27: The Longevity Switch in Your Cells – Unlocking mTOR for a Healthier Life with Dr. Dudley Lamming

So before digging into today's topic of utilizing and harnessing influencing MTOR to prolong your lifespan and health span, I want to introduce you to the topic and then we'll discuss the brilliant gentleman that's coming on today. So welcome to the show. Before we dive into today's conversation, I want to take a few minutes to introduce you to the key concept we will be discussing. Mtor. It's a term you'll hear a lot today. So what exactly is mtor? MTOR stands for Mechanism target of Rapamycin. It's one of the most important regulators in how our bodies grow, repair and age. Think of it like a master switch that tells our cells when to build and when to conserve energy. When MTOR is turned on, our bodies focus on growth, building muscle, making new proteins, storing energy. This is great when we need to recover from workouts, heal injuries or develop as children. But when MTOR stays active all the time, especially due to constant food intake and high protein consumption, it can accelerate aging and risk and increase risk for diseases like cancer and diabetes. On the flip side, when MTOR is turned off, our bodies shift into repair mode, clearing out damaged cells and focusing on longevity. This is why things like fasting, exercise and certain compounds can be powerful tools for potentially extending lifespan and health span. The key takeaway? MTOR isn't good or bad. It's actually all about balance. Too much activation can speed up aging, while strategic inhibition can help us stay healthier longer. With that foundation in place, let's talk a little bit about Dr. Dudley Laming and explore ways to better manage MTOR for optimal health and longevity. I am so excited to have today Dr. Dudley Laming, who is a leading researcher in the field of aging, metabolism and longevity. He is an Associate professor and Vice Chair for Biomedical Research at the University of Wisconsin's Department of medicine. With a PhD from Harvard University and postdoctoral training at the Whitehead Institute, his groundbreaking work helped uncover how rapamycin extends lifespan while also revealing its potential side effects. Dr. Laming has published over 95 peer reviewed papers and has been recognized with numerous prestigious awards including the 2018 Nathan Schock New Investigator Award. His research focuses on how diet and macronutrients influence aging and age related diseases like diabetes and Alzheimer's. Beyond the lab, he's played a key role in the American Aging association even serving as its President and has worked in the lab alongside Dr. David Sinclair who is world renowned in his work for longevity and anti aging. In short, Dr. Laming is at the forefront of discovering how we can Use science to extend not just lifespan, but healthspan, helping people stay healthier for longer. I am so thrilled to have him on today's show. Let's dig in. Welcome to Modern Thyroid and Wellness, the podcast that explores the intricate dance between health, wellness and thyroid, unraveling the threads that weave our vitality together. I'm your host, McCall McPherson, and I'm so thrilled to guide you on this journey to optimal wellness. So thank you so much for being here today, Dr. Lamming or Dudley. I am really, really excited to hear this conversation and to have it with you. And I feel like we are all going to learn quite a bit today. So strap in everyone. I wanted to open the conversation with just some basics, like what exactly is mtor and how does it play a role in our longevity, aging, disease?

Thanks for inviting me and yeah, I'm happy to chat about MTOR and related things. My web focuses on the biology of aging and has for some time now. So MTOR is this really central enzyme that acts as a sensor of various different nutrients. And so when you think about a cell or person, it's very important to coordinate the availability of nutrients with processes like building new cells, building muscle or adipose tissue. And so MTOR acts as a sensor that integrates all different sorts of nutrient information. And so some of the primary ones that senses are amino acids, sugar, cholesterol, and then the availability of hormonal cues that indicate it's okay to grow because you always want to make sure that your body is in control of those processes or could lead to uncontrolled growth like cancer. And some of the things that it senses are hormones like insulin and many others.

Interesting. Okay, so my mind went first to like almost it's sensing if you're in a hibernation state, like if they need to pull back the building of muscle, et cetera, and preserve resources. But it's. Is it more like the opposite where we don't want uncontrolled growth?

So downstream of MTOR are basically all the processes that you can think of that that you might need to build a new cell or to make a cell larger. And those include things like nucleotide synthesis, to copy your DNA, protein translation, and ribosome synthesis. Ribosomes are essentially protein factories. And when you make a new cell or a larger cell, you're going to need more of them. And things like lipogenesis. Cells have a membrane is primarily composed of lipids. And when you divide cells or make a bigger one, you need a lot of lipids and. And so an MTOR senses that all the different types of nutrients that it needs to build these processes are abundant and that growth cues are permissive for growth. Then MTOR activates and it engages these things. And so we absolutely need MTOR activity in order to survive and grow. So it's very key to have MTOR activity. Conversely, when one or more of those nutrients is missing and you might be in a hibernation state or you might be in a fasted state, MTOR signaling is going to have to downregulate because it's going to need to tell all those processes to cut back. Instead, it's it. And some other systems will upregulate things like autophagy, which helps to recycle damaged proteins and instigate other things like burning lipids and sugars to make more energy to get you through that time of fasting or hibernation. And so you always need some MTOR activity that. That's essential. But, yes, I agree that you don't want too much. And so uncontrolled MTOR activity is associated things with, like, cancer and a variety of different developmental and genetic diseases that lead to bad outcomes.

Interesting. I'm going to back up to one. One question back, Dudley. And how did you end up in this field, like studying mtor? How did that happen? I'm so curious.

So back when I was in graduate school with David Sinclair, I was working on yeast, and one of the things that started to become really interesting at that time in a number of different model organisms was the role of MTOR signaling and regulating aging. And so this was first found in C. Elegans, where it was shown that if you downregulate MTOR activity via different genetic interventions, you wound up with worms that lived a lot longer. And then shortly thereafter, the same thing was shown in Drosophila, a type of fruit fly, and then in 2005 in yeast as well. And so this was really interesting, and I thought that this might be something interesting to continue working on, and that was really stoked as well by data that then sort of accumulated for years. People knew it was ongoing experiments where people were testing a drug, rapamycin, for its ability to extend the lifespan of mice. And so that was one of the main drivers that led me to think about doing postdoctoral research on MTOR and to really explore some of the roles of rapamycin in that regulation of aging.

Oh, cool. Okay, thanks. So when I think about mtor, and I know most people have probably heard of this to an extent, I'm curious about Ways that people can take a little bit of control over this, how they can manipulate their lifestyle to influence MTOR or, or diet. Give me a little bit of tips and tricks that, that we have control over to, to shift things.

So MTOR senses that nutrients are present and in particular it senses dietary protein is one of the really strong agonists and something that turns MTOR signaling odd really strongly. And so you might imagine that there are times when you really want a lot of MTOR activity. And so people who are athletes may try and time when they consume dietary protein and how much dietary protein they consume to match when they're exercising. So they might eat a lot of protein supplements either right before or right after they exercise, both in a way to provide protein for muscle to build and repair itself after exercise, but also to stimulate mtor, which stimulates muscle growth. So conversely, you might imagine cutting back on protein by might be a way of lowering MTOR signaling. And that's certainly true in mice. And so for the last 10 years or so my lab has done a lot of research on essentially protein restriction, eating a low protein diet as a way of increasing health span and lifespan. And I'll say that first of all, we always think about protein as something that's universally beneficial primarily because of that interaction with muscle. And, and also because people who are elderly become frail and a lot of that is due to protein deficiency and muscle wasting. And so high protein diet supplements are prescribed to people who are elderly and having this sarcopenic muscle loss. But it actually turns out that if you look at the population overall, which remember mostly doesn't consist of athletes, 70% of the American population is overweight or obese. And the people who number people, people who are really engaged in exercise pro programs is probably pretty small. And so if you look at the overall population in America and Europe, what you see is that people who have more protein intake actually have higher rates of diabetes, higher rates of cancer and increased mortality. And in one of the most sort of shocking results in a couple years ago, a twin study came out in Britain showing that if you looked at twins who are eating different diets, the twin who was eating more protein actually was more likely to be sarcopenic. And so the one who was on a lower wow. Had better muscle health as they aged. And so that's sort of like one of the highest classes of human studies that you can get from in terms of a twin study is very rigorous. And so we see the same thing in mice. And so mice that are fed low protein diets generally speaking are leaner, have better glucose tolerance and control of their blood sugar, and generally speaking tend to live longer and maintain their fitness better as they age. And so relative to mice, they're eating sort of normal diet, protein diets or high protein diets. Those animals grow frail more quickly.

How fascinating. And is that irrespective of where they're getting protein? Like I know when I think about the blue zones, right, they generally they eat a low protein diet, but when they do eat protein, often it's for from legumes and beans and things that aren't just animal based protein. Is that part of the study or is it simply macro counting of protein?

Overall, for the most part we're talking about macro counting of protein. And so while there is variation in protein content between protein sources, for the most part that's sort of been overstated. And you really don't change levels of any individual amino acid by more than about 20% even by switching to a vegan diet. What you're mainly doing there is switching to a low protein diet diet. And so we think generally speaking that low protein diets are beneficial. Probably one of the reasons that happens is that MTOR signaling is downregulated. And it's pretty clear in mice that if you look across the board in multiple tissues of mice, that low protein diets downregulate MTOR signaling. A lot of my, what my lab works on now is trying to explore why that happens. We think that mainly those effects are driven by reductions in just a few key amino acids. One of those amino acids is called isoleucine. It's one of the three branch chain amino acids that people may be familiar with because they're often in supplements to increase muscle growth and strength. So it's definitely true, at least in our hands, that if we restrict just isoleucine, we have mice that are leaner and healthier. And in our studies we find that male mice on a low isoleucine diet live about 30% longer, about 7% longer. For females and both sexes, we see improvements in frailty as well.

Wow, that is so fascinating. And I assume leucine's heavily present in like animal based protein or what foods are is that most prominently present in.

So note notably this is isoleucine, which is actually probably the least abundant of the three branched chain amino acids. Leucine is probably present, generally speaking in food about 10 time higher levels. And it's also sort of the key amino acid for muscle growth. And so you might be able to at Least in theory, disassociate some of the benefits of muscle growth from detrimental effects of isoleucine, if you are careful. Generally speaking, isoleucine again is sort of present in every food. And so we're trying to pursue a different bunch of different strategies, including trying to understand if we could make drugs that sort of mimic these effects. But generally speaking, I got this actually first off of a, off a bodybuilding website, but it turns out to be true. In the USDA food database, it well, of the major meats, turkey has the lowest amount of branched chain amino acids. And so if you were gonna make a trade off in your diet, substituting turkey for other meats is probably one of the easiest ways to lower BCAAs and isoleucine.

And so in BCAAs, I assume in most of them, isoleucine is present. So if you're taking BCAAs, you're likely taking extra isoleucine.

You definitely are, because for the most part all of these supplements are made from whey or casein protein that has been chopped up or hydrolyzed. You could supplement just with leucine, but free amino acids taste bitter. And so it's not something that's easy to do in a sort of strict dietary supplement.

That is absolutely fascinating. And just a follow up question, when we are talking about lifespan increase of 30%, which is enormous, are there any healthspan data markers that you guys analyze as well?

So we measure, generally speaking, frailty using Susan Hallett's clinical frailty index for mice, which has been validated against clinical frailty indices for humans as well. So we look at a whole bunch of things, how the animal walks, how its reflexes, you know, change, how its hair looks and so on. And so in, particularly in males, we see across the lifespan from, you know, what essentially would be a 60 year old mouse onwards, the animals have reduced frailty relative to mice eating a normal diet.

Interesting.

And we also look at other health span markers like glucose tolerance, insulin sensitivity, energy expenditure, grip strength via a couple different mechanisms and cognition.

Wow. And any change in the people with lower isoleucine in those markers as well.

So these are mice, but in that particular study we didn't see any benefits, but we do see benefits of protein restriction and isoleucine restriction in mouse models of Alzheimer's disease.

Oh, fascinating. Interesting. And so I know so much of your data is based on mice, but if you had to or were able to extrapolate for human sort of data or tests that you all would like to look at in the future? What would you say would be a balanced diet for humans when they are particularly, what would that diet look like when they are particularly trying to influence MTOR in a positive way for longevity?

Almost certainly it would be a low protein diet. And from the, we, we collaborated with Luigi Fontana when he did his protein restriction study about 10 years ago, sort of short term, but generally speaking, we were taking people who were on a protein diet, standard American diet, beef ribs, whatever they eat in Missouri, and switching that over to meals in the hospital, the hospital cafeteria that contain a lot more plants, some fish, various oils, you know, and calorie consumption in, in Dr. Fontana's study actually went up by about 10% because the, the, the low protein meal wasn't quite as satiating. But the patients in the, in the study all lost weight.

Interesting. Okay, so less. And any rough estimate of how much protein for humans, like per kilogram of body weight, for example.

So a general guideline as I understand it about is about 0.84 grams per kilogram. And so most Americans are well above that. And so we don't recommend necessarily that anyone be in a protein deficient state. But generally speaking, the people in the study were probably around 0.8 to 0.9 grams per kilogram. But on overall, they're eating about 7 to 9% of their calories from dietary protein, versus about 17% or so for your average American.

Got it. That's really helpful. And it's so fascinating because at least in the world of like functional and sort of progressive medicine, we're all hearing more protein, more protein, more protein, more protein. So it's so fascinating to have this conversation of the flip side of, hey, maybe we actually are getting a lot of protein already and maybe we're exceeding what we should be eating as opposed to hyper focusing on eating more and.

More and more, I will say that is affected by exercise as well. And so this again is a mouse study, but in our mouse studies, we can protect at least from the metabolic consequences of too much protein just by having those mice undergo resistance exercise training. And so when they're undergoing resistance exercise training, of course they get bigger, stronger muscles and they have reduced fat mass and improvements in glycemic control. So it seems like exercise is protective against some of those effects. One thing that is interesting is in the long term though, the mice that were exercising in eating a low protein diet became eventually just as strong as mice eating a high protein diet.

But took longer, however, they took longer to get.

Yeah, and interestingly, they didn't get big, well defined muscles in the same way that you might, seeing a high protein.

Diet, did more lean. But with the protective mechanisms involving mtor.

Well, we don't know per se that MTOR is necessarily involved in this. It's actually quite complicated to test that in mice because you do need MTOR for life. And so we can inactivate MTOR in different tissues. But correlatively we see that generally speaking, low protein diets downregulate MTOR signaling.

So basically we want it to shift off and on. We don't want it on all the time, we don't want it off all the time. We wanna, it's almost like metabolic flexibility. We want MTOR flexibility. Is that right?

That's true. And in fact, people who have sarcopenia, one of the, one of the things that seems to be happening there is that they actually have MTOR signaling stuck on all the time and that seems to be negative.

Fascinating. Okay, any, I want to circle back and, and definitely bring up the fasting component too, but is there anything else in terms of exercise that we should know about the mechanisms of influencing this or anything else that you want to add to that piece of the conversation before we shift gears a little bit?

I don't think so. Why don't we, why don't we talk about fasting?

Yeah, so I am a huge proponent of fasting. I. Fasting has absolutely changed my life and it is something that I encourage so many of our thyroid patients to do because of just the metabolic disadvantages of being hypothyroid. So I'm curious to understand a little bit how fasting impacts MTOR and if it's beneficial or harmful, et cetera.

So fasting definitely downregulates mtor. It's probably the easiest, fastest way to do that in terms of acutely anyway. There, there's sort, sort of some long term compensations that, that happen that make it actually a little bit more tricky to look into. And so we've mainly looked into this in the context of calorie restriction. And so calorie restriction, as sort of traditionally done in rodents and other animal models and some now somewhat for people as well, basically involves eating one meal a day. And so the animals are fed one meal a day and then they don't eat anything until the next day at the same time. And so one of the things that mice in a cage normally do is they have free access to food all the time here. Calorie restricted animals tend to binge eat because they're Hungry because they haven't eaten in a while. And so they eat their food relatively quickly. And so essentially they're fasting for about 21 hours a day between meals. And so this definitely has a lot of consequences. One of the things that we were able to show using a number of different feeding paradigms is that this fasting period seems to be essential for some of the benefits of calorie restriction. And so, and that moreover, fasting alone was sufficient to show various different metabolic improvements. Work by another laboratory has also sort of suggested that fasting on its own may be able to extend lifespan at least by about 10% or so. And so it definitely seems like fasting has really strong benefits. The MTOR signaling question is actually quite tricky to analyze. One of those reasons is that as soon as the animal stops eating on a fasting diet, they actually have really high MTOR signaling because they just consumed an entire day's worth of calories all at once. And then over the course of a day, their MTOR signaling goes down, down, down, down, down. And then by the end of a day and they're ready to eat their next meal, their MTOR signaling is really low. There's some other factors involved as well. So animals that are on calorie restriction or that are fasting have better insulin sensitivity. This is something that's very clear in our work and seems to be carried over to humans as well. But if you're more insulin sensitive, that means when you have a burst of insulin following eating means your emtrosaline goes higher. And so what you're really thinking about probably is both that on off pattern that you mentioned, and then also sort of the idea of like a time average level of MTOR signaling over the course of a day. And so we think that fasting and calorie restriction both probably lower the average level of MTOR signaling over the day, but it definitely also enhances these peaks and troughs.

Interesting. Okay, and then are you guys, have you studied at all a more balanced approach to fasting? Like, I don't know, a 16, 8 or like. I generally recommend people fast no more than four to five days a week, and then they eat in a 24 hour period the other days just to keep, keep our physiology not stressed. Have you guys looked into any other methods other than sort of what I would describe as omad or one meal a day?

So a number of people have tested and this used to be more prevalent essentially every other day feeding in mice, where mice would essentially get food Monday, Wednesday, Friday, and they'd get something like two meals worth of food on Friday to last them to Monday. And that's been shown to extend lifespan. Extends lifespan very well. But your question is actually, have you tried a less severe fasting regimen? And sort of. And so Rava di Cabo's laboratories basically wound up accidentally doing this while they were exploring some primate. Primate studies further in mouse. And what they wound up doing was feeding animals enough food that basically they ate for about 12 hours a day and then fasted for about 12 hours a day. And that was associated with about a 10% increase in lifespan.

Interesting. I love it. Okay, I want to shift gears a little bit, and I want to talk about medications that have. That can influence mtor, one of which is certainly rapamycin. And I was curious, too, if you have any opinion on metformin. So if not, that's okay. But I would love for you to tell listeners what rapamycin is and how it works in relation to MTOR.

Sure. So rapamycin is a compound that was discovered 1970s, I think maybe late 1960s. It's named after Easter island, where it was discovered. The natives called it Rapa Nui, the island. And so it was initially explored as something that could essentially inhibit cell division, which it does, and eventually was developed for use as an immunosuppressant. And so essentially, it was widely used in organ transplantation for a long time as a primary immunosuppressive medication. Now, there's a variety of other ones as well, but rapamycin is still used in the clinic for a variety of indications. It's also used to inhibit MTOR signaling for people who have genetic diseases associated with MTOR signaling, like tuberous sclerosis. And rapamycin is a great MTOR inhibitor. It works very well in extending the lifespan of mice. And it was shown by a number of studies by the NIH intervention testing program, which are all done at three separate sites. Everything's blinded, and they tested lots of compounds. So it's done very rigorously and extends the lifespan of mice anywhere from 10 to about 25%, working relatively equally well in young mice and old mice, which is quite cool. We don't know how rapamycin extends lifespan per se. Other than that is, of course, a very specific MTOR inhibitor. So it's working through mtor. Rapamycin does slow the rates of cancer, which is a major cause of death in mice. Other things that it may do is it may have positive effects on cell senescence, it may have positive effects on epigenetic Aging and the methylation clock that you've heard about. And almost certainly it seems to have some benefits for cardiac biology as well. And so in all of these cases, rapamycin may be very beneficial. So rapamycin works by inhibiting mtor. One thing that is important to know is that there's two MTOR complexes, MTOR complex 1 and MTOR complex 2. The pharmacokinetics and mechanisms of how rapamycin inhibit each of those complexes is different. The long and the short of it is that mouse and other model organism studies show that Inhibiting MTOR complex 1 extends lifespan, while inhibiting MTOR complex 2, for the most part, shortens lifespan. And certainly the inhibition of mtor complex 2 in various tissues is associated with a variety of conditions that you see develop in a subset of humans who take rapamycin, particularly at high doses, for a long period of time. And that includes glucose intolerance, the development of diabetes, and hyperlipidemia. Rapamycin is also an immunosuppressant, we believe, for the most part, that requires inhibition of both MTOR 1 and MTOR 2, based on the biology of how that works. And so the less MTOR complex 2 inhibition that you have overall, probably the better, both from the perspective of these metabolic effects and the immunological effects.

Interesting. And when you are thinking about the influence on MTOR Complex 2 and the development of glucose intolerance and hyperlipidemia, et cetera, is that with standardized dosing for immunosuppression, or is that with microdosing that people advocate for in the longevity sector?

So a study that. So, generally speaking, we think that There are about 3,000 people in the United States who are taking rapamycin off label for geroprotective benefits. There's no. It's not FDA approved, so it's hard to get an accurate count, but we think that's about how many people there are. Currently, we've been doing an observational study where we've been collecting blood samples from these. Some of these individuals, and we've been trying to analyze those now. So hopefully we'll have some results later this year. But overall, most people, it seems, who are taking rapamycin off label are actually not doing microdosing per se, but are doing intermittent dosing. And so, generally speaking, an immunosuppressive dose would be something like 1 milligram to or more of rapamycin per day daily, whereas people who are doing these intermittent doses are taking something like 6 milligrams or more. But Only once a week or once every two weeks. And based on our mouse studies, we've shown that you get less side effects of rapamycin due to MTORC2 inhibition. And you get less inhibition of MTOR complex 2 when you do this intermittent dosing regimen. That said, your inhibition of MTOR1 is not quite as effective. Basically as rapamycin is cleared from your body, intermittent dosing means that by the time you're near the end of your dosing period, you pretty much have normal MTOR levels. And so daily dosing is better from the perspective of inhibiting MTOR Complex 1, but you also get a greater risk of these various MTORC2 related side effects with daily dosing.

So it's all about trying to discover the balance between the two. And that's what you guys are kind of working on right now.

We've been working on, on that for, for a number of years. And we've shown that intermittent dosing is capable of extending lifespan in mice while it was not done in parallel. Overall, it does probably seem less effective at extending lifespan than daily dosing. But for the most part, these various side effects don't really bother mice. And we don't actually know that the side effects bother humans either. We know that people develop these conditions, we know that generally speaking, diabetes is bad and having high blood level of lipids are bad. The diabetes effects in a human are permanent. But a lot of people who are on immunosuppression get diabetes anyway. Hyperlipidemia probably is bad, but we don't know that rapamycin associated hyperlipidemia is bad because people who are on rapamycin for immunosuppression, if they develop hyperlipia, they just get switched to another immunosuppressant.

Got it. Okay. Interesting. Yeah, that's fascinating. And any studies looking at more microdosing but on a daily level throughout the week so that MTOR isn't returning to baseline before the next dose. Cuz I do know most people take it weekly for longevity. And yeah, three to six milligrams is what I've seen so far. But any like micro, micro dosing testing happening right now?

I'm not aware of any studies that are testing anything lower than 0.5 milligrams a day.

Cool.

But could be, there are other, it could be that there, there are, there's probably about 10 different clinical trials of rapamycin ongoing right now for various different age related diseases, including Alzheimer's disease, insulin resistance to extend fertility for periodontal disease. So all of these various things are starting to be investigated now in sort of reasonably short term clinical trials.

Interesting. And then do you have any knowledge on how or if metformin influences mtor? I've thought that I've read that on, on a few occasions, but I'm not honestly sure of the interaction and influence.

So mtor. So metformin is best characterized as an activator of ampk. AMPK is another is a key energy sensor that actually works opposite from mtor. So it turns on when energy is low and it actually works to in part by suppressing MTOR activity. And so as you might expect, if you treat with rapid treat with metformin, what you get is lower MTOR activity. And this is probably related to part of its mechanism of action where essentially AMPK is or, sorry, Metformin improves insulin sensitivity in the liver in part by downregulating MTOR activity. That's bec come aberrantly high. We know that metformin extends the lifespan of people with type 2 diabetes. That's been known for decades. It's a very effective diabetes medication. It's unknown whether metformin extends the lifespan of people who are not diabetic. Interesting mouth studies are also what some might say are inconclusive. There have been a couple now studies showing that metformin can extend lifespan by 10% or maybe a bit more. But there have also been both mouse studies and a rat study showing that metformin does not increase lifespan.

Interesting. Thanks for that. I appreciate you deviating from, from the conversation to take me through that.

And I, I just say that that's also there's probably at least 10 times more more mouse studies showing rapamycin extends lifespan than studies showing that metformin does.

That's great to know. That's fascinating. I want to shift the conversation to implementation in people's real lives and what that could look like. And it might even be in part a recap of what we've already discussed. But I'd love for you to share three ish practical steps that people can take and implement in their lives to influence mtor.

Well, I think as we sort of, sort of talked about, generally speaking, being in better health is associated with lower MTOR signaling in general. And so obesity and insulin resistance work in part by raising MTOR activity. So people who are in better metabolic health are going to have lower MTOR activity on average, or more importantly, they're going to be able to turn MTOR on and off during the day as they're Supposed to. And as nutrients become more available or less available. Available people who have insulin resistance, particularly in the liver, are gonna have high MTOR activity all the time. That's gonna lead to negative consequences for both lifespan and health span. As we talked about, low protein diet is definitely associated with lower MTOR activity and that's gonna be a diet that is probably still protein sufficient. So meets those recommendations of around 0.8 grams per kilogram of protein, but it's probably below 10% of daily calories, at least in short term studies where people have been on these diets for six weeks or so, it seems like that leads to increased leanness, decreased fat mass, lower blood sugar and so. And overall improvements in other markers of health. So we don't know about the long term consequences of those diets, but certainly the people in the blue zones that were on low protein diets, that would seem to indicate that those diets can be healthy over the long term. People on those might need to exercise more to promote lean mass retention. That's something that's always associated with weight loss, that people might lose a bit of lean mass unless they're exercising. And yeah, fasting could definitely help improve sensitivity to nutrients for both MTOR signaling and other signaling pathways as well. You know, I certainly wouldn't recommend rapamycin to anyone. People can obviously talk to their doctor about the pros and cons of those types of pharmacological. Pharmacological approaches.

Thank you for that. And then I have one final question that is purely out of my own curiosity, selfishly. And, and there might not be any research to date about this, but I'm curious if there is or if there is research being conducted on the influence of MTOR with the utilization of GLP1 medications.

Yeah, I think that'd be something that'd be really interesting to look into. And so far as I'm aware, there's not. It wouldn't actually surprise me that GLP1 compounds might be associated with lower MTOR activity as well. But that might also vary by tissue, depending on how sensitive tissues are to GLP1. As far as I know, nobody's done any studies combining rapamycin and GLP1 treatment.

You'll have to keep me posted if that happens for sure, because I'm so curious.

Well, there's.

Well, thank you so much for this conversation. It was absolutely enlightening and fascinating for me and I'm sure it was fascinating for all of our listeners and I appreciate you taking the time to come share your, your knowledge and brilliance with us.

Happy to do so. And thank you for inviting me. And good luck.