70: Rapamycin and Longevity: What the Research Really Says with Dr. Ben Bikman

Hello and welcome to the Metabolic Classroom. My name is Professor Ben Bickman. I am a biomedical scientist and professor of cell biology. Thanks for joining me for the lecture today. Today's lecture topic is rapamycin. Now, along with that comes a lot of thoughts where you hear that word and you immediately are making some connections. And I want you to make those connections. If among the handful of connections you may be making longevity is at the top of, then you are in the right place. This is the lecture for you. I am going to present during the lecture a bit of, I hope, a bit of a nuanced view, highlighting some of the justification for its use. But my bias will become, I think, a little clear because it's informed by what I consider to be a pretty substantial amount of evidence that is not often discussed that encourages us to, well, have a more nuanced and I would say balanced and perhaps even a slightly negative view when it comes to rapamycin use, especially how it's used and how it's talked about. So how it's talked about is overwhelmingly in the context of longevity. And look, I get it. Everyone wants to live a long, healthy life. And this focus of longevity where rapamycin is discussed is wholly centered on an intracellular protein called mtor. In fact, it's funny because the name of this protein complex, mtor, or sometimes mtor, actually has the name rapamycin in it, that acronym that I'm saying, mtor. MTOR is mammalian target of rapamycin. So this is one of those instances where the drug was used and the use of the drug identified a target, in other words, which was then called mtor. Now, we're going to go through some of the evidence on it, but essentially the evidence is thematically revolves around this idea that MTOR inhibition is going to allow an organism to live longer. Now, as we sort of finish the introduction and move on, despite the enthusiasm and the. The claims that many bring when they talk about rapamycin, the actual application of rapamycin in human studies looking at aging is incredibly uncertain. And I would suggest that the risks, that the negative side effects in fact outweigh any, any possible positive benefit. Okay, now, before we get into rapamycin directly, I wanted to just set the stage a little bit and talk a bit about the role of MTOR in aging. This is a topic I've discussed previously in, in a previous lecture that you can find in the channel. But basically, as the overview, MTOR is one of those critical cellular mediators that affects the ability of the cell to grow it influences the metabolism of the cell, including, with nutrient metabolism, including protein synthesis. This no surprise means that MTOR is quite relevant in muscle. And I want you to be thinking of the muscle and I even want that announcement that, that news, that fact to sit in your mind and have you consider it when you start thinking is this something I actually want to be inhibiting all the time? Now the focus on MTOR has led to a focus on protein because protein when, when you eat dietary protein it is converted into amino acids which are then absorbed and now are flowing through the blood or you just are eating the amino acids directly depending on what your supplement amino acids will activate mtor. And this then if, if you believe inhibiting MTOR is a solution to promoting longevity, then you are okay with that. Then you don't mind if, if you're restricting protein. You know, more protein means more mtor. If MTOR is activated, that means a cell or an organism is going to age faster. All right, well then let's just bring down the protein, thereby lowering amino acids, thereby reducing MTOR activation, thereby promoting longevity. Now the organism will live a little longer. That, that is the absolute crystallized viewpoint when it comes to protein restriction, which undoubtedly you've heard of. If you've kept your finger on the pulse of longevity research at all, you know that there is a, a very substantial comp. Collection of voices that declare that protein is the villain here and it is completely because of protein's ability to activate mtor. Now I am going to focus on the role of insulin later on and just show you how silly I think that is. One reason it's also silly is that some of the most ardent advocates of such a view, their own evidence challenges that where people find that the older you get, the less protein you eat, the higher your mortality is. Let me just say that again that there is this rep. This, this correlation where if, if the older the person's getting, the more protein they're eating, the less they are likely to die. Especially if it's animal protein. There was a huge multi country study published years ago. I'll make sure that's in the show notes that you can read the documented this that the, that had the highest animal protein consumption had the. Were the most likely to live a long time. All right, so that is sort of, that's giving you an overview. Of course one fundamental aspect of this that I would be that it would be a failure on my part to leave out is the role of autophagy. You've heard of autophagy before to really understand the perspective that MTOR inhibition promotes longevity. Autophagy is, is in the middle of those things. So if you're looking at this in a linear way, inhibiting MTOR leads to longevity or the organism living longer. By inhibiting mtor, you enable autophagy to occur. That would be a critical mediator between these two things. Now autophagy, I hate to bring in a new term with a new definition. You probably know it already, at least at a superficial level. It is at a superficial level, just the idea that the cell is renewing itself, that it is breaking down its older components. You know, it's rebuilding its mitochondria, it's rebuilding its lysosomes, it's rebuilding its endoplasmic reticulum, it's renewing its own membrane. You know, for example, that's the idea when it comes to autophagy, that a cell is able to recycle its parts and thus keep its parts in, in sort of useful or functioning, if you will. And that that allows the organism to live longer, to, to survive longer. Okay, now with all of that having been said, let's move into rapamycin itself as a reminder. Mtor, this critical mediator that wants a cell to grow, but thereby perhaps putting it on a clock, making it have a bit of a shorter lifespan, as the theory goes. It is named after. MTOR is named after the drug, mammalian target of rapamycin. Like I said, so it's named after the drug. It was identified because it was identified as the target of this drug. Now why are some people so enthusiastic about it? It's because the animal evidence is quite convincing that animal studies show that rapamycin extends life by up to, you know, 60% in these animals, which, which is absolutely a mind boggling amount of time. And any of these claims I'm making, you can just look in the show notes to get some of the references. So that's really naturally you would look at that data and make a lot of very positive conclusions. It's no surprise that by inhibiting mtor, rapamycin has been shown to enhance autophagy. So you're helping the cells clear out their older parts. And you have a bit of an anti aging effect as the theory goes, because of the activation of autophagy, which is able to occur because of the inhibition of mtor. And MTOR doesn't want. Autophagy could be viewed as a wasteful process. You're recycling parts. MTOR could say, I don't want to waste energy, I want to be storing Energy that may sound a little familiar. If you've heard me discuss some topics on metabolism before, there's a particular hormone that could describe, that could be used in that same way. You know, thematically saying to a cell, I don't want you to waste energy, I want you to store it. We're going to revisit that hormone in just a minute. Pardon me if I'm being a little too vague. I don't think I am, but I'm teasing you a little bit. I'm making sure you're staying, you're staying with me throughout the lecture. So we, we have mtor, we have rapamycin, inhibiting it. Animal evidence, very, very convincing. Now I'm a basic scientist. I, my laboratory is literally right down the hall from where I am right now. I am conducting basic science research all the time being, meaning that I am seeking out, I'm seeking the mechanism of certain events within cells, this or within organisms. And so in my lab we commonly use cell cultures, you know, growing cells in a little petri dish. And we commonly use animal models too, rats and mice. It just because one reason why, because we can perfectly control for every variable. Now why am I bringing that up? We also do human work too, but that doesn't happen in this building. Why do I mention the animal work? In my own experience with it is because of what I said. You can literally control every variable. These are not free living animals. They're not animals that are encountering any challenges. They encounter. No, they live in absolutely, totally sterile environments. That's going to become very relevant as we get to some of the negatives of rapamycin in just a bit. They, like I said, they have no physical challenges. They exist. They spend their, their lives in a very, very comfortable space. They don't need to use, they don't need to run away from any threat. They don't have any, they don't have any physical challenge. I guess I can just put it like that. That then creates a point of concern as we try to take the animal studies and then extrapolate and apply those data to humans. That is what I consider to be an essential and oft overlooked consideration when it comes to those who are advocating the use of rapamycin for human longevity. But also, let me just say there are no human studies that show that rapamycin that even hint that even can be extended to show that rapamycin extends lifespan or prevents age related diseases. Nothing, not a single human study can show that. And that's because you cannot conduct longevity research in humans, it's impossible. You cannot put humans in an enclosed space throughout their entire life where you can control every variable like we can do with the animals. Now, the nice thing about using that in animals is that it does let us eliminate variables, but these are variables that cannot be eliminated when it comes to human research. So let me just state that one more time so that you can have some of these same cynicism that I do. When it comes to those who advocate the use of rapamycin for human longevity, it is based on no solid evidence in humans whatsoever. It's only extrapolation from animal studies or correlation from, you know, in, in perhaps human studies where you say that rapamycin results in this change, and this change has been shown to correlate with this phenomenon of longevity. But even then, that's pretty weak stuff. Correlation is not causation. Now, having said that, and me mentioning the data, data in cells showing the inhibition or the activation of autophagy which is implicated in longevity, the evidence in animals, which is very convincing, albeit with substantial limitations in that that data's at those data being applied to humans. And then of course, the absolute unavoidable reality that there is no comparable evidence in humans at all. None, zero, zilch, nada. Okay, now having said that, let me actually discuss with you some of the negative consequences of rapamycin. I haven't even discussed them yet. I've only shared with you some of the positives, but with a heavy emphasis on the limitations of those positive findings. Okay, now some of the negative uses. I think it's appropriate to start with the first one being immune suppression. Why is it appropriate? Because that is in fact its intended use. If you were discussed to discuss with a clinician perhaps anywhere outside of the US where rapamycin has just garnered a reputation and longevity that I don't think is deserved. Most instances, it would be thought of as a drug that is used for people who have, have, have had tissue transplants. Like, let's say someone has received a kidney from a donor. Part of the problem when you introduce someone else's tissue into a different human body, that new human body is going to identify that as a foreign tissue and thus is something that should be attacked and destroyed. So how can you convince this recipient's immune system not to destroy the newly introduced tissue, like for example, a kidney transplant or a heart transplant. Whatever tissue you're talking about that's been transplanted from one human into another, well, one way you can help prevent that person's, the recipient's immune system from destroying the newly integrated tissue or to allow it to integrate is by turning off or compromising the person's immune system. And rapamycin will do that very well. So there's a fear that with long term use, rapamycin will suppress the immune system leading to an increased risk of infection that is a consequence. So the person's just getting sicker more often because their immune system is being inhibited by rapamycin, which again is something that it does well. Also there is some metabolic disruption and maybe I should say cardiometabolic in this case because I'm going to have another metabolic point that I bring up in a moment. You can guess which one that might be if you know me well enough at all. But there's evidence another study that will be in the show notes Fang et al in 2013 finding that rapamycin can this was an animal study, but it increased triglycerides and by quite a bit actually. Triglycerides is one of the best predictors of heart disease, far better than ldl. Cholesterol is just as a base measurement, LDL has very little or no predictive power. Triglycerides actually do and can be quite telling with regards to heart disease risk. And wouldn't you know it, long term rapamycin use increases triglycerides lot. Now one variable here that I consider to be a great irony, albeit a tragic one when it comes to the exploration of rapamycin in longevity is what it does to muscle. Now earlier I alluded to the muscle and I hope that that sort of put something that, that I greased the skids a little bit that this was a topic that you that struck a chord because mtor, when MTOR is turned on, it wants to promote the synthesis of proteins from the base structure amino acids. That's very relevant in muscle tissue. Thus it's no surprise. Well and then maybe one more variable. Let me add if you actually look at correlational evidence of human longevity. Now again I'm citing correlational evidence, but so too do the advocates of rapamycin. So I'm just using their same tools. But one of the most consistent variables that predicts longevity or correlates with longevity is muscle mass. In other words, you want muscle mass. The more muscle mass you have, the more likely it is that you're going to live a longer, healthier life, that your health span is going to be extended. When you inhibit MTOR by with rapamycin, guess what you inhibit. You inhibit the muscle's ability to make muscle. There is some. There are multiple studies that show this very, very well. So there's a study by Klein, look in the show notes that looked in animals and identified muscle atrophy from rapamycin use. And then there is some incredible human evidence that is very damning. And this is mostly out of the Fluckey and Rasmussen labs in at Texas, Galveston. They're really on the front end of this and have been for decades, a couple decades at least. But finding that in humans, rapamycin use significantly blunts muscle protein synthesis. Now, this is not surprising. You must activate MTOR in order to activate muscle protein synthesis, which you must have in order to have muscle mass, certainly to gain it, but even to keep it, because you're always breaking down stuff. You need to rebuild it at least at the same rate you're breaking, breaking it down. The more you can have that balanced in your favor as you age, the more muscle mass you're going to retain. And as the correlational evidence suggests, the longer you're going to live. So one of the most damning studies here is the one by Dickinson in 2011. And they found they looked at humans, had them work out and, and looked, identified a certain degree of muscle protein synthesis. And then in humans that were taking rapamycin, guess what happened. That same rate of muscle protein synthesis was all but eliminated. So you significantly blunt your muscle's ability to rebuild itself, which of course over the long term is going to result in a significant reduction in muscle mass. Now, speaking of muscle mass, that allows me to transition into another topic, which is somewhat related only because of its connection with hormones. One way to get very muscled in men or women is to have higher levels of testosterone. Now it's a little more nuanced. It's not just straight testosterone. It can also include how sensitive or how responsive the muscle is to that testosterone. So it's not all about testosterone level, but it absolutely has an influence. Well, unfortunately, human evidence suggests that with rapamycin use, testosterone production drops. That is going to make it difficult for at least a man, certainly even a woman, because testosterone is relevant in females as well, to have a sufficient amount of testosterone to help promote muscle gain or at least help protect the muscle from loss with aging. Now, it goes even a little further than that. In, in men, there's evidence to show that rapamycin inhibits spermatogenesis. Now, spermatogenesis is the kind of complicated term suggesting or, or touching on the gonads, the testes, ability to produce sperm, as the name suggests. Now, let me just pause there for just a moment and. And go on a little bit of a rant because it's something that I find so frustrating and yet it's something I also feel very passionate about. Let me just ask you, at the risk of sounding like your philosophy professor, which I don't want to be, what's the purpose of life? What is your. What is your purpose? What is your goal? Let me just share with you mine and perhaps that will help reveal some of my bias here. My purpose isn't, or my main goal in life now is not to live as long as I can. Is that terrible? Is that disappointing to you? Maybe that is your goal. I'll tell you what my goal is. It is to be the best father I can be. And husband, of course. My wife is my absolute priority. Now. Pardon me for sounding a little personal, but I actually don't mean for it to be personal. I can step outside of my own experience, but I can't help but see this through my own experience, which is why would I care so much about myself living long? I want to be able to reproduce. I want my children. I look at my children as my immortality. Forget longevity, everyone's going to die. I want to make sure that I have created posterity, which can then create its own posterity, and that therein lies my immortality. Now that might sound a little silly, but let's just zoom out of my own personal experience and go to the 30,000foot view. It's somewhat amusing to me that where you, you have these sort of comparing competing theories of creation. How did humans become human? How are, how are we here? Now? There are these two competing theories, although they're not necessarily in competition, but I'm going to deliberately separate them. You have this idea of creation, a theory of creation, that humans were created by a supreme being. Or alternatively, you have this theory of evolution. Now, if we're being fair, we have to say they're both theoretical. I am a very religious person myself. My thought is, however it happened, it was overseen by a supreme being. Frankly, now I'm trying to remove myself from it. But what's funny to me is that despite these ideas being perceived as competing theories, they actually have one very, very strong thing in common, which is reproduction. One of the fundamental aspects, one of the fundamental tenets of evolution is this idea of natural selection. Why is an organism evolving? It is actually to get a competitive advantage with reproduction. It's not to live longer, it's to reproduce better. What was the first commandment given to Adam and Eve in The Garden of Eden in. In Genesis, in the first book of the Old Testament, it is be fruitful and multiply and replenish the earth. And so basically, it once again is reproduction that is like the central commandment given to not only Adam and Eve, but to all life that they may be fruitful and multiply and replenish the earth. That is like this central tenet of creation, in this case by God. So regardless, whatever sort of camp you ascribe to, and I don't care whichever one, and I actually just believe either could be perfectly fine and it's not. They're both very, very valid theories either way you look at it. I truly don't care where you fall as my student listening to my lecture. But you have to appreciate the fact that the one thing these two differing theories have in common is reproduction. Why would I want to take something that's going to compromise my ability to reproduce? Now, I'm bringing it back to rapamycin because whether it's men, even in females, Cadasi et AL in 2012, finding that it alters reproduction and could delay puberty in females, anything that prevents or compromises human reproduction, I cannot believe it's a healthy or good thing. All right, thanks for humoring me on that. What is a little bit of a tangent, but hopefully you can see it in context and why it's relevant. Now, what is the. The last, the final negative effect of rapamycin that I want to discuss? I know what you're thinking. You're thinking, boy, Professor Bickman has gone a long time without mentioning insulin resistance. Well, here I go. Rapamycin can induce insulin resistance and glucose intolerance in humans. Tatarani at in 2011 showed this very well, and there are many studies that show it as well in humans and animals. Rapamycin use makes the body insulin resistant. Now, why should I even bring that up? After all you're thinking? Ben, this is a discussion of rapamycin. Keep insulin resistance out of it. Well, remember, the context for rapamycin is longevity. And if we're talking about longevity, you cannot ignore insulin. Or if you do, you're being naive and you're just putting your head in the sand because you don't want to hear it. Let's come back to mtor. If MTOR matters for longevity. In other words, if increasing MTOR is sufficiently powerful to inhibit autophagy to such a degree that a cell is forced to get old and decays, and by extension, the organism gets old and decays faster, so it shortens longevity again. If MTOR matters there, then you should be much more interested in insulin than you are amino acids or dietary protein, because insulin activates MTOR far more than amino acids do, even at physiological levels. So there are some interesting studies. Again, all these will be in the show notes. I have more studies there than normal. Gran et Al in 2011 found that insulin increased MTOR activation far more than leucine did. And leucine is the most anabolic of all amino acids. If you want to turn on mtor, leucine is the way to do it when it comes to an amino acid. But not only did insulin increase MTOR more, but by after about 12 hours, the Leucine signal was long gone. Leucine had stopped activating MTOR. Insulin was still activating MTOR. MTOR, in other words, was still turned on after that one initial insulin stimulus 24 hours later. Now, this matters because as I mentioned earlier, MTOR is relevant for muscle building. But the, the perfect way to help your body have muscle building is to turn MTOR on and then off. Well, then protein is a perfect way to do it. I would say part of the problem then with insulin is that we live in a culture now where the average person is spending almost, not even almost every waking moment in a state of elevated insulin. Because the first thing they do when they wake up, where insulin has finally come down overnight over some degree of fasting, overnight, hopefully longer than shorter. What do we do in all throughout all of the world, this is not just a western problem. We, we spike our insulin with refined starches and sugars. Then we do it again for our afternoon, for a morning snack and then lunch, then afternoon snack, then dinner, then evening snack. And so a person is never giving insulin a time to come down. That means then that MTOR is constantly elevated. And if MTOR does matter to longevity, well, that's when it matters, when you really can't turn it off. And this is evidenced in multiple lines in human studies and in albeit correlational human studies, which again, that's what others use to study longevity. So I will too. But also in animals where insulin sensitivity is a critical and consistent variable for longevity, low insulin, low fasting glucose consistently linked to a longer lifespan. For example, if you start to manipulate insulin production levels in an animal to kind of moderate it and bring it down, they'll live much, much longer. You put animals on a ketogenic diet in mice, this has been studied just a couple years ago. They once again will live longer. Naked mole rats are famous for their longevity. And guess what? They're extremely insulin sensitive animals with very low fasting insulin levels, even in humans. One of the most consistent themes across longevity, certainly with human, with familial longevity. So where you look at families where just an inordinate number of family members are living into their 90s or their hundreds, they are consistently very insulin sensitive people with low fasting insulin levels. That matters again, probably. So those are all, all facts. It probably matters because MTOR probably matters. But once again, the idea is that if you want to just let MTOR come down sometimes, you don't need a drug like rapamycin to do it. You can do it through fasting. In fact, one final maybe comment here. Look at the work of Cynthia Kenyon. I hadn't planned on bringing this up. This is what kicked off all of this original longevity research. How did her fruit flies live so much longer in this, this fortune, this serendipitous accident, this moment? It's because one of her laboratory technicians forgot to feed them and they were accidentally getting fasted more often and they lived longer. If, if so, fasting is the fastest way to bring down insulin. No surprise that it's so consistently throughout so many cultures, through so many millennia, has been used as a way to be healthy and even perhaps live longer. So we want. So rather than take a drug that is going to inhibit MTOR all while a person is drinking their sugary drinks and juice and eating refined starches and sugars, activating insulin, and then needing to artificially inhibit MTOR with rapamycin, then you get all the consequences of rapamycin that I outlined earlier. Rather than doing that, rather than restricting protein, you're eating a low protein diet, all while drinking your sugary sodas and juices and eating refined starches and sugars, spiking your insulin, it is laughable to me, and it seems like such an obvious variable that is so apparently overlooked. If MTOR matters, then insulin matters more than rapamycin does, and insulin matters more than dietary protein does, which has little to no effect on insulin. It's the refined starches and sugars that should be controlled by controlling carbs. Insulin will be at a lower level. That will allow MTOR to be less active. Less often or more oftenly, more often, it will be less active, which enables autophagy. And now you have cells that can live longer, and by extension, the organism is going to be healthier and live longer as well. So if MTOR matters, then insulin matters most. All right, that's the end. So as much as I wanted this to be a discussion on rapamycin. There are variables that we could not avoid. But I hope you feel like you have a much better understanding of the use of that drug, why some people feel it's justified and it is in some instances, like tissue transplants. And in other instances, I would say it's not like, for example, trying to live a long, healthy, reproductive, capable life. Anyway, thanks for joining me. Thanks for being a student in the lecture today. I hope it is helpful material. Until next time, more knowledge, better health.