Muscle and Health Podcast with Keith Baar

Perhaps you want to feel great about how you look at the beach. Maybe you play a sport in which it’s important to be powerful and strong relative to your weight. Or you might simply be interested in continuing to function well as years pass by. Whatever your goals are, you should be interested in the mass and quality of your muscle tissue. Here we detail some of the reasons why the subject of muscle and health is relevant to us all.

An important point is that a larger, stronger musculoskeletal system early in life provides a bigger buffer against the development of dynapenia and sarcopenia. So, even if we’re happy with our bodies as they are, we should take preemptive measures now against the possibility of developing of dynapenia and sarcopenia. But what are the key determinants of the mass and function of the musculoskeletal system across the lifespan? This brings us to the latest episode of humanOS Radio.

In today’s show, I speak with Dr. Keith Baar, Professor in Residence in the Department of Physiology and Membrane Biology in the UC Davis School of Medicine. Professor Baar’s laboratory members study muscles, tendons, and ligaments in vitro and in vivo to understand the molecular determinants of musculoskeletal function, as well as the roles of exercise in health and performance.

In this wide-ranging conversation, we discuss a variety of subjects, not just those related to muscle mass and aging. These include:

Tune in below to find out more about muscle and health!

On Soundcloud, iTunes, Google Play, Stitcher, and YouTube

Do you want to learn more about muscle and health? You can help support the work of the humanOS team by making a donation. If you do, thank you so much – we really appreciate your support! And no worries if you can’t chip in, the important thing is that you benefited from listening today.

If you think other people would benefit from listening to this show, you can help us spread the word by leaving a review at iTunes. Positive reviews really help raise the profile of our show.

Dan prepared for and conducted the interview, Greg wrote the first draft of this blog post, Dan edited the draft, and Dr. Baar continues to do the hard work!

Keith Baar - 00:00: ... and so the more you can maintain mitochondrial function through life, the better you're going to age and that's without a doubt. If you're in your 50s and you're the strongest 50 year-old, you're two-and-a-half times more likely to make it to 100.

Dan Pardi - 00:16: Okay everybody welcome back to humanOS Radio. Today I have with me Keith Barr who is a professor in residence at the department of physiology and membrane biology at UC, Davis in Northern California. He does molecular exercise physiology, in other words he looks at the cellular events that take place in response to different forms of exercise especially resistance training and how that translates into the physical capacity of a person doing exercise. This subject is so much more important than for just those looking to be better at athletics. Maintenance of muscle mass across the lifespan especially into old age is a key determinant of health and longevity.

00:50: Keith, welcome to humanOS Radio, it's a delight to have you with us.

Keith Baar - 00:53: Thank you very much. It's great to be here.

Dan Pardi - 00:55: Tell us about your academic path and how that has led to the type of work that you're doing in your lab now.

Keith Baar - 01:01: I went to college to be a physical education teacher and still many days dream of being a physical education teacher. I think it would be a wonderful and a bit more carefree thing to do. When I got to the University of Michigan I got interested in the science behind a lot of what was happening there. I got an opportunity to be a strength and conditioning coach and assistant coach with their Michigan football team there, and so I got a chance to really see how people were applying what we knew about muscle into trying to make people bigger and stronger.

01:31: As I was looking at that, you look at it and you see all these guys come in and they do a program that's very similar but some of them will grow huge and some of them stay small and really got curious about why people were responding so much differently. Went out to do a master's degree at University of California, Berkeley, after doing a couple years in Berkeley went back to the Midwest to the University of Illinois in Chicago the medical center there. Did my PhD where I discovered one of the central proteins as far as growing any cell but specifically for muscle cells and that was mTOR, and the contribution of mTOR to muscle mass regulation.

02:06: And then I had an incredible opportunity to do a first postdoc with John Holloszy who's a legend of exercise science who basically had done seminal work into how mitochondria respond to endurance exercise, and I went and worked with him and discovered that one of the molecular transducers of endurance exercise, a protein called PGC-1alpha that's really important for maintaining or growing mitochondria. After that we went back to the University of Michigan for a second postdoc where I was learning how to engineer tissues, so we'd engineer muscles and tendons and ligaments.

02:38: From there I got my first faculty position at the University of Dundee in Scotland, which is one of the best life science institutes in the world and it was an outstanding place to be for the first five years of my faculty career. And then once my wife and I had established a family and we wanted to come back to Northern California as one of the places where our young daughter would have a lot of opportunities that was when we decided to come to Davis and we've been working here ever since doing a lot of musculoskeletal work. Trying to figure out how nutrition exercise and age affects our musculoskeletal function.

Dan Pardi - 03:09: I got my master's degree in exercise physiology from Florida State in 1999, so since my degree in exercise phys. now molecular exercise physiology which is understanding of the cellular mechanisms that are causing the effects of exercise, and then activity physiology that was probably introduced 10 years after I finished which is all of the negative changes that happen when we're not using our body, so it's really-

Keith Baar - 03:30: Most of the time when we look at things scientifically we use a sedentary group as the control group, but in reality evolution would have had a sedentary group would have been the rarity because we evolved to be moving all the time, and if you weren't moving you were dying. As society has changed and you've gotten all of these modern diseases of inactivity related disease that's changed how we look at things.

Dan Pardi - 03:52: So what are some of the interesting questions that you're exploring currently in your lab?

Keith Baar - 03:56: The big things that we know is that if you're in the strongest sort of the population, you're two-and-a-half times more likely to make it to your hundredth birthday, and that's if you're in the strongest third of the population at midlife. If you're in your 50s and you're the strongest 50 year-old, you're two and a half times more likely to make it to 100. In humans the number one correlate with longevity seems to be muscle mass and strength, because basically the stronger you are the more you can survive certain diseases.

04:21: The best example is cancer where fully 30% of the people who died from cancer actually died from muscle weakness associated, and if you're in the strongest third of the population you're one-quarter as likely to die from cancer, and it's not that that type of exercise that makes you big and strong is going to prevent you from getting cancer. What it's going to do is it's going to allow the chemotherapies to work, which are poisons essentially, and it's going to give you the strength to survive the chemotherapy treatment that is enough to put the cancer into remission but you're strong enough to survive that, and if you are in that strongest third you're more likely to be able to survive the intervention of chemotherapy.

04:59: And the way that we look at it is we do strength exercise so that we have a long and happy life because it's going to increase our longevity and it's going to increase our quality of life because we're going to be able to do more things. We do endurance exercise because it feeds the brain and it is the only known stimulus to grow brain cells and to improve learning and memory and to decrease depression, Alzheimer's and Parkinson's. And we also use it for cardiovascular disease because endurance exercise is number one thing that you want to do to decrease cardiovascular disease which is killing one in two Americans.

05:33: We do different types of exercises for different tissues, and that's really important, but the really key thing is that being stronger is going to let help you live longer. So what we're doing in the lab is we're trying to figure out why our strength goes down with age, regardless of who you are. You could be the great Jack LaLanne who would be training really late into his life, still super strong but his strength is still going down. You could be a masters athlete who's working at the world-class level, your strength is still going down.

06:02: And the interesting thing for us is that the strength goes down about three times as fast as your muscle mass goes down, so you're actually getting weaker faster than you're getting smaller. What that means is the quality of the muscle is going down as we age. To us that's really important. What we think is happening to some degree is there's two things. One is that our muscle mass is a balance between how much new proteins we make and how many proteins we break down and get rid of. A lot of people think that the best way to grow a muscle is to stop getting rid of proteins, so if you think of it as a sink, the depth of water in your sink is determined by how open the plug is, and how long the faucet is.

06:41: It's easy if you've got a slow drip of water coming out of the faucet. If you plug the drain it'll eventually grow the amount of water you have, the same thing with muscle. If you close off the break down your muscle is eventually going to get a lot bigger, and that's what happens with things like anabolic steroids. They're decreasing the rate at which you break down proteins, so your muscles start bigger they don't start necessarily stronger, because the breakdown is necessary to get rid of old proteins that have been damaged. Those proteins are going to be things that we need to get rid of because they don't function well.

07:12: So what you'd ideally want to do is you'd want to have good breakdown but you'd want to control everything at the tap. You want to increase the flow of the synthesis or you want to increase how much you're making, how much the tap is turned on, that's the important thing to make good quality muscle. If you look at women versus men, women have a higher rate of protein breakdown and the reason for that is that testosterone as much as it does things to turn on the tap what it does primarily seems to plug the drain. The way that it does that is it blocks the cortisol receptor. Cortisol is a hormone which causes the breakdown of muscle, as one of the byproducts of what it does.

07:49: In women there's less testosterone so that cortisol has more effect so you break down protein more quickly, but they still are actually able to synthesize muscle a little bit faster than men. So if you look at muscle quality, and that means how much force you get for the size of the muscle women actually have a slightly better muscle quality as it's turning over faster. We want muscle turnover to go fast. As we age what happens we're decreasing the flow from the tap. The muscle is eventually shrinking down but if we just plug the drain it's not enough to give us a stronger muscle, it might make bigger but it's not making it stronger. And so what we need to do is really understand how we increase synthesis rates.

08:27: When we're young it's easy. We do some exercise and we eat, both of those things increase synthesis. As we get older there's something called anabolic resistance, what it does is it decreases protein synthesis. It decreases the making of new muscle proteins, and the result of that is that our muscles start to shrink, even if we eat the normal amount of protein of a young person that's not enough to maintain our muscle mass as we get older, and the inherent thing is that we decrease activity.

08:53: The hardest thing I get from my students is I'm telling students that if you've got an old person who's greater than 70 years of age, you want them to lift the heavy weights, and they're like, "Oh no they can't do it." "My grandmother is in a house with two stories. She has to walk up and down the stairs all the time, that really scares us. We're going to put her into one-story house." There's a nice paper that just came out that showed if you move people into a one-story house from a two-story they actually died sooner. You're losing function faster. All of those things that we try and protect our elderly from, they're absolutely necessary in order for them to function well.

09:24: So what we've been looking at is that component of strength. We can increase strength by either making the muscle bigger by turning on synthesis or we can increase strength by actually looking at proteins that are slightly outside of the muscle, the connective tissue proteins that are outside. We have this system where we have a motor in the middle of our muscle, those motor proteins are contracting and that's going to produce the force. In order for that force from those little motor proteins to get to our bones to move our body, it has to get through a lot of connective tissue, and when we're young one of the biggest things that happen when we exercise is that we increase the expression of genes that make up that matrix that surrounds our muscle, the collagen.

10:06: One of the genes that goes up biggest from resistance exercise in young animals is a transcription factor that increases collagen. It goes up 120 fold within an hour and a half after exercise. In old animals when we do the exact same exercise, it only goes up about 20 fold, and we don't see the increase in collagens in the same way. And so we've got two things that are happening as we're aging. We're not getting the signal from our exercise of our feeding to increase the synthesis of new protein, and this matrix quality is going down so that we can't transfer the force that we have, so that our muscle quality is going down.

10:43: We're trying to figure out ways in which we can return those to normal in older individuals.

Dan Pardi - 10:47: So let's go back to this idea that the strongest top third, if we break that group up do we have any resolution into whether the top 10% or so have additional longevity benefit or is it really just about maintaining adequacy of strength and muscle across the life span?

Keith Baar - 11:00: Right, so what you would do is you try and figure out different populations. The study of the midlife strength and longevity to over a hundred years, that's in a study of Hawaiians, so it's not a study where you've got elite athletes. So what you're looking at is a population strength. There are a number of studies that have been done on Olympic athletes, and there you don't see a longevity effect. You don't see that they live any longer. Now there's a whole bunch of confounders there because at the time that all of those data were being collected there was a huge amount of performance-enhancing drug use which has direct effect on cardiovascular function and really shortening lifespan.

11:35: The question then becomes, do we have this elite group that actually seen more benefits? But some of them are dying younger because of performance-enhancing drugs or are we just seeing that they averaged maybe a little bit above average? The majority of the effects seems to be from just being strong. You don't have to be the strongest of the strong to see a longevity effect. You have to be in the top third, and the top third that's not a very challenging thing to get into. And so you just have to be able to function within your body, and is relative to your body size as well, so if you are a small person who's strong that's going to have as good or better effects than a big huge person who's weak.

Dan Pardi - 12:13: Can you maintain adequacy of strength by doing body weight type activities or do we need to do heavier resistance training in order to get to that maximal benefit?

Keith Baar - 12:23: So we know two things about strength and muscle mass. If we just want to regulate our muscle mass we can use any weight that we want and we can just exercise until we can't exercise anymore, it's called going to failure. So if you go and you do an exercise like a body weight pushup, if you go until you can't push up anymore and you can't lift your body off the ground that's enough of a stimulus to cause the muscle to grow bigger. If we want to get stronger it seems like lifting a heavy weight is important. We're not talking about lifting the competitive weight here. We're talking about lifting a heavy weight relative to yourself, and trying to progress the weights that you lift.

13:00: You can always get stronger doing any exercise. So I can have athletes who do only push-ups, only sit-ups and only chin-ups and they'll get much much stronger. They'll get much bigger as well but they'll get a little bit bigger than they will get stronger, in other words their muscle mass is growing really really well but their strength is only growing okay. For what we're talking about for longevity that's completely enough. If you're doing body weight exercises and I did a little mini TED talk on how to live longer happier life, that look if you do two exercises, a push-up, the other is a step back lunge and all I did to make the step back lunge a little more challenging was I picked up my 65 pound dog and I held her in my arms and that's giving me an upper body workout as well while I do my lower body.

13:45: All of those things are body weight approximated exercises and that's good enough to do the majority of what we're talking about, so if you can do a pressing exercise, a pulling exercise with your body weight and you go to failure, that's two exercises for your upper body, something like a step back lunge because it's going to take stress off the knees as you do it, as you go backwards instead of forwards, those three exercises are enough for most people to get the strength that they would need to be functional.

Dan Pardi - 14:12: It definitely gives people more options about what they can do because otherwise you'd think we really do need to just be doing strength training, CrossFit style or powerlifting, sounds like you could actually widen the breadth of the different types of workouts you could choose to do.

Keith Baar - 14:26: Yeah, and so the big issue there is that when I say, "Lifting a weight," the reason that I want people to lift a heavier weight, when you lift a heavy weight from the force velocity relationship in muscle, which means that the heavier the weight is the slower the velocity of the movement. The lower the velocity of the movement, the healthier it is for your body. The difference between the powerlifting and the CrossFit, there what you're trying to do is you're trying to move the weight as fast as possible. So the other studies that we've been doing recently looking at older muscle, we've looked in our animal models we see that what happens with age is that dystrophin protein goes down.

15:03: Over time we're becoming muscular dystrophy. All of us are becoming dystrophic. It means that there's more shear between muscle fibers that are side by side, neighboring muscle fibers sliding past each other, and the way that cells work is they're never supposed to slide past each other because their connections along the length, and when they slide relative to each other that puts little holes in the membranes cause serious damage to the muscle cells in this case. We just recently published a paper in the Journal of Physiology that shows that as animals age, and that includes us, there's an increase in inflammation that causes an increase in a small molecule called a microRNA, and specifically we looked at a micro RNA called microRNA-31.

15:46: It binds to the dystrophin message and it prevents it from being made into protein, and so the result is that as we age the slow microRNA goes up because we have a little bit of inflammation chronically, that decreases dystrophin protein and it makes our muscles more prone to injury. The faster we move the more prone we are again, so now what you've got is as you age if you're doing a fast movement you're going to actually get even more injury rates than if you're doing a slower movement, that's why we're looking to do relatively slow movements, and that's the only reason I use the idea of a heavyweight because that wilL slow you down when you do the movement.

16:23: So we're not saying that you're doing lifting as heavy as possible, what you're doing is you're lifting a weight that makes you go slowly. And the other thing that we would suggest is before you do this is you start very slowly with a relatively low weight and you slowly progress, and every time you come into the gym you add a little bit of weight if you've made your target, and if you do that what's going to happen is you're going to get less pain and soreness associated with the initial exercising, because if I have you go in and work as hard as you can the first time you're never coming back because you're in pain for six days. The pain that you get for those periods of time afterward is related to how little dystrophin there was, how much shearing there was, and as a result how much injury there was within the muscle.

17:03: And so if we can start slowly and build and progress into it slowly you're going to see less of the injury, you're going to get more of the positive effect, and eventually you're going to get much stronger.

Dan Pardi - 17:13: Since you're looking at the molecular targets of exercise, let's talk about mitochondria. I just interviewed Professor Michael Ristow about his work looking at how antioxidants can limit the beneficial effects of training. How much of the longevity effects, of the resistance training or training in general do you think may be mediated through mitochondrial biogenesis or new mitochondria formation that takes place from the stress of exercise, and the positive effects of having additional mitochondria and larger mitochondria through exercise and how that might push everything outwards in terms of the aging curve?

Keith Baar - 17:43: The most interesting thing in this area I think. If you look at where certain studies are done, if you do a study in old people in Holland, and you have them do training, their muscles grow and their strength grow beautifully. If you do the same study in Texas or in England their muscles don't grow as well and they don't get as good a response, and the difference is their baseline activity level. So when we talk about mitochondria that's what we're talking about this idea that as we get older we get more inactive. If you control for activity levels, there's no decline in human mitochondrial levels, that's really important because when we do studies on mechanistic animals.

18:21: So if we do it on rats or mice what we see is a sharp decline in mitochondrial function with age, that's not something that's inherently true in humans. Luc van Loon has done a lot of studies on training in older people in Holland and they have beautiful responses, and the reason that they have a good response is because they're biking to the store and they're walking here and they're walking there, and we do the same studies in Galveston, Texas when Blake Rasmussen does it he sees no response because in Galveston, Texas everybody gets in their car and drives there and gets back in the car and goes home and sits in front of the TV and there's no activity.

18:54: When we're talking about mitochondria, we're talking about two ways to maintain them. There's the exercise way, and we can still do that late into life, where we're going to do endurance based exercise and a little bit of high intensity work. I was just teaching a basic exercise physiology course that just ended last week and what the last point I made for them was throughout life you're going to want to do endurance exercise six days a week, that doesn't mean you go out and run. Endurance exercise for us in an older population for the cardiovascular benefits all you have to do is be over 40% of your maximum.

19:27: So if you just take your age subtract that from 220 you'll get about what your theoretical maximum heart rate is. If you then say 40% of that is going to be this, if you get to that, that's a walk for most people. So if you're going walking in at a good pace that's enough of endurance exercise to actually have the positive benefits on the cardiovascular system. It's also going to have a lot of benefit on the rest of the musculature, keeping mitochondria working well. Maybe twice a week, once or twice a week do something a little higher intensity where you find yourself out of breath, and it doesn't have to be exercise. You could be dancing, it could be whatever, and if you can do that twice a week, all of those things will maintain mitochondria and that's the exercise way.

20:07: The other way that seems ... from some of the work that we've been doing in animal models is that if you do a ketogenic diet, and what a ketogenic diet is in the animal model is protein is about 5% of total intake, the rest of it is fat so it's almost completely fat. In humans you can increase the protein and increase the carbohydrate, but in animal models because they make sugar so well you need to keep those other things low. When we do that over the lifespan, the first thing that we see is that in a mice we increase longevity by 13%, and it seems like we're doing that because you decrease the risk of cancer. All we're doing there is we're inactivating mTOR throughout the body, and because eight out of 10 mice died from cancer then that has a huge effect on longevity.

20:51: That's not true in humans, 20% of people die from cancer, so it's not going to have quite as dramatic an effect on longevity. The one thing we noticed in the muscle is that there's a huge increase in mitochondrial mass, and it maintains mitochondrial mass late into life. And again, the mouse is probably a good model for human Americans in this situation, because the mouse is stuck in a very small cage, so they don't do a lot of exercise just because they don't have room to do it. They would love to but they can't, whereas we don't do it just because we don't want to not because we can't.

21:24: But because the activity levels are fairly similar it might model the human American relatively well, and the result is that if we can use this dietary intervention to do it, it could be a way that if people are unwilling or unable to exercise maybe they can maintain mitochondrial function for longer and have a little bit better function later in life. But you're exactly right that if you don't have good functioning mitochondria you're going to deteriorate as far as what you can do, and so the more you can maintain mitochondrial function through life the better you're going to age, and that's without a doubt.

Dan Pardi - 21:58: I had a great conversation many episodes ago with Neil Copes talking about the longevity benefits of a ketone beta hydroxybutyrate is having its positive effects, and one of them is by the induction of reactive oxygen species just like exercise, just like others xenohometics like polyphenols from plants and flavonoids and isothiocyanates et cetera, they all will induce reactive oxygen species which keeps that mitochondrial biogenesis coming along. I personally do a ketogenic diet for about six weeks, twice a year. If you don't mind sharing, do you go into ketosis as a strategy?

Keith Baar - 22:29: I don't have the focused energy to be able to do it. So what we're actually studying in our lab and together with a colleague by the name of John Ramsey who's probably one of the best longevity experts in the world, what we're doing is we're seeing how many days you have to have the animals in ketosis can you go once or twice a week and still have the same beneficial effects of being on the diet for the whole time. There's some good data that say that if you can even just have one or two days a week where you're in a ketotic state it has a big beneficial effect. So there is a possibility that that is going to be able to be a beneficial way of doing it, where you don't have to have the stress of doing it all the time but people could incorporate it into their routine.

23:15: But as you said, you can do it for a few weeks but it's difficult, and so most people throughout the world are going to have a hard time of doing that. What we're looking to do is see whether we can do anything and discover anything that can have the same effects. We know exercise does it. We know that the ketones do it. We have a sense as to how they're doing it as well, there could be free radicals. We see this huge change in acetylation pattern, which proteins become acetylated, have that little tag put onto them, and so those two things together are giving us an outcome that is actually having a beneficial effect on maintaining mitochondrial mass. So now for us the question is can we find anything else that can do that without some of the stresses associated with the two things that we know will do.

Dan Pardi - 23:58: Let's talk about things like testosterone for longevity. We can learn from the fact that growth hormones often given to help people age better and it actually ends up limiting lifespan, so people that have acromegaly die 10 years younger, people that have Laurence syndrome died 10 years older, though while it can maintain the youthfulness of skin and nails it also can accelerate the production of cancer. What about testosterone and then SARMs and exercise by medics?

Keith Baar - 24:22: So I'll just touch on a couple of things there because that's a great question. So the first thing is this idea of growth hormone injection as a healthy longevity thing, we've known since Kevin Yarasheski did a bunch of work early on that it didn't really actually increase muscle mass at all. What it seems to do is it seems to increase IGF-1 levels and that has a positive effect on collagen which as you said has this great effect on skin and hair and makes you feel and look a little bit younger. What I always tell people is that if you want to increase growth hormone, all you have to do is lift your legs heavy and your growth hormone goes up 10 to a hundredfold.

24:56: And it's actually as it goes up for a longer period of time than if you injected yourself with growth hormone, and it goes up to a higher level. So if you want to do it all you have to do is go into the gym and lift the weight heavy for 30 minutes and you'll have this huge effect. I actually tell people the same thing about testosterone. If you're a guy who's considering testosterone, if you talk to a beautiful woman for 30 minutes your testosterone goes up the same amount as if you had an injection. So there are physiological ways to do this, but then the question is whether they are functionally important, and that's really the big question.

25:30: So there's a bunch of data that would suggest that we know for sure that testosterone isn't needed for the resistance exercise effects. If I take a group of men who have prostate cancer, and as part of their prostate cancer treatment they're given an anti-androgen which is a chemical castrating agent that eliminates testosterone because that slows the growth of the prostate cancer. If we put them onto a strength training program, their muscles grow as big and strong as people who don't have the anti-androgen, so you don't need that for hypertrophy. If we take a group of women who have 10 to 100 times lower testosterone and we put them onto a strength training program, their muscle mass and strength goes up as much or more than men.

26:12: So you don't need testosterone in order to have the exercise effects of what your training is, and so that's a really important thing because if I look at all of these commercials on television and they say, "Well, I'm in the gym and I can't do this and I can't do that." Testosterone doesn't really have that effect, and what they'll tell you is you can exercise more frequently. The reason you can exercise more frequently is because it's slowing that breakdown process. Remember how we talked about the drain, what testosterone is doing is closing the drain. Normally what we do is if we have a hard part of exercise we need to get rid of all the stuff that's been damaged, and when we do that we take out more than we really needed to, and as that process happens, if I go to do the same exercise tomorrow I'm not as strong because I have taken out some of that muscle that I was using to do that.

26:58: The most famous case of this is Floyd Landis in the Tour de France. He goes up a really big mountain stage on one day, he performs horribly, and he was supposed to win the whole thing so the next day he comes in, same, it's going to be another big mountain stage and suddenly he's miles ahead of everybody and he finishes way ahead, "Oh, I ate this great steak last night." And sure enough he had taken testosterone, because what had happened is he did the heavy exercise, normally that would cause all kinds of protein breakdown which would limit his performance the next day, by injecting himself with testosterone he stops the protein breakdown. Some of that muscle is still functional, and so he can perform at a higher level than everybody else who didn't take the drug.

27:40: So what the testosterone is doing and what the SARMs are doing, and the same thing that happens in boys with [inaudible 00:27:46] where they use SARMs and in all of these other groups is it slows protein breakdown, that's basically slowing the process of clearing out the debris. Again, if you go back to the sink analogy, if you're a guy and you and you shave, if you plug the sink yeah the water is staying there but if at the end you see that there's all this junk in the sink because it hasn't drained out, it hasn't cleaned out, but if you're turning on the tap to clean your razor instead of putting it into the water that you've accumulated you don't see all that junk in there because it just flows right through.

28:19: So what testosterone is doing is plugging the drain to a large degree and accumulating a bunch of the junk, and yes in the short term it's going to make you stronger, in the long term it's going to actually decrease performance.

Dan Pardi - 28:31: That's interesting. If you're working within a physiologic range then testosterone is not going to add meaningfully to performance benefits to a well constructed resistance training program. If you have super physiological doses then you're going to only be accreting protein but the quality of that muscle mass might not be quite as high because you're just not doing that cleansing process. What's coming to mind right away is fasting. I do Valter Longo's prolonged fast, five-day fast a couple of times a year. Would a periodic suppression of the anabolic response within muscles and an enhancement of autophagy responses, so clearing out, could you have some sort of interesting balance where you have growth hormone and testosterone, but then once every six weeks or so you do a five-day fast then you go back on to more of an anabolic phase, could that be an advanced strategy in the future?

Keith Baar - 29:16: So what you'd have to do is you would definitely have to combine the anabolic agent with growth hormone, and the reason for that is that as the testosterone is building muscle mass it's actually having a negative effect on collagen synthesis within the tendon, so the tendons become smaller and more brittle, and this is why statisticians can tell which baseball players use anabolic steroids because what happened is their performance got really good for a short period of time and then they got injured. They can go back just looking at statistics and say "This person, this person, this person took steroids." You get a big muscle and you get a small weak tendon, the results is ruptures of either the muscle or the tendon.

29:51: The reason then that you would have to take growth hormone is because growth hormone increases collagen synthesis. If you do this, one of the big places you get collagen synthesis is the aorta. One of the problems with growth hormone and one of the things that kills acromegalics early is that they get huge high blood pressure because the stiffness of the collagen in their aorta means blood pressure goes through the roof and it's very difficult, so there are concerns there obviously. The way the growth hormone works to do this is increase in IGF-1. IGF-1 is a primary thing that turns on mTOR, and again mTOR is associated outside of ... Yes, muscle will grow, but it also is important in any other tissue growing and that tissue growth is usually related to cancerous tissue growth.

30:33: The question then is can you come up with an idealized program using a couple of different agents, really get in there and use some of that. It's not something that I've considered too much, and this is what the rapamycin data does, is it says that if I use a very low level of rapamycin what it's doing is it's knocking out mTOR throughout my body, and that's having a good effect because it's keeping cancer at bay, but it's at a low enough level that when I eat I still get an mTOR response in my muscle. When I do exercise I still get an mTOR response in my muscle, so having that as a component, not a bad thing.

31:09: So if you have something like a rapamycin or something like chloride deficit or something like a ketogenic diet, those three things are working similarly in extra muscular tissue keeping mTOR levels low, and also in the muscle probably through potentially increasing insulin sensitivity. On top of that, what other things could you add into it? If the person wasn't willing to exercise, and you're looking for ways to increase those types of targets, something like a SARM would increase muscle mass. We know that myostatin keeps muscles small, and so if we use myostatin inhibitors we can grow muscle. The problem again is that that muscle mass isn't strong relative to its size.

31:50: If I grow my muscle all over my body but it's not strong enough, what I'm actually doing is increasing my disability, because if I put on one pound of muscle or one pound of fat I have to get two pounds stronger to be able to walk the same speed, one pound to lift my body and one pound to propel it forward. So in order for me to get functionally stronger I have to get stronger only in the muscles I need, in the case of walking that's my legs. I don't want to have big upper body if I don't need it because I'm just carrying around a weight. So if I have a really big upper body and I'm trying to get up out of a chair and my legs aren't strong enough I'm not going to be able to do that.

32:29: So functionally when you take a SARM, it's going to grow every muscle and it's going to grow some of them more specifically but it's going to grow every muscle, and if you're not getting enough strength in your legs you're actually going to decrease your ability to move around and do your activities of daily life. It wouldn't be the way that I would address it, because what you'd have to do and what's functionally important is to target what you're doing to the muscles you want to keep, and that's true for athletes, that's true for older people, that's true for everybody.

32:57: If I want my legs to be stronger so that I can walk across and I can do all of my activities of daily living, I need to make sure that I'm doing exercise for my legs before I eat because that means that there's going to be more blood flow to my legs and it's going to target more of what I eat to the legs so that those muscles are now going to get more of the amino acids from my meal, and that's how I would really do it is I would try and say, "Look, every day before you eat go for a 15-minute walk. Maybe do a couple of little squat type things to try and get your legs lots of blood flow into them, and then sit down and eat." And now all you've done is you've targeted those amino acids that you've eaten to the place that you want them to go.

33:39: The best example is a friend of mine, Luc van Loon in Holland. He's done this beautiful study where he takes people who are admitted to hospital in a coma and he electrically stimulates one of their legs, he doesn't electrically stimulate the other. He can maintain all of the muscle mass in the one leg that he's stimulating even though the other leg goes down 20 or 30% in muscle mass, so it doesn't take a lot of activity. If he does that little bit of exercise to delay, and then they're giving the feeding to these individuals more of the amino acids go to the exercised leg, the exercised leg can maintain its strength and its mass much better than the non exercised leg.

34:15: You have to target what you're doing, and with a SARM and with growth hormone goes everywhere so there's not really a good way to target it, so that's really the challenge.

Dan Pardi - 34:23: For that listener, if you're not familiar with the term SARM, it stands for selective androgen receptor modulator. It's like testosterone but they have altered the structure of these compounds so that they're more selective for anabolic versus androgenic signaling. This is that interesting question where if you have a population that is not exercising, will there be pharmacological measures that actually create better outcomes in those people that won't do the things that are within their control to age better, but then what are the downside risks?

Keith Baar - 34:51: So one of the examples of that that we did back when I was at Washington University with a guy named Clay Semenkovich is we over-expressed what's called an uncoupling protein, and an uncoupling protein makes it so the mitochondria doesn't produce ATP efficiently so you need to use more energy to make the same ATP, and so it's like fen-phen or all of these drugs that are uncouplers. And what we found is that sure enough the animals were small but they would die much, much sooner because the uncoupler couldn't be targeted just to the muscle, and so what ended up happening is that there were so many mitochondria in the heart now, the heart because it's pumping all the time, about 20% of its mass is mitochondria.

35:29: Now if you bring an uncoupler that's a huge stimulus for the heart, and then we've got so many mitochondria in the heart there wasn't space for the contractile machinery so the heart function went down. Question is whether we can target our interventions well enough so that we can improve things without having a negative effect somewhere else.

Dan Pardi - 35:45: What are some strategies to keep your ligaments healthy across the lifespan?

Keith Baar - 35:49: A lot of what we're seeing with our tendon and ligament aspect is that again the activity is important but as we age we're making less collagen as we age. It's one of the reasons why our hair and skin doesn't look so good is that the collagen is not turning over the way it used to earlier. We've been looking at ways which we can manipulate how much collagen people make using nutritional interventions, and one of the easiest things that we've done is looked at using collagen or gelatin as a nutritional supplement to try and increase the rate of collagen synthesis.

36:22: We've done a number of different studies in our in vitro ligament model, and then we've done a number of studies in humans as well, and what we can see is that if I feed somebody gelatin with some vitamin C and I have them do say six minutes of activity just to stimulate their body to make collagen and I look an hour later, we get a really big improvement if we've taken gelatin or collagen before that. We've done this with a lot of different people including some professional athletes is one of the things that they'll do is we'll come in in the morning, they'll take some blood. They'll have one of these different drinks an hour or later will take the blood and then they'll ship it to us and we'll look at how many amino acids are in the blood and then we'll take their blood and we'll use it in our in vitro model.

37:02: So one of the engineered ligaments will have the blood from when they were fasted. The other will have the blood from after they've had gelatin or collagen, and what we'll see is that just treating them like that for six days, how much collagen is in the tissues goes up significantly? You get a three-fold increase in the mechanics of the ligament after the gelatin or collagen, and you get an improvement to the function as well. So what this is telling us is there's something that is digested and absorbed when we're taking in the collagen or the gelatin and it's having a positive effect on our body's ability to synthesize this tissue.

37:36: We talked about strength, remember I said that it's important to have these collagens in order to transmit the force. It's also important for our tendons to have those collagens in order to maintain their function. Only 80% of 80 year-olds have at least one tendon that's ruptured, and that's going to impair their ability to be active. There's the nutritional component but it goes back again to moving a heavy weight, and the reason I really harp on this is because when you move the heavy weight, you move it slowly you get shear forces in the collagens in the tendon, that decreases the stiffness of the tendon. If you see old people moving around, it's not that they have great range of motion.

38:14: They're so stiff they can't do these things that are normal activities, sitting down into a chair, going down stairs, all of these eccentric loads are very difficult because the tendon stiffness increases. We must have our muscles lengthen while they're contracted. All of those things become easier if you lift that heavy weight and have a little bit of collagen a couple of times a week at least.

Dan Pardi - 38:36: And let me clarify the timing then. Earlier we were talking about a protein shake before exercise, that food is going to actually divert some of the blood flow to digestion which wouldn't necessarily be good for training. It sounded like in this study though the collagen pre exercised was actually good for integrating and creating healthier collagenous tissues within ligaments. So would you want to have a collagen/ weight protein shake before lifting weights? But 45 minutes you have plenty of time to digest, could you have it afterwards? Do you have to have it within your week? What's your thoughts on timing?

Keith Baar - 39:07: The first thing is that anything is better than nothing. If you take it at the wrong time you might have a smaller effect than what we're looking at but it'll be better than not having something. The ideal situation is you take a little bit of say a hydrolyzed collagen mix and you put it into some orange juice and you drink that about an hour before you're going to exercise. Muscle has a huge blood flow to it. Tendons have almost no blood flow. Ligaments have very little blood flow as well. So what we do is we try and put the nutrients that we need for those tissues into the system before the exercise, because the way they get their nutrients is when the tendon is stretched it squeezes out the water from the tendon and then it has to absorb water from the environment.

39:49: It's like a sponge, squeeze out the liquid from the sponge and then it's going to open up and it's going to suck in the liquid of the fluid that's around it. So the fluid around it has all of these nutrients that we want to improve collagen synthesis. After you squeeze it out by doing your exercise it's going to suck in liquid that's going to have a lot of these amino acids that are going to be important for collagen synthesis. Then right after you exercise within a half-hour or even later, now you're going to take in something like a whey protein that's designed to improve muscle function. So the collagen itself should have very little effect on muscle size, because in order to increase muscle size we think leucine is important because leucine activates mTOR.

40:26: Collagen is doing it through other amino acids, it's not necessarily the leucine that's important. So collagen for the connective tissue would come in before, ideally, and then afterwards we do something like a whey protein where it would have that leucine rich protein that would stimulate muscle growth, and then the two things together would stimulate the collagen and the muscle growth so that you'd have an ideal situation. That's kind of complicated so not everybody is going to do it so then what you're doing is you're doing best, and the case is that you take the gelatin you put it in with your post-exercise recovery drink and that's okay, it's not perfect but it's better than nothing.

Dan Pardi - 41:03: So have your collagen shake an hour before you workout and have a whey protein shake or that high protein meal within half an hour afterwards and that's important.

Keith Baar - 41:11: Yeah. The timing afterwards doesn't seem to matter as much unless you're older. The reason it matters more as you get older is because you become a little bit more insulin resistance as you're older, so if you're older the exercise increases blood flow to the muscle. If you're older and you're less insulin sensitive, and you don't get that increase in blood flow to the muscle from the feeding, you don't get as much of a beneficial effect from your protein shake. It's not like a window where the muscle only reacts for a short period of time. It seems like it's much more about whether you're getting the blood flow and the amino acids to the muscle that's important.

41:44: In an older person who maybe is a little bit less insulin sensitive the exercise is going to target those amino acids better, so getting them closer to after the exercise is going to be important, whereas if you're a young person for a full 24 hours after you've exercised, you're still going to get a positive effect of that exercise.

Dan Pardi - 42:01: Okay, so if you're a younger population but still insulin insensitive because you live in the modern world and you sit a lot, that might apply there as well.

Keith Baar - 42:09: It certainly would.

Dan Pardi - 42:10: Well, Keith I know we're right up against the time of your next meeting but I really appreciate all the work that you're doing and your commentary on all this. It's so important. Thank you for your time and I appreciate it.

Keith Baar - 42:20: Thank you. It's great talking with you and keep up the good work.