 Okay, I think we'll get going now. We have quite a number of people in attendance, and that makes us here in Hamilton at CLSA's National Coordinating Center very happy that all of you are taking the time to join us today. So my name is Mark Oranis, and I'm on faculty at McMaster University in Hamilton, and I'm also one of the Associate Scientific Directors of the Canadian Longitudinal Study on Aging. And I am one of the leads for the CLSA seminar series. Many thanks also to Laura Lawson and Valady Pietro at the National Coordinating Center for their assistance in putting together the seminars. Without further ado, I'd like to introduce Russell Hepple. He is the Director of the McGill Research Center for Physical Activity and Health. He's also an Associate Professor in the Department of Kinesiology at McGill. He's received the Cheshire Senior Award from the founder of the Cheshire du Cadet Sonsi for 2013 to 2015. He's currently a Principal Investigator for two research projects, the mechanisms of motor unit protection by exercise training in aging muscle, and also the relationship between denervation, mitochondrial dysfunction, and muscle atrophy in sarcopenia. And today, Russell is going to speak to us about mechanisms linking healthy brain and muscle aging in elite octogenarian athletes. After Russell's talk, we will be entertaining questions. However, because if there's too much crosstalk on the webinar system we get feedback, I would ask that you type your questions into the chat feature and I will read them out to Russell after you have typed it in. So by all means, Russell, take it away. All right. Thank you, Mark, for the introduction. And I'd also like to just start by thanking the organizers of this webinar series. This topic has actually really been a lot of fun. I hope that you enjoy what I'm about to tell you and can see the promise that we've got in this study. So I would be reticent if I didn't thank all the different people that have contributed to this research. I think it's important to start there. First off, I'd like to thank Tenya Tavasalo. She actually was the brain trust behind this whole thing and thinking about coming up with the idea of studying these elderly athletes. And then together we developed the rationale around them as maybe a model of super healthy aging. And Josie More, he's our clinical colleague at McGill University. He takes the muscle biopsies for us. And then there's been many others, collaborators from many different places, Rob Erskine at Liverpool, John Moores in the U.K. and Charles Rice and Tim Doherty and their crew of Jeff Power and Maddie Allen from the University of Western Ontario. They've all been really instrumental in the work that we've done. And then our crew at McGill University, there's been several trainees involved, a couple of postdocs, she'll just be you and Sally Spendiff and numerous other trainees involved at pretty much every level. And it really was a team effort. So I'm the lucky one who gets to talk about it, but really everybody has contributed hugely here. All right. Well, since I'm from an exercise physiology background, a question I'm often asked is, oh, he's exercised the cure for aging. And if you read the literature, particularly the headlines in the newspaper on occasion, you might be left with that impression that, hey, yeah, exercise is a cure. Well, I'm here to deliver the sobering news that it's not. It's certainly the most effective thing that we have for aging in a healthy fashion, but it's by no means a cure. And to convince you of that, I'm going to show you just two photographs here that I think are well worth the proverbial thousand words. So when you look at this, this gentleman here, I've covered up his face, but you obviously know he's older, and some of you may have seen this photograph before. But you may not realize how old he is. He's 67. And I think that you could all recognize that in light of his physique, which is impressive for even a 20-year-old, he's doing remarkably well. And so I show this photograph often just to make the point that the most studied age group in the context of aging, at least in terms of exercise capacity and muscle changes, et cetera, is in this 65 to 75-year-old age group. And at that age, much of what we're looking at, not all of it, but much of it is a product of just not being physically active enough. And if we were all of us to ramp up our level of physical activity in an educated fashion, we would be capable of much more than we probably are currently achieving. Maybe we wouldn't look quite as impressive as this gentleman here, but we could all look probably a lot better. But this age kind of ends the good news, because 12 years later we have a photograph of this guy who has continued to work out at an extremely high level. And I think that you don't need a microscope here to see that he has lost probably 25 to 30% of his muscle mass over that 12-year period, in spite of the fact that he has continued to work out very hard. So to me, this really illustrates the point that exercise, although definitely beneficial, it cannot prevent the aging of the musculoskeletal system. And the other thing that I use these photographs to illustrate is this critical age. And so this of course varies from one person to the next, but somewhere around the age of 75, after that age, things in terms of your muscle decline and probably many other systems in your body, the rate at which they decline is much more substantial, more aggressive. So things start to deteriorate more rapidly, and I think that's really illustrated in these photographs where you see this gentleman here. Across a fairly narrow time span, 12 years, he's definitely started to go down. And this is often what we see. Now as you heard from the introduction, muscle aging is really my primary area of interest. We're kind of branching out a little bit, as you can tell from the title of this webinar. But to study muscle aging, we employ a variety of techniques going from the whole body, where we might measure something like muscle strength. We can also look at the muscle using magnetic resonance imaging to look at some general characteristics of the muscle from a structural point of view. We can get biopsies here. This is our colleague, Josey Morey, taking a biopsy from one of our super athletes here. That's Olga Kotelko lying on the table there. And from those biopsies, we're actually able to do a remarkable amount of measurements. We look at some of the muscle morphology. We can look at mitochondrial function. And we can characterize the quality of the mitochondrial DNA. And I'll tell you a little bit about that as we go along in our athletes. And then I also, in my lab, do more work at the kind of neuromuscular junction. And we use a variety of animal models. And this is just one of them. It's a mouse known as the sarcomaus produced by a small biotech company in Switzerland called NeuroChin. Anyway, we use a variety of these approaches to try to understand what's going on in the aging muscle. And so much of what I'm about to tell you about what happens to aging muscle is informed by these different approaches. So first off, if we look kind of at a big picture level beyond the atrophy that's apparent from the outside of an individual, if you look inside the muscle using magnetic resonance imaging, you also see, in addition to the loss of muscle, you have a replacement of muscle that's lost by connected tissue as well as an infiltration of fat. So the muscle becomes less flexible, stiffer, et cetera, as a function of this connected tissue infiltration. And the fatty infiltration is also thought to reduce insulin sensitivity and maybe predispose you to type 2 diabetes as you age. Now, within the muscle, many of you will have been subjected to the dogma that this is really a problem of a fast twitch or type 2 muscle fibers. And I'm here to reign on that parade because what I would like to first point out to you is that a lot of the literature on which that information was based was done in animals and human muscle is quite different from animal muscle in the sense that first off, we don't have type 2B fibers, whereas the rodent models on which much of the aging information is based do have type 2B fibers. But not only that, our fastest muscle fibers, the type 2X fibers, they're in remarkably low abundance. And if we exercise train, they tend to pretty much vanish. So the major muscle fiber types in human, really it's type 1 and type 2A, those are by far the most important. And falling off from that, when we look at what happens to those muscle fiber types as we age, by far the biggest change is actually an increase in these type 2AX hybrid fibers. So these are muscle fibers that co-express both type 2A and type 2X myosin heavy chain simultaneously. And that's the more dominant effect rather than a slowing of the muscle, which is often what we're taught in textbooks, etc. And so this information that I've shown you here is based upon more current methodology for assessing fiber type in muscle, and it's using primary antibodies against each of the main myosin heavy chains. All right, well, what else do we see in the muscle? If we look at the histology here, between 23 years of age and 71 years of age, what you generally see is that there's a reduction in muscle fiber size. And again, in contrast to what you might have thought type 2 muscle fibers being more impacted, here you can clearly see that the red, blue, and green muscle fibers representing type 2A, type 1, and type 2X respectively, they all atrophy with age. The type 2A fibers, which are the red ones here, they perhaps atrophy somewhat more than the other fibers, but nothing is spared. And I think that's an important point. Then when we go to the more extreme age, and I think the importance here is that at 82 years of age, more reaching clinically relevant ages in terms of individuals maybe having some negative consequence related to their muscle atrophy and things like an increase in fall risk, perhaps impairment in mobility, and maybe even reduction in the ability to complete activities of daily living. So when we go to that more clinically relevant age, the story is actually quite different. And some of the muscle fibers look not that different than they were a decade earlier. But what is really striking is between those relatively healthy looking fibers, there are these very small and angular muscle fibers. And as I'll show you in a moment, those are denervated. So that's really a characteristic of aging muscle at this advanced age that I think is received with too little attention to this point. And this is really what's driving much of the atrophy. You can clearly see that these denervated fibers are by far the smallest in the muscle. So they're really important in explaining the acceleration of atrophy at this more advanced age. Now, as promised, this slide shows you the denervated muscle fibers more clearly. So if you've got a normal muscle fiber, they would appear orange in this labeling scheme. And if you're denervated, you appear green, and you can clearly see that the green fibers intermingling amongst the orange ones. And so this is in normally aging, healthy human muscle, and you can see these starting to pop up. And I believe this is from an 82-year-old. Now, what causes that denervation? Well, starting actually somewhere in our 40s, we have progressive cycles of denervation and re-innovation. And this is due to changes in the stability of the neuromuscular junction. So that's that point of contact between the nervous system, so the motor neuron, and the muscle fiber. And it's the means by which you activate the muscle fiber. So this point of connection on the muscle fiber size, the acetylcholine receptors are there to receive the neural signal in the form of acetylcholine from the motor neurons. And those acetylcholine receptors are organized into these clusters that have a pretzel-like shape. So if you look at this four-month-old rat single muscle fiber, you can see a pretzel-like configuration. But when we go to an older animal, that pretzel-like configuration is severely altered. And now we have fragmentation of those acetylcholine receptor clusters. That makes it more difficult for the motor neuron to properly target the muscle fiber and you get these spontaneous denervation events. Now, as I mentioned, you get these starting probably in our 40s, and normally you get re-innovation following a denervation event. But as we get to more advanced age, the capacity for re-innovation seems to falter, and we end up with accumulation of these denervated muscle fibers that are eventually atrophied and lost. Now, going on at kind of a bigger level in terms of the neural system, we also have loss of the motor units themselves. Remember, these are the smallest functional units of the muscle. So we've got a motor neuron that plugs into multiple muscle fibers and there's a range in terms of the size of these different motor units. But as we age, there's this progressive deterioration. So this is some data from the University of Western Ontario group for the blue and the red bars here, showing about a third of the loss in motor unit number between the age of 27 and 66 years of age. And then the green bar is data that we've collected in our lab more recently, also in collaboration with the University of Western group. And you can see that there's a further deterioration in the number of those motor units. So we have alterations in the nervous side, neurogenic components of muscle as we age, and that these are really important in explaining both the atrophy of muscle as well as some of the changes in the coordination and activation patterns. All right, well, let's kind of get a little more cheery here now that we've dealt with the negative aspect of what's going on in aging muscle. Let's talk about these octogenarian athletes. And just to kind of give you some insights about why octogenarian, well, as I've said on a couple of occasions now, the more clinically relevant age in terms of the consequences of muscle atrophy are these over 75-year-old subjects. So we wanted to target athletes who were in that same age range because that makes their athletic performance all the more remarkable because really we're looking at an age where it's better known for kind of severely declining physical capacity rather than feats of impressive athletic performance. Well, I probably don't need to introduce this person to most of you in the audience. That's of course Nancy Reagan being escorted with President Obama several years back. And just to show you as a comparison, this is a lady here, Olga Kotelko, who's the same age. She's 92 and so too was Nancy Reagan in this photograph. And I think you can clearly see that there are very different ways in which aging has affected these two women. Nancy is not unlike what you might expect for a 92-year-old. She's somewhat physically frail and needs a little bit of assistance to walk. Whereas our friend Olga here is still throwing javelins and jumping and sprinting and doing all sorts of other remarkable things, including by the way is unbelievable as this may sound, throwing the hammer. And that happens to be her favorite event. So this just shows you how disparate these two poles can actually be when you go to these extreme ages. And this leads me to ask the question that I think you can already see where I'm going here. Does everyone age at the same rate? So these two individuals here, this is again Olga Kotelko doing a long jump. And this other gentleman here is an 800-meter runner who happens to hold the world record for the over 80-year age group for the 800 meters. And those of you who know anything about track and field, this gentleman ran at the age of 80, 250 on the track indoors for the 800 meters, which is pretty fantastic. So in answer to the question, does everyone age at the same rate? I think it's pretty clear the answer to that is no. Many normal people at these ages would not be capable under any circumstances of doing what these individuals do. So clearly there's something different about them. And that kind of begs the question then as somebody who comes from an exercise physiology background, I've been asking myself the question, what determines athletic performance in the elderly? So when we look in a young, healthy individual, in this case a distance runner, what maybe determines whether this person is going to be one of the better runners in a field is whether he has a big heart and good cardiac functions so that he can deliver blood flow to his muscles, what the capacity is for conducting that blood flow within his muscles, his capillary supply around those muscle fibers as well as the amounts of mitochondria within those muscle fibers. Those are all important determining features in whether or not this person is going to be one of the best or one of the middle or back of the packers. And do those same criteria also apply when we look at an older individual? I've used this picture specifically because you can see this fellow is quite hunched over and I think it's hard to imagine him trying to run. So then if we think about what might determine his athletic performance, clearly what maybe prevents him from running are things like maybe arthritis in his ankles, his knees, maybe he's also got some impairment in his muscles, severe muscle weakness, the number of motor units are probably very low, etc. There's many different things, but the point is these are all kind of age-related deterioration issues that are actually determining his performance. So instead, I actually have a follow-up picture of the same guy on the left, we've got this guy here. This is Ed Whitlock, some of you will have heard of this gentleman. He's a remarkable marathoner. And if you didn't know what he looked like when he was 20, you might think that he was actually suffering from age-related muscle atrophy, but he's not, he's always looks skinny like this. And in fact, he's preserved himself remarkably well. And about three years ago, he ran the Toronto Marathon in, believe it or not, 350 and 51. So that's a remarkable performance. It's not as fast as he was when he was younger. So he's definitely still slowing down, but he's doing things at the age of 80 and now he's 83 that others just couldn't even imagine. So with that as a backdrop, that's really what inspired the design for this study because what we wanted to do was take the very best athletes that we could find and study them and try to understand what it was that allowed them to do the remarkable things that they do. And much as, say, somebody who's working with animal models of aging and maybe you're working with worms or mice, and you've got a model that exhibits impressive longevity, that's really what these master's athletes are to me. They are a model of optimal aging or superior aging, and they do things that the average person just is not capable of. So what is it about their physiology, about their genealogy, et cetera, that might facilitate that superior performance? And I think if we can understand some of those secrets, we might be really onto something important. I will also mention that the athletes that we recruited, we purposely were looking for individuals from a variety of athletic backgrounds because really our first question was not what is the effect of exercise. That's been pretty well studied. What we wanted to do was to look at the best of the best, whether you're a sprinter, a power athlete, or an endurance athlete. We wanted to look at those people and see if there were common features amongst those athletes from different backgrounds in explaining why they're able to do what they're doing. And I think that might give us something that's more applicable than the general population. So we took two groups. We've got our non-athletes, individuals who come from a wide background of athletic or physical ability, let's just say. They're not athletes by any means, but we do have some subjects that are quite physically active, playing golf regularly, for example. And other subjects who are really not doing much at all and quite sedentary. So we have a range, and that was purposeful to get a span of what one might see at that age. And they're approximately similar in terms of the male and female distribution. The age was about 81 years of age, and that's similar between the two groups. And then also the body mass index you can see here is much lower in the athletes, which is probably not that surprising, and largely reflects their better maintenance of the low body fat as they've aged. Well, we did a whole battery of tests on these individuals, and I'm only going to show you a snippet of what we've actually collected. But we obviously did some measurements of their peak exercise performance. So this is a cycler-gometer test. Many of you will have heard about doing a progressive test to exhaustion to measure VO2 max, so that this is a measure of aerobic capacity. And the significance of that is that our aerobic capacity declines progressively as we age. It's on the order of 5% to 10% per decade, increases a little more aggressively as we reach those older ages. And it's an important predictor of our ability to maintain functional autonomy. And what we see here is that the VO2 max of our athletes is nearly double that of the controls. And in fact, it's pretty much identical to what one would expect for healthy young adults of university age. So that's pretty remarkable given that they're 80 years of age. They're performing like people who are 60 years younger just to put that into context. In contrast, the non-athletes had an average of about 20, which puts them on the healthier side of what one would expect at the age of 81. The average probably for 81 years of age would be maybe around 15 mls per minute per kg. So these folks are on the higher side of that. And just to also point out that you probably need about 12 mls per minute per kg for your aerobic capacity to maintain your independence. So these folks are on the positive side of that, but some of them were getting pretty close to being on the wrong side of that. All right, we also did a number of clinical function tests to kind of make some comparisons that way. And so some of you will be familiar with these tests and more familiar than I am. So we had them do four meters walking at a fast pace. And clearly you can see that the athletes are performing this much more quickly. Similarly, when we have them do a stand-up and go, they're able to do this much more quickly than the non-athletes. When we have them do chair stands, repeated chair stands, the athletes were able to complete them much more rapidly. And then this last measurement is by far the most interesting and striking one, and it's their balance time. And just to put this into context, so what they're doing is they're standing on one foot. And if you can stand for 60 seconds, that's it. We stopped the test. So there were many of the athletes who actually were able to stand for more than 60 seconds, but we just took it as 60. So this is actually an underestimate of the difference between the two groups. And you can clearly see that the athletes are just head and shoulders above the non-athletes. Now one of the other reasons why I think this particular test is so important is that balance is obviously determined by many, many coordinate factors in the neuromuscular system, all away from the proprioception, you know, in the foot and ankle and coordination of the motor units therein, and all the way up into the cerebellum and other parts of the brain that are necessary for coordinating that balance. So it's an integrated measurement, if you want, of the neuromuscular system. And you can clearly see that these athletes are just way, way better than the non-athlete controls. Well, not only that, when we look in the muscle I mentioned to using magnetic resonance imaging, we can look at the distribution of fat and connective tissue as well as the muscle with age. And you can see that the master athlete here, in this particular example, has not only got better preservation of the total amount of muscle that's there, but the quality of the muscle just looking at it is far better. So they've got less fat and connective tissue infiltration. And not only that, when we look at this, so this is just a measurement of the cross-sectional area of the muscle, and you can see that it's better retained in the athletes. And if we look at the muscle strength, not surprisingly, it's considerably better in the athletes. It's probably about 40% higher. Now, one of the things that's been implicated in explaining aging on kind of like a big picture sense has been what's known as the mitochondrial theory of aging. And many of you will have heard of this before. And one of the central features of this theory is that it's the progressive deterioration of the mitochondrial genome, the mitochondrial DNA that leads to accumulation of mitochondria with aberrant function that in turn leads to some of the negative phenotypes that we see with aging in many different cell types, skeletal muscle included. Now, although there is some controversy about the importance of mitochondrial DNA degradation with skeletal muscle, and just for the record, I actually don't think it's that important in explaining aging of muscle, it does provide us with a biomarker of aging. And so if we look at this in our athletes, one of the things that we see, so what I'm showing here in the middle panel is one of the features of a severely aberrant mitochondrion is that they lose the activity of the terminal acceptor, electron acceptor in the electron transport chain, cytochromoxidase. And those fibers can be identified histologically. And in this particular experiment what you're seeing is the fibers that are gray or blue have very low or absent activity for cytochromoxidase. And so these are respiratory, they're not capable of respiration anymore and the muscles are severely impaired from that point of view. And we can quantify that. We've also looked at the mitochondrial DNA and in this particular case this is just the number of mitochondrial DNA copies per unit of muscle in the athletes versus the controls and you can clearly see that the athletes have about double the copy number. And so we would regard this as evidence of a lower rate of aging in the athletes from the perspective of the mitochondrial DNA. When we look at some of the elements that relate to the neural function, I've already mentioned to you the supreme balance in the athletes. When we look at the motor unit, so this is Mattie Allen from the University of Western Ontario who did these measurements in our lab. And as I mentioned to you before there's this progressive loss of motor unit numbers with age and what you can see in the athletes is that they are definitely preserving more of them. They're not preserving youthful levels, the youthful level in this particular muscle. It's the tibialis anterior that we measured. It's around 150 motor units and they're down probably about half of that but they're definitely doing better than the non-athlete control. So there is some protection at the level of the motor unit. And not only that, when we look at the muscle in terms of its fiber size and fiber type, first looking at the fiber type I mentioned to you that the major change with normal aging is a big increase in these type 2AX hybrid fibers and what you can see in the athletes is that there are no very low levels of these type 2AX hybrid fibers and in fact from a fiber type perspective the muscle of these master's athletes looks very much like physically active but not athlete individuals who are about 10 years younger. So that's the red bars versus the purple bars. The red bars are 71 year old physically active subjects. The purple bars are our master athletes. And so these athletes look a lot like individuals who are 10 years younger and that's not just at the fiber type level. That's also in terms of fiber size and you can see that their fiber size is, as I mentioned, very similar to what you see in the individuals about a decade younger. So they're doing much better and you could take this as another criterion or indicator that they are biologically speaking younger than their chronological age compared to their non-athlete counterparts. All right. So all of this nice information at the muscle level which maybe is not that surprising giving that they're athletes, one of the things that we were wondering about is if your muscles age well, will your brain follow? And I think this is a really important question. I don't think it's been addressed very much up to this point but I think there's huge potential here because I think most of us would agree if we could find a way that would allow us to preserve not only our muscle health as we age or at least better retain it, as well as our cognitive health, that would really be the key to aging healthy and aging happy. So because then we could be physically active and engaged in every way that's meaningful to us as individuals. So I think this is a really important question. And just to give it some context, there's quite a bit of evidence now starting to accumulate showing that physical frailty parallels cognitive impairment. So this is some work done from David Bennett's group published a few years ago now showing that those individuals who had high level of physical frailty had a greater risk of mild cognitive impairment whereas those who had a lower level of physical frailty were at a lower risk of mild cognitive impairment. So this is an emerging line of evidence that there are these important links between the way that we age physically as well as the way that we age cognitively. And so we thought that our athletes might provide a really novel way of examining this in a little further depth. Now I've mentioned to you quite a bit about the aging of muscle and the importance of aging in the neuromuscular side of things. And just to draw a link to what's going on in the brain, it's well established that there's this progressive loss of neurons in the brain as well as we age. And this is just measured here as cortical thickness. And you can see that there's a fairly gradual age, sorry, gradual decline up until the age of 80, but very interestingly a much more aggressive loss after that age. And the interesting thing for me is that that actually parallels the age at which the muscle loss accelerates dramatically. And so I think that this loss of neurons from the brain and maybe loss of motor units from the muscle that these are parallel events that have a similar cause. So if we look at the other side of that coin in our athletes where we have preservation of motor unit numbers, we might also expect better preservation of their brain. So that was really what influenced our interest here. And so what we did is we did a number of cognitive function tests and I'm just going to give you the highlights of this. This is in collaboration with our colleague, Kathy Shabaston, who's now at the University of Toronto, but was with us here at McGill when we started this study. And the highlights are that the athletes had better verbal and learning memory, better cognitive processing speed, overall they had better cognitive function. So these are all things that are speaking to better preservation of function. And so overall the nature of the superior functions that we saw in these athletes were indicative of a protection of both the temporal and frontal lobes of the brain, which were, of course, reasons of the brain that are quite susceptible to age. So we have this evidence of not only better preservation of the muscle but preservation of the brain in our athletes. And so that, of course, begs the question of what might link brain and muscle health. And I think this is really still very much an unanswered question, but we are starting to get some sense in the literature of what might link brain and muscle health. And we're just beginning to delve into this ourselves, but we really are only scratching the surface. But to give you some backdrop, what's kind of come out over the last several years is that muscle, in addition to its important role in terms of locomotion, et cetera, is also being seen increasingly in endocrine fashion. In other words, there are many, many molecules and the numbers that are often bandied about are in excess of 400 different molecules that are released from muscle into the bloodstream and could have far-reaching effects that go well beyond the muscle itself and perhaps explains why physical activity has such profound benefits at a whole-body level. So this is really an emerging area and there's still so much to be learned here, but we're focusing just on neurotrophic factors because, of course, we're interested in things that might explain protection of the neurons. So as it turns out, muscle produces many of these neurotrophic factors and some of them are important in maintaining the fidelity of that neuromuscular junction, so keeping the motor neuron happy and keeping the acetylcholine receptors where they're supposed to be underneath the motor neuron. But as well, some of these things can diffuse out into the blood and I'm sorry, the animation here doesn't work the way that I want to because they just vanish, but what it should have shown you is that those little triangles were going into that red thing, which is a capillary, which then carries them to the rest of the body and potentially the brain. So I think this is a really important thing to look at, but as I mentioned, we're really just scratching the surface. So one of the things that we wanted to look at is the most well-known neurotrophic factor, something called brain-derived neurotrophic factor, or BDNF. And it's the most abundant neurotrophin in the mammalian brain and for that reason we thought we'd look here as a starting point. Now, in the context of muscle, one of the things that has been revealed is that BDNF as well as another neurotrophin, Neurotrophin 4-5, these both act through the same receptor on muscle. It's the trachea B receptor. And if you were to knock down the trachea B receptor, so not completely knock it out but knock it down so you have less expression of this receptor and therefore less neurotrophin signaling, one of the outcomes is that the neuromuscular junction is unstable and it actually takes on features that look remarkably like normally aging muscle. So from this point of view, it's clear that alterations of BDNF level with age could have an impact and maybe do play an important role in explaining the aging of muscle and the deterioration of the neuromuscular junction. And there is actually some other evidence out there that supports this idea. And if we look at this in our athletes, one of the things that we found measuring this in the serum, these are under resting conditions. We've taken blood samples from these individuals and when we look in the serum, we find that the athletes have considerably higher BDNF levels under resting conditions. So this is not following a lot of exercise. It's actually a minimum 48 hours after the last bout. And in spite of that, the athletes have higher levels of this BDNF. So perhaps this is an important component of explaining both the protection of the muscle and the protection of the brain. And that's something that we're pursuing, but of course this is just one of many different molecules that might be important here. So we have a lot of work yet to do. But the other thing that we wanted to do is because I'm interested in not only the effect of exercise in this neuro-protection, but also whether there might be genotypes that maybe facilitate higher levels of these BDNFs and other neurotrophins in the blood. So I thought it would be interesting to look for maybe some different genetic variants that could predispose you to higher levels of BDNF with age. And there's not much information on which BDNFs might promote higher levels, but there is some information on BDNF single nucleotide polymorphisms that actually are associated with lower BDNFs. So we started there, but we're hoping to find some others that actually are more associated with a positive relationship as opposed to a negative. Great. One of the single nucleotide polymorphisms which involves availing to methionine substitution, what you end up with is a lower BDNF release in response to muscle contractions. And not only that, this particular SNP is associated with a greater risk of dementia. It hasn't been looked at in the context of muscle health before, but we think it might be relevant. That would be something that we'll be looking at in the future. So at the starting point, we thought we'd look at this particular allele and see whether or not it is differentially distributed between our athletes and the controls. The idea that we had beforehand was that perhaps the athletes might have a lower representation of this less favorable BDNF SNP. So that's what we thought. But what we actually saw, so the veiling is the good SNP and the methionine is the bad SNP, so the methionine is the one that's associated with a higher dementia risk and a lower BDNF release from muscle in response to contractions. And what you can see is that the athletes don't have a lower representation of this at all. And just to put this in context, the approximate abundance of this particular allele in the general population is about 20%. So we have about the normal distribution that you would expect in our two groups. But when we did look at the BDNF levels in our different groups, as it relates to these different SNPs, something interesting did pop out. And what we found is that, although this didn't make any difference in the non-athletes, when we looked in the master athletes, the individuals who have the CC genotype, so that's the better genotype, they actually add higher BDNF levels in their blood than did the individuals with the poorer BDNF genotype. So we do have some indication that maybe this genotype is playing some role. And I think an interesting thing would be to follow up with these individuals at some time point later, and perhaps as little as five years might actually make the difference at the age we're looking. And we would predict that those with the CT genotype and the lower BDNF release in their bloodstream might have a poor retention of both their muscle as well as their cognitive function at this later point. So that we'll have to see. That could be an interesting avenue. So just to wrap things up before we take some questions, it's clear here that our elderly master's athletes have much greater retention of muscle mass and function that is typical for their age. And some of these things are actually really, truly remarkable, the balance being one of the most impressive things. They also have superior retention of cognitive function speaking towards a link between healthy brain and healthy muscle aging. And in particular, since both the aging of brain and muscle seem to be related in part to loss of neurons, we believe that this is evidence of superior neuro-protection in the athletes and that's, of course, something we're trying to understand. And in particular right now, we're chasing a hypothesis that muscle-derived neuro-protective factors contribute to this difference. And then lastly, because I think this is really an important aspect as well, is understanding what genetic components versus lifestyle, lifestyle being the exercise component. So what genetic components might explain this better neuro-protection and the reason why I think this is so important is that up to this time in kind of the research history, most of the literature is focused on understanding the effect of exercise. And that's nice because we can actually obviously modify the amount of exercise that we do. But it's pretty clear that if we took everybody who's listening to this webinar right now and asked you to start to exercise and do the same type of exercise training program as these elite oxygenary athletes are doing, how many of you do you think would be able of being ranked in the top three in the world? And I think that the answer to that, unfortunately, no disrespect intended, is that probably not many of you. And if we looked at the population as a whole and looked at people over the age of 80 and said, all right, we're going to have you do the same types of exercises these oxygenary athletes are doing, it would be a fraction of 1% that would be capable of competing with these folks head to head in a meaningful way. So I think it's pretty clear that these individuals that we've studied here, they are exceptional for reasons that go beyond just the fact that they're exercising. And to me, that's the part that we really don't understand and that we need to understand, and that's what I'm really interested in. So before I take questions, I'll just leave you with this parting thought. If you do a Google search for the fountain of youth, which I have done on numerous occasions, you can find a lot of interesting things, and this is one of them. So I'll leave you with that. Thank you. Great. Excellent talk. Thank you so much. So now, for members of the audience, if you have some questions, please type them into the chat session. And once again, very, very interesting and lively presentation, Russell. Thank you so much for agreeing to take time out of your busy schedule to present today. We have a question from Harry Shannon from the CLSA National Coordinating Center. Harry is a biostatistician who works on the sampling portion of the CLSA. And so Russell, read out his question. How much do you think the cross-sectional nature of your data matters? Maybe the athletes whose cognitive function declines stop working out so you're left with a survivor group. That's a fabulous question. And actually, I'm kind of counting on the fact that we have a survivor group here because I want to have people, I want to study the people who have been able to better withstand the ravages of aging than is normal. So I don't view that as a weakness. I actually view that as a strength, and that's precisely what I'm trying to get a handle on is that survivor effect. What allows them to be a survivor? Because to me, there's a lot of important information to be gained if we can understand that. Great, thanks. So are there any other questions from the audience? Would anyone like to pose a question? One has just come up. Okay, I'm seeing the one from Harry. Oh, here's one. Okay. So it's a question from Heather Kinsey at, again, our National CLSA Coordinating Centre. Did you find any added benefits of anaerobic power elite athletes over aerobic endurance athletes for preservation of cognitive function in the leader in life? The answer to that is quite simple. No. There were some interesting things in terms of the BDNF response in the endurance athletes. In that, it seemed like those with the superior genotype had higher levels of BDNF, but we didn't see that in the power athletes as much. But in terms of the overall BDNF levels between the power athletes and the endurance athletes, they were actually remarkably similar and so too was their cognitive function. So we haven't found anything there that differentially separates these power athletes from the endurance athletes beyond the obvious, which is that some are endurance-based and some are power-based. If you look at the morphology of the muscle, you do see some of the expected differences in fiber types, so the power athletes tend to have more type II fibers and the endurance athletes tend to have more type I fibers. But beyond that, we didn't really see much in terms of distinguishing features in the rate at which they were aging by other criteria. Excellent. Thanks for the response. We have another question. Great talk. It's written, to what extent do the master's athletes have joint repair? Well, I actually don't have firm numbers on this off the top of my head, but I know we have that data somewhere. But my recollection is I don't believe any of them had any sort of joint repair beyond maybe somebody had a meniscal terror, that sort of thing. But I don't want to say for sure that there was none. I'll just claim ignorance at this point and say that we need to look at it. But certainly there was no major reconstructive surgery. I don't think that this is a bunch of folks who'd all had ACL injuries at some point in their life history. Great. Another question. What is the history of the control group? Were they active individuals over their lives as for the master athletes? Were they master athletes over their entire lives? It's kind of a mixture in the non-athlete controls. Some have been reasonably active and others not really very active. In terms of the athletes, on average they had been competitive for about 20 years. But there was a huge variation. We had Olga Kotelko, who didn't start track and field until she was 77. We had another subject who didn't start track and field until she was, I think, 70, but prior to that or 71, and prior to that she had been into tennis at a pretty high level, but not the same level of competitiveness as she has as a track athlete. So there's a large variation in that group. Some are kind of late adopters and some have been very active over their entire lifespan. But to me that is one of the remarkable features of this is in spite of the relative homogeneity of their athletic performance at the age that we've studied them, their history is actually quite divergent. Okay, a question here. How does the time you start exercising from young age, middle age, or older age impact your muscle health in old age? I think the answer to that is we don't really understand that fully. There's just not much data out there at all. I would say that based upon what we've seen in this group of athletes, that if you are protecting your motor unit numbers, that's got to be a good thing. And since that starts before the age of 60, it probably speaks to the importance of starting before the age of 60 in terms of exercise. And in terms of human studies, longitudinal studies, there's not really nothing to go on, but having done this before in an animal model, we've actually started exercise training in animals that were 28 months of age. These were rats. And so that would put them at about 60 years of age in terms of a human equivalence in their lifespan. And when we exercise trained them for a period of life that would equal about 15 years in human terms. So take them up close to the age of 80 in human terms. We actually found that although there was an initial benefit of the exercise, when we got to the more advanced ages, the muscle actually looked worse in the trained animals, which is not at all what we expected, but just to also put it in context, the animals that were exercise trained, even though their muscles didn't look very good, they were actually quite a bit better from a mortality point of view. Their hearts had better preservation of function. There was less connected tissue infiltration. They had better survivorship. They maintained a lower body fat, and they just generally looked a lot better. So even though their muscle wasn't doing so well, they had better health. So it's not always about muscle. And when we think about the benefits of exercise, it's obviously more important to maintain an overall degree of health. Great, thanks. We have a question from University to share. Look, you mentioned that humans have type 2x and not type 2b muscle fibers. Could you provide some description like it's up to school down here? Some description of type 2x fibers relative to metabolic properties such as oxidative capacity, strength, et cetera. Are they similar to type 2b in animals? So that's a really great question. So as I had mentioned, the type 2x fibers are not very in very high abundance in humans, and many of them exist in the hybrid form, so they are found with type 2a expressed at the same time. And once you exercise train, those type 2ax fibers become largely type 2a. So from a physiological standpoint, and that's also in sprint athletes, by the way, so even if you sprint, you lose those type 2ax fibers. From a physical standpoint, how important they are in explaining performance. I think we have to conclude that they're probably not that important. But in terms of their metabolic properties, they are the least oxidative, so they have the lowest mitochondrial content and they tend to have the lowest number of capillaries. So when they convert to type 2a fibers, they become more aerobic, so they have higher mitochondrial contents and higher capillaries once they convert. So they are the least aerobic in humans. Great. Next question from Ena at the MCC. Does the type of exercise make a difference? Swimming is, for example, very different from weight-bearing exercise. So again, another really great question. And put simply, I would say we don't know yet. It is our intention to expand our study now to look at some different athletic populations. I want to stress again that we're not primarily interested in effective exercise per se. We'll look at different athletic populations and continue to pick the best of the best to study them because what we're trying to understand are features that are common between these superb performing individuals rather than differences. But of course, we will be looking and seeing whether there are differences and trying to understand what that might mean in the bigger context. But I honestly don't know the answer right now. Great. Thanks. So we are nearing the close of the seminar, but we might have time for one or two quick questions if anyone has any burning issues that they'd like to ask. By all means, you'll have your chance right now to ask. Maybe I'll ask a quick question. Just thinking beyond this research. If I was a clinician thinking about how some of this might be of use to me in the future, what do you think might be some of the clinical applications of this work? Well, obviously a lot of what drives aging research these days as well as age-related disease is trying to find ways to better retain our function as we age. If we think just simplistically, the majority of the healthcare dollars are actually spent on the oldest individuals. And there's a variety of reasons for that. Some of them have to do with impaired physical function. Some of them have to do with impaired cognitive function and then a million other things in between. So obviously our goal is to try to find ways to really kind of collapse that period of declining health so that you maximize the health span. So that instead of spending maybe the last 10 or 15 years of your life in pretty declining health, maybe we can compress that to maybe one or two years. That would be what we'd be looking for. Now whether we'll achieve that, that's another story, but that's certainly our goal. Great, thank you. Okay, I think that's going to conclude today's presentation and Q&A period. I enjoyed the presentation very much. It's not something that I'm very familiar with. So that was why I enjoyed it because I learned something new today. And I thought, Russell, thank you so much for this superb presentation. And on behalf of everyone at the Canadian Longitudinal Study on Ageing, I would just like to thank you for presenting this to us today. You're very welcome. It was a pleasure. The pleasure was certainly ours for this great presentation. So we thank you very much. And we hope that you'll be able to return sometime with further results. Okay, I'd be happy to do so. Excellent, thank you very much. Have a good day, everyone. Thank you for joining the presentation today.