they want to start eating more, they would. So, it's like that's not the experiment we ever hear about. And so, the idea for studying this pathway isn't just to say, okay, this works and now we know how it works, but as you pointed out, mimetics, so can we target the molecules in the pathway so that we can help people achieve the benefits of caloric restriction without necessarily having to do the kind of awful part of restriction? I think that's really cool, and especially it might be very good for people who are undergoing certain, have certain diseases or have certain impairments that it might make it difficult ever to do dietary restrictions, so I think that's a really great thing that the field is kind of getting towards now.Eric Topol (06:15):And I think in fact, just today, it's every day there's something published now. Just today there was a University of Southern California study, a randomized study report comparing plant-based fasting-mimicking diet versus controlled diet, and showed that many metabolic features were improved quite substantially and projected that if you stayed on that diet, you'd gain two and a half years of healthy aging or that you would have, that's a bit of an extrapolation, but quite a bit of benefit. Now, what candidates would simulate caloric restriction? I mean, what kind of molecules would help us do that? And by the way, in the book you mentioned that the price to pay is that the brain slows down with caloric restrictions.Coleen Murphy (07:10):There's at least one study that shows that.Coleen Murphy (07:13):Yeah, so it's good to keep in mind. One of the big things that is being looked at as rapamycin, looking at that TOR pathway. So that's being explored as one of these really good mimetics. And of course, you have things that are analogs of that, so rapalogs, and so people are trying to develop drugs that mimic that, do the same kind of thing without probably some of the side effects that you might see with rapamycin. Metformin is another one, although it's interesting when you talk to people about metformin who work on it, it's argued about what is exactly the target of metformin. There's thought maybe also acts in the TOR pathway could affect complex one of mitochondria. Some of the things we know that they work, and we don't necessarily know how they work. And then of course there's new drugs all the time where people are trying to develop to other target, other molecules. So, we'll see, but I think that the idea of mimetics is actually really good, and that part of the field is moving forward pretty quickly. This diet that you did just mention, it is really encouraging that they don't have to take a drug if you don't want to. If you eat the right kind of diet, it could be very beneficial.Eric Topol (08:20):Yeah, no, it was interesting. I was looking at the methods in that USC paper and they sent them a box of stuff that they would eat for three cycles, multiple weeks per cycle. It was a very interesting report, we'll link to that. Before we leave the caloric restriction and these mTOR pathway, you noted in the book that there some ongoing trials like PEARL, I looked that up and they finished the trial, but they haven't reported it and it's not that large. And then there's the FAME trial with metformin. I guess we'll get a readout on these trials in the not-too-distant future. Right?Coleen Murphy (08:57):Yeah, that's the hope that especially with the Metformin trial, which I think is going to be really large the FAME trial, that just to give the listeners a little background, one of the efforts in the field is not just to show that something works, but also to convince the FDA that aging could be a pharmaceutical, a disease that we might want to have interventions for. And to do that, we need to figure out the right way to do it. We can't do 30-year studies of safety and things to make sure that something's good, but maybe there are reasonable biomarkers that would tell us whether people are going to live a long time. And so, if we can use some of those things or targeting age-related diseases where we can get a faster readout as well. Those are reasonable things that companies could do that would help us to really confirm or maybe rule out some of these pharmaceuticals as effective interventions. I think that would be really great for consumers to know, is this thing really going to do good or not? And we just don't have that right now in the field. We have a lot of people saying something will work and it might and the studies in the lab, but when we get to humans, we really need more clinical studies to really tell us that things are going to be effective.Eric Topol (10:12):Right, I'm going to get to that in a bit too because I think you're bringing up a critical topic since there's an explosion of biopharma companies in this space, billions of dollars that have been put up for in capital and the question is what's going to be the ground rules to get these potential candidate drugs to final commercial approval. But before I leave, caloric restriction and insulin signaling and the homolog and the human to what your discovery of DAF-16, FOXO and all this, I just want you to comment, it wasn't necessarily developed in the book, but as you know, the GLP-1 drugs have become just the biggest drug class in medical history, and they do have some effects here that are very interesting. They are being tested as in Alzheimer's disease. Do you see that this is a candidate too that might promote healthy aging?Coleen Murphy (11:12):Yeah, I'm so glad you brought that up because my book, I finished writing it right before all this stuff came out, and it's looking really very compelling. People are on these drugs, they lose a ton of weight, but their blood biomarkers really become very good and on top of just the changes in weight and those kinds of effects. Let me just say, I think the biggest thing, the biggest risk actually for aging people right now are cardiovascular problems, cardiovascular disease, and these drugs, no doubt, it's going to basically make a huge dent in that. I'm absolutely sure of that. What I also find really interesting with those drugs is that the users report that they have fewer cravings for other things. So, this is not being looked at to treat alcoholism and drug addiction, other things, so it really opens up a whole new world of things that are bad for us that maybe we could avoid this with these peptides. It's almost staggering. I really think this going to be a huge, and as far as an aging drug, if you reduce your weight, you improve all your cardiovascular function, you don't feel like drinking all the time, all these things might be really great and I do think that people will live longer.Eric Topol (12:32):Yeah, no, it does have that look and you just have to wonder if as these will go on to oral drugs with triple receptors and very potent, maybe even avoiding peptides in the future too, that this could wind up being something that's exceedingly common to take for reasons far removed from the initial indication of type two diabetes and more recently of course, obesity. Now the next topic I wanted to get into with you were senolytics, these agents that basically are thought to reverse aging or slow aging. And again, since everything's coming out in a daily basis, there was a trial in diabetes macular edema where giving senolytic after people had failed their usual VEGF treatment was highly successful. So, we're starting to see, at least in the eye results. I wonder if you could describe how you conceive this field of senolytics?Coleen Murphy (13:41):Actually, I think they've made great progress in the past couple of years because there were some initial failures, like some of the things for osteoarthritis that went through I think phase two, but I think that one of the great things about the longevity biotech field is that they're starting to identify not just longevity, these age-related disorders that they could actually use. And so, it's kind of doubly beneficial. It tells us that the drugs actually do something and so maybe it'll be used for something else in the future and you get through, you can test safety, but also helping people actually have a very real problem that's acute that they really need to take care of. And so that's really exciting. Then in addition to the example you just mentioned, I was at a conference last summer where it was being explored whether some of these senolytics could be helpful for middle aged survivors of childhood cancers who do show various health effects from having gone through chemotherapies at a young age. So that's really exciting. Could you help people who are not aging, but they actually are showing having problems that we kind of associate with aging. And senolytics were at least the first thing I'd heard about that are actually being used for that, so there may be other approaches that help as well, but I think that's really great.Eric Topol (15:05):Well, and just to be clear the senolytics, I guess could be categorized at least one function might be to help clear dead cells. These senescent cells are bad actors and either they're taken out or they're somehow neutralized in their impact of secreting evil humors, if you will. Are there other forms of senolytics besides that way of dealing with these senescent cells?Coleen Murphy (15:33):I know that some people are exploring senomorphs, so things that make those cells just arrest but I do want to mention, of course, we lost a great Judith Campisi recently, and she was the one who discovered and described the senescent associated secretory phenotype, and she did amazing work in that field really opening that up. So, this idea that bad cells aren't just bad because they don't function, but they're actually toxic to other cells.Coleen Murphy (16:04):That's important for listeners to know. Yeah, so I don't know. I think that one of the things I'm excited about in the aging field is that it doesn't seem like there's one magic bullet. A lot of researchers will spend their time working on that one thing so if you only talk to that one person, you might get that impression, but there's a whole host of things that for bad or good, that things go wrong when we age, but those all end up being maybe targets that could help us live longer or at least in a healthier way. And so, we've already talked about a couple of them, but readers will see as we learn more, there might be more ways to help cells survive or to help us replace ourselves, for example.Eric Topol (16:45):I mean, I think what you're bringing up here is central because there's all these different, as I can see it, shots on goal that of course could be even used as combinations, no less senolytic interventions so we're getting closer as we started this conversation to fulfilling what you, I think is in store in the years ahead, which is extraordinary. Along with the senolytics, I wonder if you could just talk a little bit about these autophagy enhancers as a class of agents, maybe first explaining autophagy and then is this a realistic goal that we should be taking autophagy enhancers, or is this something that's too generalized that might have onward mTOR effects?Coleen Murphy (17:39):Well, it's interesting. Autophagy, so just for the listeners, autophagy literally means self-eating. So this is a pathway whereby proteins basically get degraded within the cell and those parts get recycled. And the idea is that if you have a cell or protein that's damaged in some way, or it can be renewed if you induce autophagy. I think I could be wrong here, but my sense is that the cancer field is really excited about autophagy enhancers. And so, I think that's probably where we'll see the biggest breakthroughs but along the way, of course we'll know because we'll know if they're safe and if there's other off-target effects. I think that that's largely being driven by the cancer field and the longevity field is kind of a little bit behind that, so we'll learn from them. It seems like a really exciting approach as well.Eric Topol (18:34):Yeah, it does. And then as you know, the idea of giving young blood, young plasma, which there already are places that do this, that it can help people who are cognitively impaired and have basically immediate effects, and sometimes at least with some durability. It's very anecdotal, but this idea, we don't know what's in the young blood or young plasma to some extent. How do you process that?Coleen Murphy (19:10):Okay. Well, so what we do know, and this is really work that a lot of people like Saul Villeda and Tony Wyss-Coray have done where they really have, they've taken that blood or plasma and then found the parts in the plasma that actually do specific jobs. And so, we actually are starting to learn a lot about that and that's exciting because of course, we don't really want to give people young blood. What we really would like to do is find out is there a particular factor in the blood? And there seems to be many that could be beneficial. And so, we really are getting close. We as a field, and specifically like the research I just mentioned and that's exciting because you can imagine, for example, if there's one factor that's in blood, that's in young blood, that's very helpful, manufacturing, a lot of that particular thing.Coleen Murphy (20:01):The other exciting thing, again, this is Saul Villeda's lab that found that exercise mice. So even if they're the same age mice, if one of them is exercised, it makes factors that actually from the liver of the mouse upon exercise, that then gets secreted and then affect, improve cognitive function as well. So it seems like even within the blood, there's multiple different ways to get blood factors that are beneficial, whether they're from young blood or from exercise blood. And so, there's a lot of things we don't yet know, but I do think that field is moving very fast and they're identifying a lot of things. In fact, so I'm the director of Simons Collaboration Plasticity in the Aging Brain, and on that website we're developing basically a page that can tell you what are the factors and what has it been shown to be associated with, because we're very interested in slowing normal cognitive aging and blood factors seem to be one of the really powerful ways that might be available to us very soon to be able to improve that.Eric Topol (21:03):Yeah, no, I'm glad you mentioned that, Coleen. I think the point that you made regarding exercise, I certainly was struck by that because in the book, because we've known about this association with exercise and cognition, and this I think is certainly one potential link. An area that is also fascinating is epigenetics, so a colleague of mine here in the Mesa, Juan Carlos Belmonte, who was at Salk and left to go to Altos, one of these many companies that are trying to change the world in health span and lifespan. Anyway, he had published back several years ago.Coleen Murphy (21:53):Yeah, 2016.Eric Topol (21:54):Yeah, CRISPR basically modulation of the epigenome through editing and showed a number of through specific pathways, a number of pretty remarkable effects. I wonder if you could comment about epigenetics, and then I also want to get into this fascinating topic of transgenerational inheritance, which may be tied of course to that. So, what about this pathway? Is there something to it?Coleen Murphy (22:29):Well, absolutely. I just think we need to learn a lot more about it. So just for the listener, so epigenetics, we think about genetics that's basically based on DNA and chromosomes. And so, when we think about epigenetics, that could be either, we could be talking about modulation of the histone marks on the chromosomes that allow the genes to be expressed or be silenced. And then on the DNA itself, there are methylation marks. And so, people have used, of course, Steve developed a, sorry, I'm sorry. Steve Horvath developed a very nice, he was first to develop a DNA methylation clock. So this idea that you could, and that was really interesting because he based it on, he used this machine learning method to narrow down to the 353 marks that were actually predictive or correlated with age, but we don't understand how it biologically what that manifests in. I think that's not well understood. At the chromatin level, there's a lot of work on the specific histone marks that may change, for example, how genes are transcribed and so understanding that better will maybe help us understand what those changes. There's things called epigenetic drift, so genes stop being carefully regulated with age, and then how can we make that maintain better with age? It's one of the goals of the field in addition to basically understanding what's going on at the epigenetic level.Eric Topol (24:01):So now of course, could we alter that? Oh, it is fascinating as you say, that you could have the Horvath clock to so accurately predict a person's biological age. And by the way, just a few days ago, there was a review by all these clock aging folks in nature medicine about the lack of standards. There's so many clocks to basically determine biological age versus chronological age. Before we get into the transgenerational inheritance, what is your sense? Obviously, these are getting marketed now, and this field is got ahead of its skis, if you will, but what about these biologic age markers?Coleen Murphy (25:02):Yeah, I'm glad to hear that. I haven't seen that review. I should look it up. It's good to know that the players in the field are addressing those points. So just for the listeners, so these DNA methylation clocks so when Steve Horvath developed the first one, it was based on the controls from a very large number of cancer controls for other reasons, so he used a huge amount of information. It really depended on the, he was trying to develop a clock that was independent of which tissue, but it turned out there's more and more clocks that are tissue specific and really organism specific, species specific. It really depends on what you're looking at to make these, and whether you're looking at chronological age or trying to predict biological age. I think it's a little frustrating because what you'd really like to know as a consumer, if you send off for one of these clock kits, is it right?Coleen Murphy (25:57):What's the margin of error? If I took it every week, would I get the same number? And so, I think my sense is that people take it until they get a low number then, but you'd really like to know if they work, because if you want to take it, do a control and they start, get your clock number and then start taking some intervention and ask whether it works, right? Yeah. So, I think because the players in the field recognize these issues, they're going to straighten it out, but I think one part that drives a little bit of the problem is that we don't understand what that DNA methylation mark change translates into biologically. If we understood that better, I think we'd have a better feeling about it. Anne Brunet and Tony Wyss-Coray maybe a year and a half ago, they had a nice paper where two years ago where they looked at, they use a different type of clock, a transcriptional clock, and that worked really well. So they were looking at transcriptional clock in the subventricular zone, and they were able to actually see changes not just with age, but also when there was an intervention. I can't remember if they look at dietary restriction and then maybe an exercise in the mice. And so that's important for us to know how well those clocks work.Coleen Murphy (27:13):I think it'll get there. It'll get there.Eric Topol (27:15):You don't want to pay a few hundred dollars and then be told that you're 10 years older biologically than your chronologic age, especially if it's wrong. Right?Coleen Murphy (27:25):Yes. It'll get there. I think it may not be quite there yet.Eric Topol (27:30):And by the way, while we're on that, the organ clocks paper, in fact, just a recent weeks, I did interview Tony Wyss-Coray from Stanford, and we talked about what I consider really a seminal paper because using plasma proteins, they're able to basically clock each organ. And that seems like a promising approach, which could also help prove the case that you're changing something favorably with one of these various intervention classes or categories. Do you think that's true?Coleen Murphy (28:05):That feels more real directly looking at the proteins then.Eric Topol (28:08):Yeah, exactly. I thought that was really exciting work, and I'm actually going to visit with Tony in a few weeks to discuss it further. So excited about it.Coleen Murphy (28:18):That's great. He's doing great work, so it'll be a fascinating conversation.Eric Topol (28:21):Yeah, well this is also fascinating. Now, transgenerational inheritance is a very controversial topic in humans, which it is not so much in every other species. Can you explain why that is?Coleen Murphy (28:38):Well, there's a lot of, I would say emotional baggage attached here, right? Because that's what people are talking about, like transgenerational trauma. There's no doubt that traumatic experiences in childhood actually do seem to change the genome and change have very real biological effects. And that's been shown. So that's within the first generation. It's also no doubt that in other organisms, like in plants like DNA methylation, that's exactly how they regulate things, and that's multiple generations. So that's kind of the norm. And so, the question for humans is whether something like this, like a traumatic experience or starvation or thing, has an effect, not just on the person who's experiencing it, but also on their progeny, even on their grand progeny. And so, it's tough, right? Because the data that are out there are from pretty terrible experiences like the Dutch hunger winter. And so, there's a limited set of data, and some of those data look good, and some of them look weaker. Yeah, I think that we still need to figure out what's going on there, and if it's real, it'd be interesting to know. Are there ways, for example, with these epigenetic modulators, are there ways that you could help people be healthier by erasing some of those marks of trauma, generational trauma?Eric Topol (30:03):Yeah. So, I mean, the theory as you're getting to would be you could change the epigenome, whether it's through chromatin, acetylation, methylation, somehow through these experiences and it would be going through down through multiple generations. The reason I know it's controversial is when I reviewed Sid Mukherjee's book, the Gene, he had put in that it was real in humans, and the attack dogs came out all over the place. Now, we've covered a lot of these pathways. One that we haven't yet touched on is the gut microbiome, and the idea here, of course, it could be somewhat linked to the caloric restriction story, but it seems to be independent of that as well. That is there, our immunity is very much influenced by our gut microbiome. There's the gut brain axis and all sorts of interactions going on there, but what about the idea of using probiotics and particular bacterial species as a introducing the people as an idea in the future to promote health span?Coleen Murphy (31:18):Yeah, it's a great idea. So, I just want to back up and say the microbiome, the reason it's so fraught is because for a long time, people had confused correlation and causation. So, they would see that a person who has X disease has a difference in the microbiome from people who don't have that disease. And so, the question was always, do they have that disease because of a difference in the microbiome or the disease influence in the microbiome? And of course, even things that's eating different food. For example, if a child with autism doesn't want to eat certain range of food, it's going to have an effect on the microbiome. That does not mean the microbiome cause their autism. And so that's something where, and the same thing with Alzheimer's disease patients. I think that's often the source of some of this confusion. I think people wish that they could cure a lot of diseases by taking a probiotic.Coleen Murphy (32:09):On the other hand, now there's actually some really compelling data. Dario Valenzano's lab did a really nice experiment in killifish, which is my second favorite aging model research organism. So killifish, turquoise killifish, only live a few months. And so, you can do aging studies really quickly and what Dario's group did was they took the microbiome at middle aged fish, they wiped out their microbiome with antibiotics, and they added back either young or same age, and they saw a really nice extension of lifespan with the young microbiome. So that suggests, in that case where everything else is the same, it really does have a nice effect. John Cryan's group in Ireland did something similar with mice, and they showed that there was a beneficial effect on cognitive function in older mice. So those are two examples of studies where it really does seem like there is an effect, so it could be beneficial. And then there's of course things like microbiome transfer for people who are in the hospital who have had other things, because your microbiome also helps you prevent other diseases. Those being there, if you wipe out all of your microbiome, you can actually get infected with other things. It's actually a protective barrier. There's a lot of benefits, I think in order to, we don't know a ton about how to control it. We know there are these, it's gross, but fecal microbiome transplantation.Eric Topol (33:42):FMT. Yeah, yeah.Coleen Murphy (33:44):Exactly. And so, I think that is kind of the extreme, but it can be done. I think in appropriate cases it could be a very good strategy.Eric Topol (33:53):It's interesting. There was a study about resilience of the immune system, which showed that women have a significant advantage in that they have just the right balance of not having a hyper inflammatory reaction to whether it's a pathogen or other stimulus. And they also have, of course, an immunocompetent system to respond, so unlike men overall, that although the problem of course with more prone to autoimmunity because of having two x chromosomes and exist or whatever other factors. But also, there's a balance that there's an advantage, in the immune system as a target for health span and lifespan, a lot of things that we've talked about have some interaction with the immune system. Is there anything direct that we can do to promote a healthier immune system and avoid immunosenescence and inflammaging or immuno aging or whatever you want to call it?Coleen Murphy (35:04):Sure, I will admit that immunology is a field that I want to learn more about, but I do not know enough about it to give a really great answer. I think it's one of the things I kind of shied away from when I wrote the book that if I were to rewrite it, I would add a whole new section on it. I think that's a really booming field, this interaction between immunology and aging. Obviously, there's immune aging, but what does that really mean?Coleen Murphy (35:28):I feel like I can't give you a really intelligent answer about that. Even though I'd like to, and I don't know how much of it's because there's just sort of this general idea that the immune system stops functioning well, but I do feel like the immune system is actually so mysterious. I have a peanut allergy, for example. We don't even really, I mean, we can prime ourselves against that now. We can give kids little bits of peanuts, but all the things that I feel like immunology is the one that's probably taking off the most, and we'll probably in a decade know way more about it than we do now, but I can't give you a very smart answer right now.Eric Topol (36:09):Yeah, no, I do think it's really provocative and the fact that if you have these exhausting T cells that are basically your backup system of your immune system, if they're not working, that's not good. And maybe they can be revved up without being problematic. We'll see.Coleen Murphy (36:27):And I guess the real question is do we need to do something independent or is that folded into everything else? If you were giving someone a drug that seemed very good systemically or some of these blood factors, would you have to do something special just for the immune system or is that something that would also be effective? I feel like that would be good to know.Eric Topol (36:44):Now the other area that I want to bring up, which is a little more futuristic is genome editing. So recently when I spoke to David Liu, he mentioned, well, actually it was Jennifer Doudna who first put it out there, but we discussed the idea of changing the people like me who are APOE4 carriers to APOE2, which is associated with longer life and all these other good things. Why don't we just edit ourselves to do that? Is that a prospect that you think ever could be actualized?Coleen Murphy (37:20):Well, I was just at a talk by Britt Adamson just moments ago, and that field is moving really fast, right? All the work that David Liu has done, and it's really exciting, this idea that you can now cure sickle cell anemia.Coleen Murphy (37:35):Fascinating. And I think Jennifer Doudna rightly proposed early on that what we should really be hitting first are like blood. Blood's really good because it's not hitting the germline. It's really something where we can help people at that stage. I was thinking about that while Britt was talking, what are the things we'd really want to address with CRISPR? I'm not sure how high up in the list aging related factors would be compared to a lot of childhood diseases, things that are really debilitating, but certainly is true since when we're looking at APOE4. I think that's the one exception because that is so strongly correlated with healthy lifespan and Alzheimer's and things, so we really want to do something about that. The question is how would we do that? That's not a blood factor. I think we'd have to think hard about that, but it is on the list of looming on the horizon.Eric Topol (38:35):I wouldn't be surprised if someday, and David, of course thought it's realistic, but it's not, obviously in the short term. Well, this has been enthralling to go through all these possibilities. I guess when you put it all together, there's just so many ways that we might be able to, and one of the things that you also pointed out in your book, which something that should not be forgotten, is the fact that all these things could even worsen the inequities that we face today. That is you have any one of these click, if not multiple, it isn't like they're going to be available to all. And the problem we have now, especially in this country without universal health and access issues, could be markedly exacerbated as we're seeing with the GLP-1 drugs too, by the way.Coleen Murphy (39:27):Absolutely.Eric Topol (39:28):So, I just want to give you a chance to reinforce what you wrote in the book, because I think this is where a lot of times science leads and doesn't realize the practical implications of who would benefit.Coleen Murphy (39:42):Yeah, I think actually for aging research often, even when I first started doing this work back in 2000, the first thing people would ask me if they're below a certain age was, don't you think that's terrible? Make the rich people just live the longest? And they're not wrong about that. I think what it can, we should raise awareness about the fact that even these things that we consider simple, like doing caloric restriction or getting exercise, even those things are not that straightforward if you're working two jobs or if you don't have access to excellent foods in your neighborhood, right? Fruits and vegetables. If we really want to not just extend longevity but raise life expectancy, then we should be doing a lot more that's for improving the quality of life of many people. And so there is that idea. On the other hand, I do want to point out that as we discover more and more of these things, like metformin is off patent, it's like it's really old. And so, it's more of these things get discovered and more broadly used. I do think that that may be a case where we could end up having more people might have access to things more easily. So that's my hope.Coleen Murphy (40:57):I don't want to discourage anyone from developing a longevity dry. I think eventually that could help a lot of people if it's not too absurdly expensive.Eric Topol (41:04):Yeah, no, I certainly agree. And one last footnote is that we did a study called The Wellderly here, about 1,400 people over age 85 who'd never been sick, so our goal here wasn't lifespan. It was to understand if there was genomics, which we did whole genome sequencing of this group. We didn't find much like the study that you cited in the book by the Calico group. And so just to give hope that people, if they don't have what they think are family genetics of short life or short health span, that may not be as much to that as a lot of people think. Any final thoughts about that point? Because it's one that's out there and data goes in different directions.Coleen Murphy (41:55):Yeah. The Calico study you mentioned, I think that's the one where they found that your health or lifespan mostly went with almost like your in-laws, which actually points again to your socioeconomic group probably you marry people, most people marry people are in a similar socioeconomic group. That's probably what that mostly had to do with. I do think if I'm going to say one thing because a lot of these drugs are on the horizon, they're not yet available, or there's nothing I can hang onto for an FDA approved drug to extend that. I do think the one thing that I would encourage people to do even more than the dietary restriction stuff, it is exercise because that's just generally beneficial in so many different ways. And so, if we can get people doing a little more exercise, I think that would be the one thing that probably could help a lot of people.Eric Topol (42:40):Well, I'm glad we are winding up with that because I think the data from lifestyle, which is exercise as you're pointing out, as well as nutrition and sleep.Coleen Murphy (42:54):All the boring things we already thought, right.Eric Topol (42:55):That we know about, but we don't necessarily put in our daily lives. There's a lot there. There's no question that studies, I think, really have reinforced that even recent one. Well, what a pleasure to talk to you about this and do this tour of the various exciting prospects. I hope I haven't missed anything. I know we can't go over all the pathways, and obviously there've been some bust in the past, which we don't need to review like the famous Resveratrol Sirtuin story, which you addressed in the book. I do want to encourage people that this book is extraordinary. Your work that you put into it had to be consumptive for I don't know how many years of work.Coleen Murphy (43:37):There was many years of work. My editor, we sat down to lunch right after it finished. She was like, so what are you going to work on for your next book?Eric Topol (43:50):Well, it's a scholarly approach to a very important field. If you can influence the aging process, you influence every part of our body function. The impact here is profound, and the contribution that you've made in your science as well as in your writing here is just so terrific. So thank you, Coleen. Thanks so much for joining us today.Coleen Murphy (44:17):Thank you so much. It's been a pleasure.Thanks for listening and/or reading this edition of Ground Truths, aimed at bringing you cutting-edge biomedical advances via analyses and podcasts.All content is free. Voluntary paid subscriptions go to support Scripps Research and have funded our summer intern program. Get full access to Ground Truths at erictopol.substack.com/subscribe

Today, I am absolutely thrilled to have Professor Tony Wyss-Coray with us, a renowned expert from Stanford University who is revolutionizing our understanding of aging. His groundbreaking research, which recently graced the cover of Nature magazine, reveals a fascinating concept: our organs each have their own "clocks" that offer insights into the aging process and help predict diseases like heart failure and Alzheimer's. This innovative approach stems from his study of blood proteins associated with different organs, highlighting that each organ ages at its own pace.In his lab, Professor Wyss-Coray and his team delve into the mysteries of brain aging, investigating why it leads to memory issues and conditions such as Alzheimer's. One of their most remarkable findings is the potential for young blood to rejuvenate older brains, suggesting a promising avenue for reversing some effects of aging. They employ a variety of scientific techniques to explore how our bodies communicate with our brains throughout our lives.But Professor Wyss-Coray's influence extends far beyond his lab. He has shared his pioneering discoveries on prestigious platforms such as TED talks and the World Economic Forum, earning recognition in Time Magazine's list of people transforming healthcare. His entrepreneurial spirit has also led him to found companies dedicated to tackling brain diseases, and his contributions to science have been honored with numerous awards.In our discussion today, we aim to unpack Professor Wyss-Coray's recent discoveries in an accessible manner, exploring their significance for the future of aging research and what they could mean for our understanding of how to maintain health as we age. We'll also discuss the impact of exercise on reversing aging and dive into more tips and interesting points about keeping our bodies and brains healthy.Takeaways:Changes in the composition of blood can impact the brain and contribute to age-related diseases like Alzheimer's.Rejuvenation can be achieved through blood transfusion, with young blood having a positive effect on the brain and overall health.While the aging process cannot be completely reversed, it is possible to slow down aspects of aging and maintain good health until old age.Lifestyle factors, such as exercise and social connections, play a significant role in maintaining good health and slowing down the aging process.The future of aging research holds promise for developing treatments and interventions to improve health and extend a healthy lifespan.............More LinksFor Crina's Instagram click here!For Dream Again Podcast's Instagram click here!Don't Forget to Live Your Best Life Now

In this insightful episode of Longevity by Design, hosts Dr. Gil Blander and Ashley Reaver welcome Dr. Tony Wyss-Coray, a distinguished expert in neurology and brain aging. Dr. Wyss-Coray shares his journey from a childhood fascination with nature to becoming a leading figure in neuroscience and immunology. His initial interest in farming evolved into a passion for understanding the complexities of the human brain, particularly in the context of aging and neurodegenerative diseases.Dr. Wyss-Coray discusses his groundbreaking research on Alzheimer's disease and the aging brain. He dives into the intriguing discovery that factors in young blood can rejuvenate older brains, offering potential pathways for treating age-related cognitive decline. This revelation has significant implications for understanding and potentially mitigating the effects of aging on the brain.The episode also explores Dr. Wyss-Coray's transition from Switzerland to the U.S., highlighting the cultural and scientific opportunities that influenced his career. His journey underscores the importance of interdisciplinary research and collaboration in advancing our understanding of complex medical challenges like Alzheimer's disease. This conversation provides a fascinating glimpse into the intersection of immunology, neurology, and the quest to unlock the secrets of longevity.Listen to all episodes of Longevity by Design at https://info.insidetracker.com/longevitybydesign Episode timestamps:Introduction: 0:00-2:12Why Dr. Tony Wyss-Coray became a scientist: 02:13-03:35Dr. Tony Wyss-Coray's career journey studying immunology, neuroscience, and aging: 03:36-07:02Dr. Tony Wyss-Coray's personal story on why he decided to stay in the US: 07:03-11:20Dr. Tony Wyss-Coray's story on becoming the founder of three biotech companies and what they do: 11:21-15:12Introduction to Dr. Wyss-Coray's research on proteomics and organ-specific aging: 15:13-15:52What is proteomics: 15:53-16:39What are the SomaLogic and Olink technologies for measuring proteins: 16:40-19:37What are the links between blood-based proteins, organ-specific biological aging, and chronic disease risk: 19:38-28:35Is aging a disease: 28:36-31:01The three waves of aging based on proteomic analysis: 31:02-37:29Are changes in blood proteins the cause or effect of aging: 37:30-43:46What are the effects of parabiosis and blood transfusion on gene expression and aging: 43:47-50:58The future of blood transfusions and synthetic drugs for improving healthspan and preventing neurodegenerative diseases: 50:59-55:07Are the effects of parabiosis or blood transfusions short-term, mid-term, or long-term: 55:08-59:17Proteomics for understanding organ aging, identifying potential drug targets, and young blood transfusions for rejuvenation: 59:18-01:01:58Biological aging of organs: 01:01:59-01:10:29What are the effects of fat tissue or obesity on metabolic health and mortality: 01:10:30-01:12:06What is the effect of accelerated brain aging on cognition and neurodegeneration: 01:12:17-01:15:52What can people do themselves to identify if they have accelerated brain aging: 01:15:53-01:18:27Sleep improves blood biomarkers: 01:18:28-01:19:09Top tip for healthspan: 01:19:10-01:21:44

The science to advance our understanding of the aging process—and to potentially slow it down—has made important strides. One of the leading scientists responsible for this work is Professor Tony Wyss-Coray, whose work has particularly focused on brain aging but has implications for all organs. I believe his December 2023 Nature paper on blood proteins that can track aging for 11 of our organs is one of the most important aging reports yet.Here is the audio and transcript of our conversation, recorded 20 December 2023, with a few relevant external links.This is the last Ground Truths post for 2023 and I hope you'll find it informative. I look forward to sharing many more exciting, cutting-edge biomedical advances with you in 2024!00:10.38Eric TopolHello this is Eric Topol and for this edition of Ground Truths. I'm so delighted to have with me Professor Tony Wyss-Coray of Stanford, a Distinguished Professor at Stanford and who directs the Knight Initiative for Brain Resilience. So welcome Tony.00:30.19Tony Wyss-CorayThank you, thank you for having me, Eric.00:32.84Eric TopolWell, I've been following your career and your work for decades I have to say and what you just published a couple weeks ago in Nature. The cover paper about internal organ clocks. It blew me away. I mean it's a built on a foundation of extraordinary work. I thought we could start with that because to me that's really a breakthrough in that when we think of aging and how to gauge a person aging with things like the Horvath clock of methylation markers or telomeres or —not at all specific to any part of the body, just overall, l but you published an extraordinary work about plasma proteins for 11 organs that predicted the outcomes things like heart failure and Alzheimer's so maybe you could tell us about this.  Seems to be a big deal to me.01:28.41Tony Wyss-CorayThank you so much I'm honored. Really, you know I think if you work on this stuff, especially for several years it feels sort of obvious to do it? But I think you know it is in a way. It is. Pretty simple. So what we argued is that the thousands of proteins that you know are present in our blood. They must originate from somewhere now a lot of proteins are you know, produced by cells throughout the body. But some proteins are very specifically produced. For example, only in the brain or only in the liver or only in the heart because they have specialized functions and we have you know being taking advantage of that in clinical medicine where you measure. Often you know one of these proteins to sort of diagnose pathology in a tissue, but we took this It's just a level further and said, well, let's just find out of thousands of proteins that we can measure assign them to specific organs and tissues. And then see whether they change with age and many of them turn out to change. We found you know about 1500 proteins or so in the study that we did although that number can grow dramatically if we you know keep.03:01.11Tony Wyss-CorayImproving our technologies or techniques to measure them and many of them come from the brain or from other tissues and because they change with age. They tell us something about the aging of that organ. And as others have shown in the field including Steve Horvath is that that prediction of the age if it doesn't really match exactly your actual age contains information about the state the physiological state or the risk to develop. Organ-specific disease.03:37.75Eric TopolRight. And you found that about 1 in 5 people had evidence of accelerated aging of 1 organ which of course is really starting to nail down ability to detect aging you know to localize it and um. What strikes me Tony is that now because we're seeing at the cusp of advancing in the science of aging a field that you have done so much to propel forward and one of the issues has been well, how are we going to prove it. We can't wait for 20 years to show that. Whatever intervention led to promotion of healthy aging. But when you have a marker like this of organ specificity, it seems like the chances of being able to show that intervention makes a difference is enhanced would you say so?04:29.28Tony Wyss-CorayYeah, absolutely I think that's one of the most exciting aspects of this that we can now start looking at interventions whether they are you know a specific intervention that tries to target the aging process, or you know just that. Let's say a cholesterol lowering drug or blood pressure lowering drug does that have a beneficial effect on the heart. For example, on the kidney or you can also start thinking of lifestyle interventions where they actually have an effect right? If you started exercising you collect your blood before and then a year after you have an exercise regimen does that actually change the age that we can measure with these different clocks.05:22.55Eric TopolRight? Well I mean it's really a striking advance and by a marker of aging so that gets me to your other work. You've done well over 10 years which is that you could identify that given young blood. First of course in mice and then later verified in people could improve cognitive function in older whether it's experimental models or in people. So what are your thoughts about that is that if that's something you've been ruminating on for many years and I'm sure there are places around the world that are trying to do this sort of thing. What do you think of that potential?06:11.40Tony Wyss-CorayYeah, so there really this recent observation or study really came out of you know that finding that young blood can change the age of different organs and you know we. We were not the first to show this. We showed it for the brain but Tom Rando who studied muscle stem cell aging showed this you know a few years earlier in the muscle and we worked with Tom to explore this for the brain, but it shows sort of that this you know the composition of the blood. It is really not just reflecting the age of organs and tissues. But it actually also affects them. It directs them in a way and so you can speculate that you know if you had an organ that shows accelerated aging. Because some of the factors end up in the blood. They might actually induce aging in other tissues and so promote the aging process and people in the field have also shown that this is true for specific cells. We call them senescence cells. So these are a specific type of cell that seem to somehow stop dividing and assume the state that releases inflammatory factors these cells too. They seem to almost infect the neighborhood where they live in with an age promoting sort of.07:41.95Tony Wyss-CorayThe secretome , as we call it, so they release factors that seem to promote aging locally but potentially across the organism and interfering in that could potentially have rejuvenating effects and so that brings us back to this observation that.08:01.23Tony Wyss-CorayYoung blood could potentially rejuvenate organs We know old blood can accelerate it at least in mice. So could we neutralize the age promoting factors in people and could we deliver sort of the rejuvenating factors. Now what's been frustrating for me is that it has been incredibly challenging to identify the key factors.08:33.30Tony Wyss-CorayI think we became to realize as a field that there is not 1 factor. There's not 1 magic factor that will keep us young or keep our organs young but rather different cells and different organs in our body seem to respond in different ways actually to this young blood. Can show this with molecular tools. We can show that every cell actually responds. So if you take a mouse an old mouse and you give it young blood every cell in that mouse shows a transcription of the response to the young blood.09:10.80Tony Wyss-CoraySome of them may regenerate mitochondria and others activate other pathways. We see that stem cells respond particularly well the stem cells of the Immune system hematopoietic stem cells um while other cells show less of a response. And that to me suggests that they respond to different factors in the young blood and that you know they have very specific um receptors Probably that recognize some of these beneficial factors and then respond in a specific way. So that's what we need to.09:33.16Eric TopolRight.09:48.63Tony Wyss-CorayFigure out I think as a field to translate this really to the clinic is what are the key factors and will it be possible to make a cocktail that sort of mimics Nature's you know elixir10:06.13Tony Wyss-CorayI Said this before it's almost like the fountain of youth is within us, but it just dries out as we get older and if we could figure out what are the key factors that that make up this fountain. We could potentially you know either, as a treatment, deliver it again or reactivate that found and so that the body produces these factors again.10:34.73Eric TopolWell, you know that's something that years ago I was very skeptical about and because of your work and others in the field. I've come a long way thinking that we're on the cusp of really identifying ways to truly promote healthy aging. And so this is a really you know extraordinary time in our lives I wonder you of course mentioned 2 critical paths that have been identified the senescent cells—removing them— or the infusion of young plasma. Would you say it's too simplistic to reduce this to decreasing inflammation or is that really the theme here, or is it much more involved than that.11:28.48Tony Wyss-CorayI think inflammation has a big part in that but you know inflammation is such a broad term and such an ill-defined term that um yeah I can say yes to your question.11:44.45Tony Wyss-CorayAnd I'm probably not going to be wrong. Um, but if we really want to know which molecular pathways in the inflammatory cascade are key to this detrimental process that seems to accelerate aging. Um, I think we have to work a bit harder and really so define what we're saying you can't just have thousands of proteins or genes that have something to do with immune and inflammatory process. It's called inflammation.12:21.25Tony Wyss-CorayThen? yes, everything is inflammation. But I think we have to be more precise. Otherwise, you can't really target it. Having said that you know if we use sort of the conventional tools that biologists use these pathway analyses if we give young plasma. To an aged organism then the top pathway or one of the top pathways in almost every cell is inflammation, suggesting that we reduce the inflammatory process. But again, it's in a very broad sense and I want to know more? what? what. What we're finding? In fact, you know 1 of our first observations when Saul Villeda was in my lab and the first parabiosis study to look at factors that might promote brain aging. Yeah, he identified beta-two-microglobulin and eotaxin is a chemokine that is involved in a lot of you know, sort of inflammatory responses and has actually recently more recently again been implicated by Michelle Monje here at Stanford. To be a mediator of you know the chemobrain as people call it at least in animal models and we showed that it's part of the age plasma that causes sort of, an acute impairment of cognitive function in mice.13:46.90Tony Wyss-CoraySo that would be an example of a bad factor and that is part of an inflammatory cascade but we want to know what exactly is it. Um, we tried a small molecule that targets the receptor One of the main receptors for this chemokine. But unfortunately that compound had some side effects on the liver and we've never got to really test. The question is this you know potentially Important. It's one of the challenges you know for drug development.14:20.82Tony Wyss-CorayYou often don't get to test your questions because the drug has side effects that don't allow you to do that.14:26.14Eric TopolWell, speaking of drugs out there this past week there was a very provocative paper from Daniel Drucker University of Toronto on the GLP-1 effects on brain inflammation and interestingly with. You may have seen it but with mice that were either knocked out of GLP-1 for their blood cells or their brain. It was clear that inflammation reduction with these drugs and they tested several different GLP-1s, all worked through the brain. Which is really fascinating and I wonder of course these drugs are now you know they craze for anti-obesity. But do you see something like that this this peptide agonist as a potential way to achieve some of the effects that you've been. Working on for a long time.15:25.40Tony Wyss-CorayYeah I think this is extremely fascinating. Um I mean these drugs. Um, we don't understand them exactly what they're doing as you know for many drugs.15:31.24Eric TopolRight? right? right.15:37.13Tony Wyss-CorayBut it's really amazing the effects that you see and you know I'm very hopeful. There's a large phase 3 trial in Alzheimer's disease ongoing. The phase 2 looked very positive very promising so you know it. It is really possible that.15:49.65Eric TopolUm, yeah.15:56.49Tony Wyss-CorayUm, that there that there are key pathways that are responsible for you know cognitive decline and a cognitive impairment and inflammation is ah is a key aspect of that again inflammation in a broad term. We need to define it but it could be that it goes through. You know, um through these glib receptors and um and that ah might be ah, some regulator of a broader process but you know we see for example with aging just with normal aging you get um activation of.16:35.96Tony Wyss-CorayInflammatory pathways in the brain vasculature and young plasma reduces these changes acutely and maybe this is you know all part just dampening that inflammation gives you some additional brain power, if you will, for lack of a better word. That much of you know at least the early stages of cognitive impairment that lead to Alzheimer's disease.17:12.10Tony Wyss-CorayRelatively transient and are more like a fog like we say you know the chemofog the chemobrain or brain fog but that you know with Covid that you also commented very prominently that. That suggests that it's not a structural damage early on but that that it might be some soluble factors that would go a long way if you could just suppress them.17:35.83Eric TopolRight? right? Well, It's really fascinating to see and I'm glad you mentioned the Phase 3 trial in Alzheimer's for this one class because I think that's expected in 2025 to read out and that'll be really important. I Wanted to ask you because now there's many shots on goal to change the natural arc of aging at all these companies like Altos and Unity and Calico and I mean there's so many of them I can't even keep track. Um, they're all taking different strategies. I Have to think because they need to have their own intellectual property. What do you see as the alluring ways that we're going to be able to modulate this process.18:25.65Tony Wyss-CorayThat's a very tough question. I think it's hard to predict I would say you know like always in in biology. First of all, as you know what we discussed earlier. It could be that. Ah, drug that tries to test the pathway like you know one that Unity tried has side effects and you know you can't actually test your hypothesis. But I think one of the key sort of aspects of the aging process is really that it's both global across the organism but it's also very localized and so it's possible that targeting the aging process will first show benefits. In individual tissues if we target you know the aging process in 1 particular tissue that might show the first benefits. But then again it could be that if there is sort of a key inflammatory driver that to some extent responsible for overall aging of the organism and you manage to target that and slow it or block it. You may have an organism-wide effect. But I think we have to be we have to be realistic that.19:51.88Eric TopolUm, yeah.19:56.99Tony Wyss-CorayYou know this is going to be an incremental process I think.20:00.92Eric TopolSo is there anything that you've seen that has grabbed you as having tremendous potential that is new or is it really you know the things that I've already been percolating that that we know about.20:17.41Tony Wyss-CorayYeah I mean just to the GLP-1 study I've been actually ah a bit involved in that. Um I find this really fascinating. Um, yeah.20:23.98Eric TopolUm, yeah, yeah, well that I spoke.20:29.81Tony Wyss-CorayI Mean not in that study that got published but in sort of more on the cognitive side.20:33.78Eric TopolWhere I right? I Thought that was especially welcome news because the drugs we have now for Alzheimer's seem to have you know some pretty serious side effects and somewhat low efficacy relative to the to the risk rssessment. So, this would be a drug that we know now as people have taken for years that I do want to get back to you with you on the durability. So if you give young blood to an old person who has let's say mild Cognitive impairment. Will you see a durable impact or is it just a very short lived one.21:13.76Tony Wyss-CorayI think some of the effects will be durable and I'm saying that because of an experiment that James White and Vadim Gladyshev did they use this parabiosis model where you suture a young and an old mouse together.21:32.10Tony Wyss-CorayLeft these mice together for two months I mean or three months and then they separated them and let them live and looked at how long does an old mouse live that was paired with a young mouse for a few months. Compared to an old mouse that was paired with another old mouse and they saw that there is clear extension of lifespan if the mouse was exposed to young blood. Now this is in the context of you know, 2 major surgeries first suturing them together and then taking them apart. But I always note that when I present this experiment but I also say at the same time that this is the problem that a lot of older people have right when they have a surgery they don't recover from it as well. And it's often the beginning of cognitive decline if you ask families. You know when did it start? Oh they had heart surgery or they fell and had you know had a hip surgery or something like that or a major infection. That is often the trigger where it's almost like you know the organism is hanging in there and it's still functioning and then there's an injury and it collapses. Um and so you know what's remarkable with the rejuvenating intervention with.23:02.11Tony Wyss-CorayWith parabiosis is that it seems to overcome this to a very significant event and they also showed you know with many other tools including with the Horvath clock that tissues are actually getting younger through this process.23:20.51Tony Wyss-CorayWe have also found that you know stem cells are rejuvenated for a long period of time if you treat with young plasma infusions in mice and so I'm hopeful that some of the effects are going to be long-lasting. But. You know, practically you would probably still treat people on a regular basis like we do with all drugs. But maybe you would do an infusion every 3 months or every six months and you know we're still trying with um.23:52.20Eric TopolPray.23:57.00Tony Wyss-CorayA company that I so that that I started Alkahest to you know, convince people to do a Phase 3clinical trial and see how far we can push this.24:09.38Eric TopolWell, it'd be really interesting to see you get that done then going back to the senescent cells which is another leading prospect. It seems to be more difficult to get these cells out of the body. We know they're bad actors but it isn't like we can you know. Ah, very selectively remove them. But what are your thoughts about that approach.24:35.76Tony Wyss-CorayI mean I'm always really puzzled and amazed at the effects that people show with you know, senescence cell removal in in animal models.24:46.20Eric TopolRight.24:49.57Tony Wyss-CorayThere is something really almost magical there that you remove these few cells and you know the body is doing much better. Um, So I think you know we should. We should keep trying very hard to translate this to humans. But it's possible that again there are they're very likely different types of senescence cells and different tissues I mean in the brain you know there are no rapidly dividing cells. So. It's not the classic. You know arrest of cell cycle.25:24.11Tony Wyss-CorayBut it's probably more like an astrocyte type of cell that might mimic a senescent state.  But I think it will be. It will be. You know very much organ specific. And may require very specific interactions or drug targets.25:44.83Eric TopolAh, right? right? Well then gets us back to kind of where we started before you're what I consider a landmark paper. Um, it would be difficult. To be able to go to a regulatory body like the FDA and say we show that this is affecting the aging process and we show in you know 3 organs 5 organs whatever the 11 organs you could track we are reversing the aging process. I mean you have that now as an extraordinary finding. Do you think that will help accelerate the field by having not having to have a whole-body aging story with an epigenetic clock but rather you know much more pinpointing. Organs that can be helped that they can be promoting healthy aging. It seems to me this is where not only advancing the theories of how to do it but the proof that you have done it. It seems like this is what. You know why I consider such an extraordinary finding.26:59.90Tony Wyss-CorayI totally agree with you but I'm a bit biased I think you know this is what we need I mean this was always a criticism to me and you know we're very good friends with Steve Horvath andMorgan Levine who you know came up with these remarkable aging clocks. But my my question was always how can you get information about the whole body aging. By looking at changes in blood cells or cheek cells. Um, that cannot contain information about how your pancreas ages or your heart ages at the high resolution. It will correlate. Admittedly, but it will not give you tissue-specific information most likely. So you know going more directly at molecules that are derived from cells across the organism is of course going to be much more informative. Um, we've just started to do this. You know it's a concept. Um, we are super excited about you know, looking now at large datasets like the UK biobank. We just get access. Through a collaboration to 50,000 individuals where we have 1500 protein measurements with a different proteomic platform and it seems most of the findings replicate.28:47.45Tony Wyss-CorayYou know, very strong risk for people who have older brains to develop the men in the future. Um, and you know we still see these extreme organ ages that I find very puzzling.29:00.89Eric TopolYeah, it's really striking and the fact that you could replicate the best biomarker for the brain.—Plasma pTau-181— through these proteins is exceptional. How much did machine learning AI help you? And deciphering this large data set of proteins was it really critical or was it just a small part.29:26.23Tony Wyss-CorayAh, oh it's certainly I mean this is I think you know the terminology are not so clear and I have to admit you know I'm not a computer scientist by any stretch. But I think this is classic machine learning using statistical elements of learning as you know. We use linear modeling. Um, but I think it will become more sophisticated. Um, and I think ai will help us to bring this. To a much higher level by but by basically learning from the relationship between proteins directly and then compare that in healthy people versus control similar to what Christina Theodoris recently did for gene expression. Ah, the single cell level. Um I think we will see that and we're trying this and I'm sure others are trying this too at the protein level but the current the current study uses really more traditional machine learning models. Um that you know are sophisticated but it's not.30:42.33Tony Wyss-CorayYou know I'm not sure we call this artificial intelligence.30:44.85Eric TopolSure. Well I think as you say it can build on that and you know putting in more models to more data sets and where the future goes. You'll get even more precision output as you know know, Tony.30:51.58Tony Wyss-CorayUm, yeah. Absolutely.31:02.44Eric TopolThis This has been a real joy. I have to say congratulations to you and your team for such exceptional work. This has been a multi-decade run, you know one layer of after another of building on the science of aging particularly the brain aging I've learned so much from you and your team.31:07.28Tony Wyss-CorayThank you.31:21.81Eric TopolI have to say the paper you just published you and your group got me excited I mean I really thought of all the things I've seen on aging this was the one that really opens it up for you know all the other possible ways to claim you're making a difference. You've got a metric that's emerging and so kudos to you and I know this is got to be of course that you probably just say oh, it's just 1 more thing we've been doing but I am so duly impressed.31:52.30Tony Wyss-CorayThank you so much. Thank you for the nice word means a lot.31:58.94Eric TopolWell keep up the great stuff because we're all, we're all depending on you so that we can have a better arc of our healthy aging process and we'll keep in touch. If you can just stay on it!32:10.30Tony Wyss-CorayThank you! Thanks so much.Thank you for listening, reading, subscribing to and sharing Ground Truths!Happy new year,Eric Get full access to Ground Truths at erictopol.substack.com/subscribe

From ancient myths to science fiction, humans have long been fascinated by the idea of transcending the limits of our natural lifespan. But what does modern medicine say about the practical, actual possibilities of extending human life? Joining us to explore this tantalizing question is Tony Wyss-Coray, PhD, a neuroscientist and director of the Phil and Penny Knight Initiative for Brain Resilience at Stanford University. While his research focuses on age-related cognitive decline and Alzheimer's disease, his work has involved identifying the “biological age” of various organs and its implications on various diseases, and treating old animals with the blood of young animals to halt, and even reverse, aging of the body. Over the course of our conversation, we not only discuss the mysterious mechanisms underlying neurodegeneration, but also venture beyond the lab to explore the philosophical and ethical dimensions of life extension. We ask: how does our understanding of aging affect our perception of self and identity? Is aging a disease to be treated? What are our social and moral obligations when it comes to prolonging life or enhancing brain function? Is immortality even desirable?In this episode, we discuss: 2:30 - How Dr. Wyss-Coray became drawn to neuroscience 4:45 - Defining neurodegeneration and aging 9:26 - The studies that led Dr. Wyss-Coray and his team to finding the gap between biological age and chronological age21:06 - Is reversing the aging of an organism's body a realistic goal? 28:31 - The possibilities and limits of treating neurodegenerative conditions 33:49 - Dr. Wyss-Coray's groundbreaking work in treating old animals with the blood of young animals to reverse aging38:51 - The philosophical and moral implications of life extension48:57 - Dr. Wyss-Coray insight into the “secrets” behind some people's longevity Dr. Tony Wyss-Coray can be found on Twitter/X at @wysscoray.Visit our website www.TheDoctorsArt.com where you can find transcripts of all episodes.If you enjoyed this episode, please subscribe, rate, and review our show, available for free on Spotify, Apple Podcasts, or wherever you get your podcasts. If you know of a doctor, patient, or anyone working in health care who would love to explore meaning in medicine with us on the show, feel free to leave a suggestion in the comments or send an email to info@thedoctorsart.com.Copyright The Doctor's Art Podcast 2023

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Hi listeners, we're shifting to a biweekly release schedule after this episode. See you in a couple weeks!---Most of us probably know someone who developed Alzheimer's disease or another form of dementia as they got older. But you probably also know someone who stayed sharp as a tack well into their 80s or 90s. Even if it's a favorite TV actor, like Betty White. The fact that people age so differently makes you wonder: is there some switch that could be flipped in our biology to let us all live to 100 with our mental faculties intact.Scientists now believe we can learn something from people whose minds stay sharp — whose brains stay youthful into old age that could lead to treatments to slow down aging for the rest of us.That brings us to today's guest.  Tony Wyss-Coray is the Director of the Phil and Penny Knight Initiative for Brain Resilience at the Wu Tsai Neurosciences Institute. Wyss-Coray's lab is renowned for experiments showing that young blood can rejuvenate old brains, at least in laboratory animals. We talked with him about this work and the prospect of achieving more youthful brains into what we now consider old age.LinksWyss-Coray lab websiteKnight Initiative for Brain ResilienceFurther ReadingQ&A: Can we rejuvenate aging brains? (Scope Blog, 2022)Gift from Phil and Penny Knight launches scientific endeavor to combat neurodegeneration (Stanford News, 2022)Young cerebrospinal fluid may hold keys to healthy brain aging (Wu Tsai Neuro, 2022)Blocking protein's activity restores cognition in old mice (Stanford Medicine, 2019)Clinical trial finds blood-plasma infusions for Alzheimer's safe, promising (Stanford Medicine, 2017)Infusion of young blood recharges brains of old mice, study finds (Stanford Medicine, 2014)Scientists discover blood factors that appear to cause aging in brains of mice(Stanford Medicine, 2011)Young blood revives aging muscles, Stanford researchers find (Stanford Medicine, 2005)Episode CreditsThis episode was produced by Michael Osborne, with production assistance by Morgan Honaker, and hosted by Nicholas Weiler. Cover art by Aimee Garza.Thanks for listening! Learn more about the Wu Tsai Neurosciences Institute at Stanford and follow us on Twitter, Facebook, and LinkedIn.

第41期脑科学新闻 | 孤独的果蝇睡得少吃得多，年轻鼠的脑脊液改善老年鼠的记忆能力导读：海德，陶火，Li Xun责编：呆苏克主播：小胡背景音乐：夜的钢琴曲五_石进Nature | 孤独的果蝇，睡眠更少，吃得更多自新冠疫情爆发以来，“隔离”就成了我们生活中“常客”。与隔离一同出现的，除了焦躁不安的情绪、人际关系的疏离，往往还有与日俱增的体重和日益减少的睡眠。事实上，这种现象不仅仅出现在人类身上，小小的果蝇也是如此。近日，来自洛克菲勒大学的研究人员使用定量行为分析和生物信息学分析来研究了果蝇在短期或长期社会隔离后大脑状态的差异，发现短期社会隔离（与群体分隔1天或3天）并不会导致果蝇睡眠不足，而长期社会隔离（与群体分隔5天或7天）则会显著降低果蝇睡眠时间。此外，缺乏社交活动的果蝇大脑状态与其饥饿时非常相似，表明长期社会隔离可能会改变代谢相关基因的表达，从而引发“饥饿”。研究人员在进一步研究中发现P2神经元对该效应有重要作用。沉默果蝇的P2神经元可显著降低长期社会隔离对果蝇的影响，而激活短期社会隔离组果蝇的P2神经元则会导致睡眠不足和更多的食物摄入。这些结果表明，P2神经元参与了调节社会隔离效应的回路，并可能发挥类似“计时器”的作用，监测隔离持续的时长。这一研究揭示了果蝇和人类在面对长期的“社会隔离”时具有许多相似之处，并建立起了一个可以用于研究社会隔离对大脑、心理的影响的模型，同时给予了我们更多利用低等生物来模拟和研究人类心理健康现象的灵感。（导读：海德）文章来源：https://www.nature.com/articles/s41586-021-03837-0图片来源：https://static01.nyt.com/images/2020/03/24/science/24BRODYISOLATION/24BRODYISOLATION-superJumbo.jpgNature | 年轻鼠的脑脊液改善老年鼠的记忆能力在缓慢老去的过程中，人的记忆力往往会越来越差，且目前尚无能够有效改善或提高记忆力的方法。在人均寿命日益延长的今天，减缓大脑衰老或设法保持大脑的认知、记忆功能成为了一个亟待解决的问题。近日，来自斯坦福大学的Tony Wyss-Coray团队尝试将年轻小鼠（10周龄）的脑脊液灌注进老年小鼠（18月龄）的脑中，发现这一举措可以显著改善老年小鼠在恐惧条件反射任务中的记忆表现。通过对海马体进行转录组分析，研究人员发现少突胶质细胞可能是介导这一变化的关键细胞类群，并在体外和体内分别证实了年轻的脑脊液能够促进少突胶质细胞祖细胞的增殖、分化。研究人员随后用SLAMseq技术对新生成的mRNA进行标记，发现了受年轻脑脊液影响最大的“头号种子”——血清反应因子。对脑脊液中潜在的血清反应因子激活剂进行筛选，研究人员进一步确定了灌注成纤维细胞生长因子17 (Fgf17)能够诱导老年小鼠的少突胶质细胞祖细胞增殖并巩固长期记忆，而阻断Fgf17则会损害年轻小鼠的认知功能。利用年轻个体的身体成分“逆转”衰老过程的研究由来已久，但其背后的机制始终难寻。这一研究揭示了年轻的脑脊液中发挥作用的关键因子——Fgf17，厘清了“返老还童”这一神奇生理过程背后的生物学机制，也为治疗方法和药物的研发提供了新的可能。此外，这篇文章还证明了通过脑脊液给药方式治疗痴呆的可行性，对当今人口老龄化问题愈发严重的人类社会大有裨益。（导读：海德）文章来源：https://www.nature.com/articles/s41586-022-04722-0.pdf?origin=ppub图片来源：https://posturepractice.com/wp-content/uploads/2015/11/aging-memory-declin.jpgMolecular Psychiatry｜调节抑郁样行为的新环路：从内嗅皮层到次级视觉皮层根据世卫组织最新报告，抑郁症已成为人类致残的首要原因，全球罹患抑郁症的人群超2.8亿。但抑郁障碍病因复杂，相关机制研究和治疗手段仍十分有限。由于抑郁症涉及多个脑区，其被视作一种“神经环路疾病”（circuitopathies）。今年四月，清华大学郭增才课题组在线发表在《分子神经病学》（Molecular Psychiatry）上的一篇文章首次揭示了一条从内嗅皮层到次级视觉皮层内侧区的神经环路在抑郁症中具有双向调节作用。研究发现，在具有抑郁样表型的慢性社会挫败应激（CSDS）小鼠模型上，其内嗅皮层Va亚层神经活性降低。通过化学遗传和光遗传学方法，研究组发现抑制Ent→V2M通路可以诱发健康小鼠和加重应激小鼠抑郁样表型，而激活该通路则可以快速缓解抑郁样表型。该通路的作用机制与驱动小鼠转向抗抑郁状态相关。这为临床抑郁症的治疗提供了潜在靶点，特别是非侵入性刺激治疗，如经颅磁刺激、经颅直流电刺激等。（导读：陶火）文章链接：https://www.nature.com/articles/s41380-022-01540-8图片链接：https://pixabay.com/vectors/mental-therapy-counseling-people-6841357/?downloadNature Neuroscience | 5-羟色胺与中脑多巴胺在厌食症的作用在以瘦为美的时代，很多人都想拥有纤细的身材。但有一类患者，却因“瘦”而饱受折磨。厌食症（anorexia, AN）患者身形极度嶙峋，由于长期不能正常进食，他们严重营养不足，并且饱受精神折磨，痛苦不堪。近日，发表在Nature Neuroscience上的一篇文章研究了厌食症相关的分子机制。研究人员发现高浓度的多巴胺会增高中缝背核（dorsal raphe nucleus, DRN）5-羟色胺能神经元的放电频率与静息膜电位，而低浓度的多巴胺则产生相反效果。此外，腹侧被盖区（ventral tegmental area, VTA）的多巴胺能神经元可以投射到DRN，并调节其中的5-羟色胺能神经元。在将ChR2光敏感通道蛋白注入VTA的多巴胺能神经元时，低频（2Hz）蓝光会抑制DRN中5-羟色胺能神经元并增加小鼠对于食物的摄入（此过程可以被多巴胺受体D2拮抗剂阻止），而高频（20Hz）蓝光会激活DRN中5-羟色胺能神经元并抑制小鼠对于食物的摄入（此过程可以被多巴胺受体D1拮抗剂阻止）。在活动型厌食症（activity-based anorexia, ABA）小鼠模型中，激活的多巴胺能神经元激活DRN的5-羟色胺能神经元，这一过程依赖于多巴胺受体D1而非多巴胺受体D2。本研究提出了厌食症可能的生理机制，可能会为未来的临床治疗提供依据。（导读：Li Xun）文章链接：https://www.nature.com/articles/s41593-022-01062-0图片链接：https://cn.bing.com/images/search?q=%e5%8e%8c%e9%a3%9f%e7%97%87&form=HDRSC2&first=1&tsc=ImageHoverTitleNature Neuroscience | 青春期抑制丘脑活动对成年期前额叶的影响神经系统在青春期时可塑性增强，此时，外界刺激可能会对神经系统造成长久的影响。此外，精神分裂症与人脑前额叶（PFC）功能异常相关。那么，青春期其他脑区的异常会影响到成年期PFC的功能吗？来自哥伦比亚大学的研究团队探索了这一问题，研究者发现，在小鼠青春期而非成年期抑制丘脑，成年后小鼠的与PFC相关的认知行为测试受到影响。并且，小鼠内侧前额叶皮层（mPFC）2，3层锥体细胞的突触前兴奋性输入的数量或功能下降，这种下降是由于投射到mPFC的丘脑神经元减少，而非丘脑本身神经元减少。研究者激活这些投射到mPFC区域的丘脑神经元后，发现小鼠与前额叶皮层相关的认知行为测试得到改善。在更深一步研究中，他们发现γ脑电波与β脑电波无法解释青春期丘脑抑制导致成年期行为学异常这一现象。随后，研究者将mPFC中每一个放电的神经元进行关联，发现在行为学测试时，存在一个关联高峰，而青春期丘脑抑制会减弱这个高峰，后续激活丘脑会使得这个高峰增强。这提示青春期时，其他脑区的改变会影响到大脑的前额叶皮层。（导读：Li Xun）文章链接：https://www.nature.com/articles/s41593-022-01072-y图片链接：https://www.piqsels.com/zh/public-domain-photo-zbqclNature | 阿尔茨海默症神经元中积累了更多体细胞突变神经元功能障碍和死亡是阿尔茨海默症（AD）的症状之一，然而引发这一具体事件的生物学机制仍不清晰。近日，来自波士顿的研究人员分析了来自AD患者和正常对照组的319个神经元的单细胞全基因组测序数据，以探究与AD相关的体细胞突变数量、突变位置和突变种类。结果显示，AD神经元中的体细胞突变数目显著增加，且与正常衰老过程中主要是与年龄有关的模式积累突变特征A突变增加不同，AD神经元中由不正常的“灾难性”事件引发的特征C突变显著增多。研究人员推测这些变化可能与核苷酸的氧化相关，并通过实验证实了AD神经元中核苷酸氧化损伤水平上升。此外，AD神经元中的突变具有转录链偏好性，提示转录相关的切除修复可能在产生突变的过程中发挥作用。本研究发现AD神经元中体细胞突变异常积累且氧化应激水平上升，为神经退行性病变和AD的发病机制提供了新的研究线索和潜在的治疗靶点。（导读：海德）原文链接：https://www.nature.com/articles/s41586-022-04640-1图片来源：https://www.google.com.hk/url?sa=i&url=https%3A%2F%2Fwww.genengnews.com%2Fnews%2Fmechanism-that-prevents-the-death-of-neurons-identified%2F&psig=AOvVaw0ldjqwYoqif9TKNyOm7OGe&ust=1653017303790000&source=images&cd=vfe&ved=0CAkQjRxqFwoTCOjEv7vP6vcCFQAAAAAdAAAAABAD

Aging, one of life’s inevitable certainties, has been a hot topic of research for a number of years. From the obvious fabled stories promising the elixir of life to the questionable anecdotes of individuals who swear by supplements or regimens, anti-aging has always appeared to be a wild goose chase. But now, scientists may be closer than they ever to identifying anti-aging agents. On Today's episode, I am speaking with Stanford University’s Prof. Tony Wyss-Coray, who has laid a milestone in the search by what is known as blood rejuvenation.Prof. Wyss-Coray began his research career in 1993 at the prestigious Scripps Research Institute in La Jolla, California. His initial studies involved work on Alzheimer’s and other dementia-related diseases, which led to a faculty position at Stanford University. Prof. Wyss-Coray suspected that blood might hold the answer to diagnose Alzheimer’s before it manifests its symptoms, and his work produced interesting results in protein level discrepancies with aging, setting the premise for anti-aging blood treatment.One fascinating topic we spoke about is the readily available means that help slow down ageing. Surprisingly - or maybe not anymore after COVID - social interaction seems even more important than a healthy diet and exercise. I hope you'll enjoy this super interesting interview and if you like it, please share it with your friends, family, or community. Sending you love, Crina

What if you could extend your healthy life by 10 or 20 years – with a blood transfusion from someone younger and healthier than you? Research by Stanford professor Tony Wyss-Coray shows potential to treat Alzheimer’s and prevent age-related cognitive decline: He’s discovered that proteins found in the blood of young mice can dramatically reverse the effects of aging when transfused into older mice. Doing the same thing in humans could increase our quality of life as we age, and our life expectancy too. We’re years away from seeing any clinical applications of this research, which gives us time to ask about its implications. Who will have access to this treatment? Who are the donors providing young blood? We could add years to our lives – but is that what we really want?Get the weekly Should This Exist? newsletter for reading list and discussion questions: http://eepurl.com/gnZTf9

潘老師健康教室 你相信嗎！？不運動也能得到運動的好處。根據美國史丹福大學神經學科懷斯．科瑞教授(Tony Wyss-Coray)在2014年的研究，將年輕鼠的血液傳輸到老年鼠的體內，證明能讓老年鼠的大腦年輕化，記憶力增加。年輕人的身上帶有蛋白質TIMP2(金屬蛋白酶2的組織抑製劑)，而運動後會產生蛋白質GPLD1，它主要是在體能鍛煉的過程中，由肝臟所產生。這兩種神祕的蛋白質，都能老年鼠年輕化，在不久的將來，人類的「返老還童」或許會成真。

飛碟聯播網《飛碟早餐 唐湘龍時間》2020.08.11 週二醫療保健單元 潘懷宗的醫學新知時間 《你信嗎！完全不運動也能拿到運動的好處！》 ※主題：醫學新知單元：潘懷宗時間 ※訪問：陽明大學神經藥理所兼任教授 潘懷宗 ◎你信嗎！完全不運動也能拿到運動的好處！ 根據2020年7月9日在《科學》雜誌上的一篇論文，相信大家早就知道，大腦可以通過日常規律的運動習慣下得到許多好處，包括增強記憶力、情緒變好、和增進學習能力等等。但卻令人驚訝的發現，通過移植經常鍛鍊小鼠(mice)的血液，竟然可以轉移體能鍛煉的好處給另一隻同年齡懶惰的小鼠，真的是跌破眼鏡。研究主要作者加州大學舊金山分校醫學系解剖學科維萊達教授（Saul Villeda）說道，在小鼠運動過程中，體內會產生一種特別的酵素，叫做GPLD1，因為透過輸血而傳給了另一隻小鼠，因此可以改善沒有運動小鼠的記憶力和學習技能。 美國史丹福大學神經學科懷斯-科瑞教授(Tony Wyss-Coray)在2014年的研究就已經證明，將年輕小鼠的血液傳輸到老年小鼠的體內，可以使得老年小鼠的大腦年輕化，記憶力增加。因此該研究團隊接著在2017年使用人類臍帶血或年輕成人血輸給老年的小鼠也同樣可以使得老化的大腦年輕化(第一次輸血後，隔三天，到第四天再輸血一次，共輸4次，約2周時間)。表示不論是年輕小鼠的血液中或是年輕人類的血液中都存在一種蛋白質，可以使得大腦年輕化，它的名字叫做TIMP2 (金屬蛋白酶2的組織抑製劑)，這項研究成果已經發表在《自然》期刊，如果一切順利，將來可以注射這個蛋白質給老人失智症的患者，來改善記憶喪失的問題。 在不久的將來，如果這項研究結論在人類身上確定，首先就能夠幫助由於年齡太大或疾病而無法鍛煉的人，因為科學已經證實，對大腦有益的干預措施之一就是身體鍛煉，但問題是許多老年人身體虛弱，根本無法進行鍛煉。儘管這篇論文成功地將運動的大腦好處傳遞給了懶惰的小鼠，但大家千萬不要以為《注射GPLD1來代替運動健身》(exercise in a bottle)很快就會出現。 目前關於單獨注射GPLD1後對身體的所有影響，還有很多未知數尚待研究，因此大家要分清楚輸血和注射是不一樣的。 美國國家老化研究所的神經科學家懷斯教授（Bradley Wise）告訴《科學》雜誌，從確定這種酵素的功能，到發展出一瓶可以給人類注射的針劑，還有一段很長的路要走，目前的研究成果僅僅是一整張拼圖裡的一小塊而已。 ▶ 《飛碟早餐》FB粉絲團 https://www.facebook.com/ufobreakfast/ ▶ 飛碟聯播網FB粉絲團 https://www.facebook.com/ufonetwork921/ ▶ 網路線上收聽 http://www.uforadio.com.tw/stream/stream.html ▶ 飛碟APP，讓你收聽零距離 Android：https://reurl.cc/j78ZKm iOS：https://reurl.cc/ZOG3LA ▶ 飛碟Podcast SoundOn : https://bit.ly/30Ia8Ti Apple Podcasts : https://apple.co/3jFpP6x Spotify : https://spoti.fi/2CPzneD Google 播客：https://bit.ly/3gCTb3G

Tony Wyss-Coray is a professor of Neurology and Neurological Sciences at Stanford University, the Co-Director of the Stanford Alzheimer’s Disease Research Center, and the Associate Director of the Center for Tissue Regeneration, Repair and Restoration at the Palo Alto VA. In this talk he talks about blood borne factors from young mice or humans are sufficient to slow aspects of brain aging and improve cognitive function in old mice, and vice versa, factors from old mice are detrimental for young mice and impair cognition.

Every culture and civilization had its dreams about eternal youth, but what if there was something to it? Professor Wyss-Coray will share an amazing development in aging research that could revolutionize how we understand aging and treat age-related diseases. Tony Wyss-Coray is a professor of neurology and neurological sciences. Classes Without Quizzes are presented by the Stanford Alumni Association. Filmed on location at Stanford Reunion Homecoming 2015.

Tony Wyss-Coray estudia el impacto del envejecimiento sobre el cuerpo humano y el cerebro. En esta charla reveladora, comparte nuevos resultados de la investigación en su laboratorio de Stanford y de otros equipos que demuestran que una solución relacionada con aspectos de la vejez podría realmente encontrarse dentro de nosotros.

Tony Wyss-Coray étudie l'influence du vieillissement sur le corps et le cerveau humains. Il partage avec nous le résultat de les recherches qu'il conduit dans son laboratoire à Stanford et de celles d'autres équipes. Elles montrent qu'une piste pour empêcher les aspects négatifs liés au vieillissement pourrait bien se cacher en nous.

Tony Wyss-Coray estuda o impacto do envelhecimento no corpo humano e no cérebro. Nesta palestra esclarecedora, ele mostra novas pesquisas de seu laboratório em Stanford e de outras equipes, que demonstram que uma solução para alguns dos aspectos menos relevantes da idade avançada pode, na verdade, estar dentro de todos nós.

토니 와이스-코레이는 노화가 인체와 뇌에 미치는 영향을 연구합니다. 눈이 휘둥그레지는 강연에서 스탠포드 연구소의 새로운 연구와 노년의 안 좋은 면의 해법이 사실은 우리 안에 있을지 모른다는 점을 보여주는 다른 팀의 연구를 보여 줍니다.

Tony Wyss-Coray studies the impact of aging on the human body and brain. In this eye-opening talk, he shares new research from his Stanford lab and other teams which shows that a solution for some of the less great aspects of old age might actually lie within us all.

Stanford neuroscientist Tony Wyss-Coray, PhD, has found that infusions of blood plasma from young mice improves memory and learning in old mice. In this podcast, Wyss-Coray, who is also a senior research career scientist at the Veterans Affairs Palo Alto Health Care System, discusses the new study along with his plans to explore whether the findings could lead to treatments for brain diseases like Alzheimer's.