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| How resveratrol and similar polyphenols PBS TV February 2005 Complete transcript of interview with David Sinclair and Stephan Elfand by PBS's Tom Bearden TOM BEARDEN: How did you first get interested in the genetics of aging? DAVID SINCLAIR, Harvard Medical School professor: Well I've been interested in this ever since I can remember really. I was looking for a frontier or of biology and I realized that aging was something we really didn't study at the molecular level. I realized it was something that we hadn't really fully grasped and I could see that five to 10 years from back in the early '80s, we might have the technology to really address the questions of what causes aging and how could we do something about it. I was particularly excited about this field because I thought if we could find out the root causes of aging and maybe the genes that control this process, you could imagine the benefit to medicine that we could develop. TOM BEARDEN: How do you go about investigating the genetics of aging? What's the process here? DAVID SINCLAIR: Well, we can study aging in people, but of course those studies take decades. So what we try to do is we use simpler organisms to try and understand the basic mechanisms and so in my laboratory, for example, we use things like simple baker's yeast that we use to make bread. We study little worms that we gather from the soil and also fruit flies. And what we're finding is that the basic underlying mechanisms that protect those organisms against aging are conserved into people and we're now at the stage where we can go in and use what we've discovered in these simple organisms and see if it's true for people. And at the moment it's a very exciting time because we're just at the point where we're getting the first glimpses that this might be true for humans as well as these simple organisms. TOM BEARDEN: You study the simple organisms because they have a shorter lifespan? DAVID SINCLAIR: Yeah, we studied them for a few reasons. One is because a yeast cell lives 10 days so we can get results very quickly. Fruit fly is about a month, but we can also go into these organisms and genetically manipulate them and add them, I mean suppress particular genes and see what effect they have on their lifespan. Protecting cells from aging TOM BEARDEN: What's been learned so far? DAVID SINCLAIR: Well we've realized first of all that aging is regulated. We didn't realize this until about 15 years ago. We used to think that aging was a lot like, as if we were cars made fresh and youthful and then we've entered this breakdown in diet. What we didn't realize until recently is that we're much more complex than a car. We fix ourselves if we're broken. If we're running out of fuel we find a gas station. And clearly, there's much more to us than just our falling apart. And we found that there are particular genes that protect us against aging and so to use the car analogy, it's as if our cars have the ability to repair themselves and go and find gas if they need to. And if we can tap into these genes, we would have a way of protecting ourselves against the aging process. TOM BEARDEN: Aging is not the same thing as lifespan. DAVID SINCLAIR: Right, so aging is the process by which we grow old and eventually die. So aging is really just the way we deteriorate over time. Lifespan on the other hand is how long we live. We typically refer to that as longevity. And so these genes that we're uncovering, we're calling these longevity regulators because they're actually extending the healthy lifespan of these animals that we work on. TOM BEARDEN: Are there commonalities between the animals and humans? DAVID SINCLAIR: Well the same genes that we're finding that extend lifespan in these simple organisms are found in people. We have all of them and they appear to do a similar function and in fact you can take a human gene and in some cases put it into these simple organisms and it works just as well as the one that is down in the flies and the worms. They're interchangeable and it's pretty exciting cause it might be that these genes actually control our own lifespan. TOM BEARDEN: These are the key to longevity? DAVID SINCLAIR: Well we don't know if these are the key to longevity in people yet, but certainly the key to longevity in simple organisms. You know, if you and I were a fly we'd be set. We could extend our lifespan two, threefold, no problem. These genes do appear to be, at least give us a glimpse in how we might regulate lifespan. How we might promote health into old age in people, but we clearly just don't know that yet. We're just on the border of getting an understanding as to whether that's the case or not. TOM BEARDEN: Similar activity of genes in smaller animals and humans, but exactly the same? Are there different effects in different species? DAVID SINCLAIR: So these, these genes do appear to be very similar at the structural level, so if you look at one you can say, well gee, it looks a lot like that, but their actually functioning as cell might be subtly different. The way to make a worm live longer is probably quite different from making a human live longer. And what we're finding is that in the worm they do a set of tasks that make the worm live longer and we're looking at humans to see what sorts of things these genes are doing potentially to make ourselves live longer. And we're getting the first glimpse of that as it appears that these genes in humans do protect ourselves against death and stress, biological stress. And so at least in the culture dish it looks really promising as though we might be onto, you know, this so-called fountain of youth, but it's a little early to say for sure. TOM BEARDEN: What's the mechanism that these genes actually protect cells (inaudible). How does that happen? DAVID SINCLAIR: So these genes in lower organisms, it's really clear how they work. They switch on other genes that protect the cell against damage and the ravages of everyday living. They also change the metabolic rate. We see that, for instance, the worms become thinner and healthier and fitter. What we think is going to be true for people, but we're not sure is that these genes will switch on cell defenses against things like free radicals which are suspected to be the cause of aging. Um, it may be that these genes protect us, protect us against a hundred different things that cause aging. Calorie restriction TOM BEARDEN: What's the relationship between calorie restriction and the activation or non-activation of these genes? DAVID SINCLAIR: First of all, let me just talk a little bit about calorie restriction. So calorie restriction is quite an amazing phenomenon. It's been known for about 70 years that if you calorie restrict a rat, they live longer. And the reason that they live longer is not because they're old and unhealthy for longer, it's actually because they stay youthful for longer. So really, this is like what we've all been dreaming of, a way to keep ourselves younger, if we could only figure out how these rats are responding to the calorie restricted diet and figure out how to use that technology for ourselves, we would have a wonderful type of new medicine where we could perhaps prevent diseases of old age, or at least delay their onset. It turns out that we think we finally understand what's going on in the animals to make them live longer when they're undergoing this strict diet. We think that these longevity genes that I was talking about are switched on by the diet. It's becoming really clear that calorie restriction is not just working because it slows down the animal and just perpetuates their life. What we think is that the animal is feeling as though it's under a type of biological stress and in response to that, it switches on these defenses and at the center of that are these so-called longevity genes. So now that we've, we think we've got a grasp on the genes that control the calorie restriction process, we think we can find ways to make drugs to have, to turn on these longevity genes and get the benefits of calorie restriction without having to starve ourselves. TOM BEARDEN: How long and how big a leap is it from the animal studies underway today to the availability of such a drug? DAVID SINCLAIR: Well it's a tough question to predict the future, but if you'd asked me that question, when would we see these drugs, if you'd asked me that 10 years ago I would have said maybe within the next 100 years we'll be lucky to see that. But actually the pace of discovery's been so rapid, it's shocking the scientific community. I'm flabbergasted at every year there's, there's another major breakthrough and so I'm changing my perspective on this. I think that certainly within our lifetime we will see these drugs that will be able to prevent diseases of aging or delay them. It might be, you know, risky to speculate any sooner than that, but I'm confident that maybe within five to 10 years we'll start to see some benefits of the types of discoveries that we're making right now. TOM BEARDEN: Not to be impertinent, but is that why you founded the biomedical company? DAVID SINCLAIR: I founded the company because I felt that my life's research wasn't able to go far enough to help people. So I got into this really to improve medicine and my life really stops at finding the genes that are responsible. I'm not capable of finding drugs, but a company is, and so I have been involved in starting a company that will take our discoveries, here at Harvard Medical School and also a number of laboratories around the U.S. and take that next step which is to find small molecules that we can turn into drugs and work with the FDA to use these to treat diseases like diabetes, heart disease, cancer and maybe even dementia, like Alzheimer's disease. TOM BEARDEN: You say treat, but do you really mean (inaudible)? DAVID SINCLAIR: I mean treat and avoid. I think that we could do both, theoretically. What we're finding with this technology is that we're in a new area. We've never been here before. We've never tapped into the body's own defenses against diseases. So I think that conservatively speaking, we might be able to prevent diseases. But there's a very real possibility that we'll be able to treat them in old people. We know that calorie restriction works in old animals to prevent their diseases and to cure them. For example, if you treat a rat with calorie restriction that has become diabetic, it reverses the disease. So you can treat animals with calorie restriction, and we think that we can treat humans with diseases like heart disease and even cancer with the types of molecules that hopefully these companies that have formed just now will be able to find. TOM BEARDEN: In effect, are we talking about tricking the organism into thinking it's under stress. That you don't have to actually restrict calories to get this effect? DAVID SINCLAIR: Yeah, that's exactly right. What we're on about here is to trick the animal into thinking that it's calorie restrictive. And so what we're doing is turning on these longevity genes when they would otherwise be inactive. And the only way that we used to know how to activate them was to restrict the diet or give a mild stress to the animal. But we think that with small molecules we can have the benefits of the diet but without having to undergo a strict diet. So the potential is there to have really big benefits on diseases. And we can treat the elderly and the sick, clearly people who cannot restrict their calories and you wouldn't want them to. TOM BEARDEN: Are you concerned about side effects? I mean if this is a stress reaction, is there the risk of serious side effects? DAVID SINCLAIR: Well there's a risk, anytime you mimic calorie restriction you might end up with the side effects from that treatment. So calorie restriction is known to, for example, cause infertility or lowered fertility and if we really can mimic this, the concern is you know we'll have this problem. But the good news is we just published a story that says that the molecules that we've developed in the lab that can mimic calorie restriction in flies and worms, give them the long life but without affecting their fertility. If anything they're longer lived and so this I think was a really important discovery that we can have the benefits of the diet without actually having a side effect. TOM BEARDEN: Assuming all that translates (inaudible). Moving to human testing DAVID SINCLAIR: Right, so we're at the point where we need to test this first of all in mice and those studies are just beginning now. And then if that works, we really want to go either into humans if it's safe, or to try it in primates as well. But we're at the point where we are in mammals and we'll know within a year or two if we're right about this. TOM BEARDEN: That soon? DAVID SINCLAIR: Sure, I mean a mouse's lifespan is about two years. We're going to be feeding our molecules out, so-called calorie restriction, the medic molecules that we call them, we're feeding these to elderly mice that are halfway through their life and we'll know within a year or less if we're having an effect. TOM BEARDEN: How about humans? How long will you have to study humans to know whether you have an effect that's worthwhile and side effects that are not devastating? DAVID SINCLAIR: I don't think that we'll see the first glimpses of the way this is working in people through an aging study. I think these molecules will come out as drugs against particular diseases like diabetes for example. And eventually people will realize, a bit like aspirin, oh wow, it's not just good for this, it's good for that. Well it seems to cure everything. You know, but it'll eventually in terms of a business model, it has to be approved by the FDA first for specific disease and then eventually I think this will be used for other types of diseases, but maybe we can even fine tune particular types of molecules for particular diseases that all work through a similar mechanism which is turning on the body's own defenses. TOM BEARDEN: To give a hyperbole but this sounds like it could be one of the most significant discoveries of all times as far as human health is concerned. DAVID SINCLAIR: It is potentially one of the biggest discoveries. And I think it's not going to be too surprising to hear that there's a real buzz in the scientific community and there's talk of dare I say it, Noble Prize fever in the air? And certainly one of the things that gets me up in the morning is you know the drive towards being the first to make some of these big discoveries. We've been here before. Let's admit that people have claimed that they've had the elixir of youth probably for the last 40,000 or more years. So I don't want to claim that we have the cure for aging, by any means, but it's really clear that, that modern medicine, modern molecular biology has finally grasped a potential way to manipulate lifespan and have a dramatic impact on health care. TOM BEARDEN: Have you given much thought to the potential sociological impact (inaudible). DAVID SINCLAIR: Yeah, in my laboratory and amongst my colleagues we talk a lot about the potential impact of these drugs. I've been talking to social policy makers. I've debated members of President Bush's advisory council about this. I think about this all the time and so do my colleagues. And what we are realizing is that if we do have a big impact on lifespan we will have to make some changes. But the good news is that speaking in economic terms, it could actually be beneficial to allow people to live healthier and possibly longer lifespans. It is a fact that if you make a person live longer, they are less burden on health care system because they're often less sick at the end of life. So that's an added benefit, but clearly there will have to be changes if we are really successful. I don't know if we'll extend lifespan any more than five or 10 years, um, at least in the foreseeable future. In fact, I doubt that we will but eventually we might be able to have significant impact on lifespan and then we will have to figure out how to solve this problem of added life. I should add that people have solved this problem already. I'm sure this same debate came up when antibiotics were invented. People have lived a long time over the last (inaudible) years. And we've solved those problems. But I don't think anyone would want to send up back 100 years to those times. I think we'll solve the problems and I look forward to a better future. TOM BEARDEN: Going back to one of the earlier question about the genesis of all this and your interest in it, has there been, for you, I don't know any other way to put this, a eureka moment where you said wow, this is what I really want to devote my life to? DAVID SINCLAIR: Yeah there was a time when I thought this is something really special. When I started the work we were working on yeast, and at the time it was considered crazy to be doing such things. And aging is so complex in people. How could you use just a fungus to understand the process? And to be honest, I had doubts about 10 years ago that this was going to be relevant, but you know you take a risk, you take a gamble and hope that it pays off. But there was a point, about the late '90s when it appeared that what we discovered in yeast was going to be applicable to higher organisms and when it started turning up then in worms and flies, the same processes were true for those organisms you know I'm a biologist, I can realize that, and most biologists will tell you, a yeast cell and a fly are more distant from each other than a fly is to a human. So we've already jumped a huge distance in terms of biology and we're just filling in the last little gap between flies, mice and people. So I think we've made significant strides, and I look forward to being able to find out whether this is true for us... Activating the anti-aging gene TOM BEARDEN: How is SIR2-1 activated? DAVID SINCLAIR: So these SIR2 activators, we get them from plants and we also make them in the lab. We make synthetic forms. And we're just trying to understand right now how they work at the molecular level. We know that if you imagine the SIR2-1 enzyme as this Pacman that they bind to and dock on the protein and make it work faster and we're mapping the interaction between the molecule, the activator and the protein. And what we think is that there's a special docking site that when it comes in it alters the shape of this Pacman, this protein and so that it works more efficiently. And then what happens is that Pacman sends out the troops more efficiently. TOM BEARDEN: Is there more than one way to do this and is that a problem? DAVID SINCLAIR: I've been talking about the molecules that we've made to activate the SIR2s, but the cell activates them a number of different ways. It's rather complex in fact. So one way is to make more of the protein, more of the SIR2-1 protein as it were and we see that happen in rats, when you calorie restrict them, you get more of this protein. In fact, there's another way which the organism can use to turn it on, and that's to make the existing protein work faster and be more efficient and there are other genes that do that which we found, in yeast and we're looking at them in humans now. And so the take on message is that there are a number of ways to turn on these longevity pathways, either with small molecules or with other methods. And I think that's an advantage. It means that there are a number of ways that we might be able to make drugs to turn on this system. TOM BEARDEN: So part of the challenge is to deal with that complexity and figure out the best way to do it. DAVID SINCLAIR: Well, if you're presented with challenges, what you do is you use them to your advantage and so what we're doing is understanding how these are regulated and figuring out which is the best mechanism that we can use in terms of medicine to activate these and we found so far the best way is to find small molecules that directly bind to the protein to activate it. But there are probably other ways that we can do this and we think that's going to be an area of future investigation. One of the interesting things about this pathway is that we can use genetics instead of small molecules to extend lifespan. It turns out these SIR2 genes can be manipulated to extend lifespan. You don't just need small molecules. So for example, in these lower organisms, we can quite easily just within a week make a new organism with an extra copy of the SIR2 gene. And turns out when you do that, these organisms live much longer and it appears that they live longer because they think that they are calorie restricted. And so we can use genetics that clearly we cannot genetically manipulate ourselves and so that's why we've taken the route of finding small molecules that we can just take as a pill. TOM BEARDEN: Was there a major intellectual breakthrough in recognizing the gene actions in this area? DAVID SINCLAIR: There was a major breakthrough in the early '90s with the realization that single genes control the aging process. In fact before that we didn't even know that aging itself was regulated. We thought that it was just a process that we couldn't do much about. It was extremely complicated. There must be thousands of genes that contribute to this so how can we ever do anything about it? It was a lost cause. But when people started to uncover single genes like these SIR2s, that could greatly extend lifespan of simple organisms at least, it was a paradigm shift. It was a real new way of thinking because finally we had this fact that a single gene can control lifespan, and if that's true, then we can find perhaps a single molecule that can greatly affect lifespan and health. TOM BEARDEN: Why do these genes do what they do? DAVID SINCLAIR: So we find these genes in pretty much all organisms on the planet. They're found in plants and yeast and worms as I've been talking about. So why is that? If they're found in all these organisms, they must be really fundamental, important for life. What we think is that they serve a really important purpose and that is to get organisms to survive adversity. We see them come on during starvation or calorie restriction. We think that's because these genes are trying to get the organism or the animal through that period of adversity. And we find that if they don't have those genes, the SIR2 genes for example, the organisms don't do as well. And so it looks as those these genes have been around for a long time and that they serve to make organisms get through periods of adversity. TOM BEARDEN: A survival mechanism. DAVID SINCLAIR: These are very ancient survival genes that we didn't know existed until recently, but we think we can utilize for the benefit of mankind activate them and use their innate defense against diseases of aging. TOM BEARDEN: I hesitate to ask you this question but I will anyway. We spoke to a young lady who's part of a society called the Calorie Restriction Society. What's your reaction to people who are apparently, at least in her mind, she's trying to activate this defense mechanism in her own body by restricting her calories, but she's doing it reducing her calorie input to the point where she looks anorexic. DAVID SINCLAIR: Yeah, certainly there are probably 100 if not 1,000 people in the U.S. who are restricting their calories with the aim of improving their health. And good on them. You know I really can't do it myself and I don't think many of us can. But there's pretty good scientific evidence that if they do it the right way they could have some benefits. I mean, let's realize first of all calorie restriction works on every organism that's ever been tested on. And if it doesn't work on people, we would be the exception on the planet. So I think there's a good chance it'll work. I think there's the danger of overdoing it. And clearly it's not that difficult to take it a little bit too far and have some problems there. But there are studies just coming out showing that in people calorie restriction does improve health. There was a recent study showing that some of these same people have improved heart health and cardiovascular so the vascular system, the blood supply is improved in these people. And there's also studies in monkeys that are now 15 years old that show that monkeys do respond well to calorie restriction and they are otherwise healthier and might live longer. So it does look very promising, but I think we do need small molecules, drugs that will mimic this if we ever want the general population to benefit from this. = end =
TOM BEARDEN: Let's talk about genetics and aging. How did you first become interested in this subject? STEPHEN HELFAND, University of Connecticut professor: I became interested in aging, I'd studied a number of other fields, developmental biology and neuroscience and I watched as we made enormous progress in development and, and in neuroscience by using an approach called genetics which is where one can utilize the ability to alter genes one at a time and then see how that changes in that particular gene can affect a physiological process. So I began to understand that aging, as far as I understand it, is not well understood and that many people spent many years trying to understand it, and we're sort of at an impasse because it's such a complicated biological process that, it's hard to understand the physiology of it and what genetics allows you to do, or at least some of the modern approaches of using mutations, single mutations that we can create in model organisms and then study, it allows us basically an unbiased, or the nonbiased approach to try to see how genes and particular protein products affect a complicated biological process. It was enormously successful in understanding how development works. How you go from a single fertilized egg to a mature individual and it's been very successful in understanding some of the underpinnings of the genetics behavior. So a number of years ago, about 10 or 12 years ago, I kind of recognized the possibility that we could use all of these techniques that have now come into fruition, the really great techniques that weren't available earlier to, to, to try it on this same, you know, a very difficult process. TOM BEARDEN: What do you mean by aging? How do you define that? STEPHEN HELFAND: OK, that's a very good question. Aging is hard to define and when I have to give seminars I start out by the fact that it is difficult to define aging. Now, one way to define aging, it would be to say processes that change over time in an organism. Now, Sir Peter Metawar had pointed out that in the English language, there is no word for aging that is devoid of the negative consequences of that. So a fellow named Tuck Finch, a number of years ago has proposed that we use age related changes as a general feature and that those things that are deleterious to our health or age might be considered senescent phenotypes. Now even there, even though that sounds like a nice way of separating to it, it's kind of problematic and that is because how do you define a senescent phenotype? How do you know, so (inaudible), the way of just, the definition for senescence would be a phenotype, a change in the animal over time or age, that leads to the animal's functioning in the next interval being lenient, allowing it or forcing it to have a higher mortality rate would be a way of defining it. So something that changes you that makes you more likely to die in the next interval would be sort of a senescent change. Now, the problem is that those senescent changes are context-dependent, and kind of what I mean by that is if you take somebody like me who's a short little guy, who can't run very fast and as I get older I run even slower and maybe you put glasses where I can't really see and you put me out in the African sofauna, some 10-to-20,000 years ago, as I lose a couple of steps I'm going to be in a lot of trouble in that context. But if you take me now and you make you a CEO of a major corporation in New York City, I could run the world. So what are senescent or deleterious changes with age in one context may not be the same in another context. So that become problematic. The other thing is that we have phenotypes that don't, that are clearly things that we recognize as occurring with age, but may not lead to any deleterious effects. So gray hair would be one example. So, and not only do we know about gray hair in general, but we also know that gray hair is part of the aging process in the sense that every culture has a term called premature graying of the hair, which means we much recognize that there should be a normal time for hair to gray and, but does graying of the hair lead to any increase in mortality? Now it wouldn't unless you live in a society where they kill people that get gray hair. So there are all these changes that are taking place, some of which may actually be positive changes with age, and it's not clear which of these are deleterious and which of them are not. Some of them, it's obvious they may be deleterious, but in other ones it's not. So the problem is, it's hard to define the process of aging. It's what they call in medicine or in pediatrics the grandmother areas of affect. How do you know your grandmother? Well I've seen her before, but how do you describe her to someone else in a way that they would know, so it's hard. So the next thing I think, I usually talk about or the way I think about it is instead of trying to find what aging is, one other way is to step back and see, well how do we measure. So by how you measure something often will help you understand what it is. And in aging at the moment, that's also a bit of a problem. We have two basic ways in which we measure aging. One is the demographic or population based approach where what people do, what you're doing is you're taking a population of individuals, whether it's, whether it's plants, whether it's animals, whether it's humans and they all start as a cohort at some particular point at which they're born or they're adults, and then you follow them over time and you make a list of what they call a life table which is really calculating when they died, and, and then you, by based upon their time of death, you can create this survivorship curve where you start with 100 percent survivorship at the beginning and at some later point, no one's alive in that population. And it turns out that the shape of this curve in a population that has optimal environmental conditions, will give you some very important information about, about the process that must be taking place in-between. Now the problem with that on the other hand though is that it's not telling you about aging. The measure that you're making is of the death of an individual. So you're just looking at the age of death of individuals and based upon the age of death of individuals you're going back and calculating this process. But in fact, you're not looking at a dynamic process. You don't know why that individual died. You don't know how, what led up to the death of that individual. There's a single point which is death. Now this is something that, that people recognized for many, many years and it's a valuable piece of information. The insurance companies for example are people that really want to know. They want to know in a population what, what are the chances of this group of individuals lasting for a particular time. So as my dad explained to me, when you take out life insurance, what you're doing is the life insurance company is betting that you're going to live and, and you're betting that you're going to die and you usually hope they win that bet, I think. But in fact what you're, what you're really doing is it's a population statistical basis. What we want to have is a physiological study, a way of determining not how old you are necessarily chronologically because, for example, some people who are 50 years old look 30, and some people who are 50 look 70. So there, there's this association sometimes between chronological age and physiological age which may be relevant for how long you're going to live. What we like to know is, is what physiological changes take place and do they take place in a particular characteristic manner? So, at the moment, most people because of difficulties of measuring physiological changes, do in fact measure lifespan and, and conclude many important features based upon what the lifespan, but they're not necessarily looking at changes in the rate of aging. Studying fruit flies' lifespans TOM BEARDEN: Talk me through the methodology that you're using to investigate the world of genetics. STEPHEN HELFAND: So we have a number of approaches that we're interested in using. The methodology essentially is that we are looking mostly at lifespans. So we take a cohort of fruit flies, so we have (scientific name) is a fruit fly, common laboratory organism, and of which an enormous amount is known genetically and molecularly and even behaviorally and in regards to aging. In fact, fruisophola and it's related species have been used in aging studies since the 1915s to explain many important features in aging. But what we do is we grow a cohort of flies through their developmental period, usually all as a big cohort and at the time that they come out of their pupal case, they close into adult form and the adult form is what people are familiar with, this little flying insect that you find around your bananas, particularly in the summertime. TOM BEARDEN: Or the lab. STEPHEN HELFAND: Or in this lab, but they're not our flies. Well I guess some of them are flies, but we'll deny it if they get out of the room. They could come in with the bananas. Actually every summer we do have that problem because people bring in fruit and then they leave it in the trash and they colonize, or so we think, so when the secretaries complain somewhere else, we say they're not ours. And in fact, if you get rid of the garbage you do well. So we take these flies as they come out of their pupal case, within just a couple of hours, because these, these organisms are basically partitioned morphologically. Anatomically two distinct parts of their lives. And what I mean by that is that when the egg is laid that's been fertilized, embryogenesis and the larval phases or maggot phases take place over a period of, of five to 10 days in which those guys are eating and growing. Eating and growing but not reproducing. The fly that comes out from the pupal case after about a five day metamorphosis period, and that can fly around, within 12 hours or so at normal room temperature is capable of mating and putting off offspring. So they're adults by all definitions that we can come up with. So the fly that, that flies around, we call the adult fly. And we take those flies and put them in individual vials, a certain number in a vial, males, in our case we allow males and females to stay together most of the time, and then we pass them every other day, sometimes every day, sometimes every other day to new vials so that their offspring don't arise and confuse us with who's the generation that's aging and who's a new generation. And each day what we do is we then look at those flies that may have, that died. And that by going um, every day or every other day and passing them and checking who's dead, we create a life table ourselves which then generates a survivorship curve. TOM BEARDEN: And (inaudible) genes. STEPHEN HELFAND: And we vary a number of different things. One of the things you can vary is environmental conditions. So the fly which is a cold-blooded organism, is very dependent upon its metabolism, based upon the ambient of the present temperature. So you can dramatically change the lifespan of the fly and all the physiological characteristics that are, go in tempo with that lifespan by changing temperature. You can also change the lifespan of the fly with reproductive status as well as with we'll talk about I guess a little bit later by nutritional or calorie contents. But we all, what we really want to get at is to use genetics to understand this process. And what we want to do and we do, have done partly is in fact to take individual genes and alter them. Now, often the term mutation is used, but in fact, the capability and for (scientific name) of the fruit fly field now, so we have such enormous control over the technology that we can actually take any gene and thus change its gene product by either increasing it in an animal, or decreasing it in the animal in any single set of cells, or group of cells at any time we want. So, we could take one gene or a group of genes and alter them. But traditionally what one in the past has done and we still are partially doing, is essentially making mutations in individual genes and then looking to see whether that mutation has altered the lifespan of the fly. And preferably looking for those that extend it. How does calorie restriction relate? TOM BEARDEN: Which brings us to the question of caloric intake. How does that relate (inaudible)? STEPHEN HELFAND: Calorie restriction which is a fairly well, is a common phenomena throughout the animal kingdom at least or actually (inaudible) as well, we find that, that under periods in which nutritional resources are diminished, the organisms in a variety of different ... organisms in a variety of different ways respond to that loss, that decrease in nutrition by altering their physiology in a way that tends to prolong their lifespan. What they're probably doing from an evolutionary perspective is saying look, I shouldn't reproduce now. I should reproduce later. Now one of the byproducts of hunkering down and waiting it out is that you have to live longer in order to wait things out. So the phenomena is that when you withdraw calories from the organ -- many different organisms, it tends to extend their lifespan. There are other phenotypes as well. What we discovered a couple years ago. First it was discovered mostly in other model org groups, such as yeast, the single-cell yeast, that there are a number of genes that directly seem to affect how calorie restriction may work. For example there's an enzyme called RPD3 and an enzyme called SIR2, both of which change, basically remove acetyl groups, a group from a protein changing the confirmation of that protein and thus changing that protein's function. RPD3 and SIR2, which are two, these two enzymes that we're talking about, when they interact say with histones, and histones are the proteins that help the chromodine structure help to maintain the chromodine structure, let me keep it in a tight form or a loose form, thus allowing that particular region of the genome, or that particular gene that's present in that place to either be expressed or not expressed. So these particular enzymes are involved in modulating through both their effects on histones and their effects on other proteins gene regulation, in other words, what genes will be expressed at that time or not expressed at that time. You can imagine if you're in an environment where you need to change your physiology in some dramatic way because of the nutrient sources that you're sensing, or lacking, what you'd like to do is change a lot of things in a characteristic altogether manner and one way to do that is to begin to stimulate some of these processes to change gene regulation in a conserved directed manner. So what we have done is we've looked in the last couple of years, particularly based upon yeast studies and based upon studies in the roundworm C. elegans, the particular genes that they seem to show both extends lifespan and may do so through a calorie restricted manner, we've done the same thing with the fly. One is we took this mutation called RPD3 which is a histone DS (inaudible), and in the yeast cell, when you decrease RPD3 activity, you both extend the lifespan of the mother cell in yeast and what we do is we do that in the fly and when we decreased RPD3 levels we extended the lifespan of the fly. So two genetically identical flies except for a mutation in RPD3 and one which decreased RPD3 led to a dramatic extension about 35, 40 percent in those flies that had a decrease in RPD3. And then the next step that we did was, or the next kind of thing that we thought about is well, how is RPD3 extending lifespan and partially due to the effect that we were able to study it and we have studied it. We began to explore some of the three ways that we know that we can alter lifespan in the fly. Ambient temperature which didn't seem to be something that we could look at, sexual reproduction and we did look and these animals, what I didn't say earlier was that in the fruit fly, if you have the female not mate, it lives significantly longer than if it's mated. So one thing that you have to do whenever you have these interventions that seem to extend lifespan is to try to maybe look into and/or exclude whether it's not due to the fact that you're now shutting down fertility. TOM BEARDEN: Excellent. STEPHEN HELFAND: And so, we look at how many eggs it can lay and we found that with RPD3 there was very little decrease. And in addition, the males are perfectly normal, so the idea that this is a reproductive problem was, was less likely. And the third thing that we were really left was, was this idea of calorie restriction. So if you take a normal fly, or sawfly and you, in its food that it's living in 24 hours a day anyway, and you reduce the amount of calories in that food, a variety of laboratories has shown that this extends the lifespan of the animal. And you can do it in a dose manner so that as you reduce the calories of the food you get a longer and longer lifespan until you've gone too far and maybe they're slightly in a starvation mode. So we took our RPD3 mutants, and one of the things we found was that if we look at a normal fly that we have calorie restricted, that we know will live longer, if we look at its activity of RPD3, we find that the level of expression of that gene is lower. It's about half or so, which was, which was what we were doing by our genetic manipulation. So the normal animal under calorie restricted conditions appears to cause RPD3 to lower to about the same level that our mutation did. When we took our RPD3 mutation and we looked at its effect on lifespan under normal food conditions, and we looked at normal flies under calorie restricted conditions and then we looked at RPD3 mutants under calorie restricted conditions. And we found that the extension of lifespan with RPD3 was sort of similar to the extension that we saw of a normal fly and calorie restricted fly. And if we put RPD3 and calorie restriction together, two different things, we didn't get an added effect. They didn't live any longer. So that it wasn't as, suggesting that the two may be in a related pathway. If they were completely unrelated, you would expect to find that they would add up and give you an extension and they didn't. That was the first clue. Now the other part that was a clue to us of what genes might be involved in mediating how calorie restriction leads to this lifespan extension, was that in addition to looking at calorie restricted animals and looking to see what RPD3 levels looked like, we also, because it was a popular gene, looked at what SIR2 levels would do. Now SIR2 has been found in yeast and in C. elegans roundworm, that when you increase the level of SIR2, you extend the lifespan of both of those organisms. So what we found in our normal calorie, a normal animal that's calorie restricted, we found that whereas the RPD3 gene was decreased, the SIR2 gene was actually increased. If we took our RPD3 mutation that's living longer, and we looked at SIR2, we found that it was increased there as well. TOM BEARDEN: So they're working in tandem? STEPHEN HELFAND: So we're not, we believe that they may be working in tandem, and that's the evidence that we've gotten most recently, which is if we take SIR2 itself in the fly and we caused the fly to increase its expression of its normal SIR2 gene, we can extend lifespan. And the things that are interesting about it is that, the first thing we did is we used a technological approach that allowed us to, that permitted us to extend, to increase SIR2 levels in all cells of the body and, and that extended lifespan say 40, 50 percent. And then we say, well what tissues might be more important? I mean and one way of asking that is where is SIR2 normally expressed? And when you, when you look, it appears that two of the tissues it's primarily expressed there in the brain, in the nerve cells of the brain and in the fat body which is part of the persofola, it's part of, sort of the equivalent of the liver or the fat cells. And that's where SIR2 is normally expressed, so we then said, well what happens if we just restrict our increase or SIR2 expression to one of those tissues. And we have the capability of doing that using molecular approaches so that we increase it just in the nerve cells of the brain. And when we did that, we got almost as good an extension of lifespan. So SIR2, an increase to the whole body, or SIR2, an increase in only neurons, both extended lifespan. Now we also did -- TOM BEARDEN: It sounds as if what you're describing is that you're using manipulation of genes to activate what amounts to be it an ancient survival mechanism? STEPHEN HELFAND: That's probably one way to step back and think about it. It looks like what we are in fact plugging into is something that's a remnant of, it's important in survival, that's right. And we're utilizing it in not a survival mode, we're tricking the animal into thinking that it needs to go into a survival mode and the idea of, so calorie restriction creates this physiological changes, and what we're seeing is that some of the changes that it creates, that are particularly relevant to the lifespan extending part, which is what we tend to be interested in, include RPD3 and SIR2. And so that, instead of the diversity of both positive and maybe negative effects that calorie restriction has in addition to the fact that it's very hard to actually calorie restrict oneself, at least for me, by looking at more downstream or the mediators of this otherwise complicated environmental process allows us to maybe intervene at those points so that we can by manipulating RPD3 or by manipulating SIR2 at least theoretically the possibility of getting the benefits of calorie restriction without some of the limitations of calorie restriction. So what we did was to, in order to tie SIR2 to calorie restriction and had it already been tied in the yeast to calorie restriction (inaudible), we did similar studies as we do with RPD3 where we, well we actually do two things. One is we took a normal animal and we showed that when you calorie restricted it extended its lifespan. And then we knocked out or we took an animal that had a mutation in SIR2 that prevented it from increasing SIR2 levels and we asked, can that animal, when calorie restricted, still respond by extending lifespan? And it cannot. So it seems as though when we block the ability of SIR2 to increase, we block the ability of calorie restriction to extend lifespan. Is gene SIR2 the key to aging? TOM BEARDEN: So is SIR2 the key to aging? STEPHEN HELFAND: Well, I know people that would like to believe that certainly there's a number of pieces of data that suggest that SIR2 is one of the central regulators of this process and it actually has a number of features to it that, that would make it an important part of the process. I mean the things we know about, so these, what I'm describing are the actual studies. We changed SIR2, we can change lifespan. We prevent SIR2 from increasing, we can block the lifespan extension. But SIR2 itself does actually have many of the features that you would want of a molecule that, that can sense how the environment is being hit and then, and then based upon that sense, actually react by changing gene regulation, a diversity of genes is the same thing. So, is it a central regulator? Well I don't know. You know I'm not so good at making those sorts of decisions, but I would say that it's a very, it's very likely to be something that we'd be very interested in. TOM BEARDEN: Is it likely to be applicable to human beings? STEPHEN HELFAND: Actually it does seem to be that it's likely going to be applicable to humans and why I say is that the SIR2 gene is present in humans and other mammals and there's actually more SIR2-like genes, so you have to figure out which one is the one you really want, but the reason why it is likely to be applicable or, or data that's (inaudible) applicable is that other individuals at the same time we were doing our studies on the fly to see whether SIR2 is involved in lifespan extension and whether it worked through caloric restriction, other groups were looking at molecules that affect the activity of SIR2. So a couple of years ago, David Sinclair's lab at Harvard went in and examined are there small molecules which eventually could be used, used as drugs that effect the activity of SIR2 and about a year and a half ago or so, he published that in fact there are a group of small molecules that activate SIR2's desatilase activity, the activity that we think is important in this process. And one of those is, is a molecule that I usually mispronounce so I will call it resveratrol which is a small plant polyphenol present in red wine among other things. ... And this molecule which some people think may be responsible for what's called the French paradox where the French don't necessarily eat the best of diets, but they have enough red wine around to offset that and make up for it. Anyway, this small molecule, he found activates SIR2 in both human SIR2 and also in yeast and went to show that resveratrol ... can extend the lifespan as it's measured in yeast. So this past summer in collaboration with David and with Mark Kator at Brown, (inaudible), Regina and I went and studied does resveratrol affect the worm lifespan, the roundworm C. elegans' lifespan and in our case the fly. And in all three cases so far, yeast, worm and flies, resveratrol when fed to the animals extends the lifespan of the animals, a modest 20, 25 percent and more importantly maybe, or we demonstrated that clearly in the fly, and I believe also in the worm, that lifespan extension is dependent upon SIR2's activity. So by removing SIR2 we block resveratrol's extension of lifespan. TOM BEARDEN: So are we talking about treatment for aging here potentially? And if so, when? STEPHEN HELFAND: We're talking about moving aging from a field where there is anti-aging phenomena that's not based on any rationale or I should say any good rationale basis. I mean yes, oxidation is something that's important and yes it's probably true that oxidation and aging go in hand and hand, and it may even be true that oxidation drives the process of aging, but in the many, many years that people have tried to use anti-oxidants to effect the process of aging, it has failed for the most part. So, we are in fact seeing what you already specifically said, the idea that by understanding at least part of this ancient pathway of calorie restriction and understanding what are the biochemical and the molecular mediators of transforming a decrease in calorie content to an extension of lifespan, by having those players along the way available to us, we should be able to come together and develop a rationale, therapeutic approach. As opposed to this being a completely pie in the sky many, many years away idea, yes I suppose that I would have to say based upon our work that in fact, we are moving either slowly or lurching towards reasonable intervention. As we talked about earlier perhaps is that it's hard to know how to study that in humans because of the length of the lifespan. And we need to develop ways of looking at that. TOM BEARDEN: Are we talking, not only about -- maybe delay's the wrong word -- maybe making people, allow them to be healthier longer? Are we also talking about a significant longer lifespan itself if the projections that might be made do come true? STEPHEN HELFAND: Yeah, I think we're talking about both. Yes, so if we're talking, so there's two things about this survivorship curve that I talked about before is there's a particular shape to it. And many years ago, Fry explained that what we're doing in the United States and through both sanitation and good medical practices, what they call rectangularizing the curve, everybody's healthier, but the point at which they're going to die is still the same, that there's this idea of a species specific lifespan that you can't really get past. And in normal terms what a species specific lifespan means is that your dog only lives about 15, 20 years. It doesn't live 100 years. That idea is based upon two things. One, the observation that your dog doesn't in fact live 100 years. But the scientific underpinning, at least as far as I see it, was based upon the measurement of survivorship data and taking survivorship data and the next derivative which is mortality rates. So by determining how people, how organisms die over time, you can determine whether the chances of you dying in the next interval is something that's going to increase or not. And Benjamin (inaudible) back in 1825 who was an actuary, getting back to why life insurance companies are interested in this, in fact developed this idea which he called the law of mortality. If he looked at humans, which is what he was looking at, and he measured the rate at which you died as you got older, it increased in an exponential rate. So, the idea being, and many people have looked since 1825, it's actually called Gompret's law or Gompret's curve, at many different organisms and many, or all of them up until quite recently were all thought to obey the Gompret's law in which then you could think mathematically speaking at least that since it's an exponential curve there's going to be some point where you hit 1.0 and nobody should make it past that and therefore maybe you can't live longer, unless of course you change the (inaudible) curve which you could do. But a couple years ago, a group led by James Lapell, at the (inaudible) Institute in Germany and Denmark demonstrated in fact that the Gompret's law is not entirely correct. That in the elder, or in the older there is in fact a mortality deceleration. So in humans it doesn't occur until about 80 years which is why we may have missed it. And in fruit flies it occurs a lot earlier. ... Back in the '90s, Jim Bopell led a group when he sat at (inaudible) Institute a group that quite international including people in the United States, Jim Kerry, Jim Kritsinger, demonstrated that, first in med flies that as they get older, there reaches a point where their mortality curve, instead of just constantly increasing in an exponential manner, actually kind of plateaus and actually they feel, actually they turn down. So what that means, the reason we didn't see that before in human terms is that in humans it doesn't seem to begin to plateau until about 80 years of age and you need a large number of individuals to demographically demonstrate this, but with med flies and with tresopholine and the roundworms, you can get a large population and you can see this plateau. The idea that Gomperts and exponential rates lead you to have a species specific lifespan may now be not entirely true which steps back to the question of in fact can you extend the lifespan, not just extend the healthy portion of the lifespan. And there's a bit of a debate on this, but the data actually suggests that, and have been published, that in fact just like with the patent office in feeling like we'll never have another invention heretofore, almost anytime some has said we've reached the maximum human lifespan, it's been surpassed within five years And due to communications, some of the earliest times that that claim has been made, it was surpassed before it was even said but the people didn't know about it. So, if you do look, and I'm not an expert in this field, in demography and population and census, the centenarian group is growing at a very high rate in developing countries. So the idea that you could extend the healthy portion of a lifespan and also the maximal lifespan I think is entirely possible. In fact, that's what's extended in calorie restricted mice and rats. They, they extend both their health and the actual longevity itself. Potential impacts of longer, healthier living TOM BEARDEN: I know it's not your field, but have you given much thought to the potential sociological implications of a much longer life population, a much healthier population? STEPHEN HELFAND: It's not my field, but yes I have. I mean, we are often asked that question. Now I, a couple of different thoughts on that. One from a sort of maybe practical perspective, if the population lives longer it's like, so the question is, will we bankrupt Social Security in the practical sense. Well, people will work longer. Many of these, maybe people don't want to hear that, but people will be healthier and longer, so many things will scale out so that the period in which you can be happy and healthy and working will be longer so you can be productive for longer. I think there actually, from a philosophical perspective, there could be some real benefits to that and, not just philosophical, but for a real benefits and this is getting a little bit off the focus here now, but I've kind of been impressed in my life that as people get older they do change their feelings about a lot of things. They temper a lot of the passions that they may have had earlier, both positive ones and negative ones. And I believe that occurs through experience and you can't provide experience to a baby. I mean they have to have it. So maybe if we have an older population that has had some of these experiences, maybe what we'll have is more wisdom that we have now. I mean that instead of it just being older people, we'll have older people with more wisdom and that'll help. The other thing is that as in all things, when we're still developing them, we're not sure what we're going to make of them. I mean, and that is up to society to do and not really up to the scientists at all. I don't think that's just a cop out, I mean it's just the fact that what scientists think they're developing and how they like to see it be used is not often the case of how it is used. I mean politics and economics usually drive what's going to happen. The other part is that if the example of mature populations in any case, that as people can be more stable, know that they can live longer, know that their children are not going to die in infancy, they begin to have less children. Maybe we'll end up stabilizing everything so that it's not like people will continue to have hundred, you know 10 children and all, everyone's going to live longer. Maybe we'll scale everything down in some proportional way. I suspect that we will. TOM BEARDEN: If the ancient defense mechanism in the flies cause this organism to have children later in life because that's the point of let's not reproduce right now, would the same thing happen in humans or is it too early for that now? STEPHEN HELFAND: Would it still happen in humans? Well, if what we're saying is that we're just changing the proportions of a period of time so that menopause would presumably happen much later, meaning in average, so yes. You would expect that you could have children later. But it might not feel later cause you might feel younger. It's sort of like the Star Trek episodes where you know it depends on the speed at which you're living, you know, just those parallel universes where everyone's living in microseconds you just hear them as a fly in the ear, but for them it's a full lifespan, so it may not be much of a problem I think. We'll adapt. There'll certainly be growing pains and bumps I suspect. But this catastrophe that we're going to overpopulate the world with the elderly, it's extremely unlikely to be the outcome of what would happen. TOM BEARDEN: How long before a viable treatment might be available? STEPHEN HELFAND: Yeah I don't even begin to think about that but you know viable, one could say right now, but the point is how do we know? Because the ability to know whether that particular intervention will in fact have an effect, unfortunately due to the process of aging itself will take a hundred years unless we can come up with some reasonable way of looking at physiological age in a short period of time to demonstrate whether we've actually slowed it or not. = end = |
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