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Extended Interview: Dr. David Sinclair

Scientists have isolated a series of genes found in many different plants and animals that seem to control the aging process. Dr. David Sinclair, associate professor of pathology at Harvard Medical School, talks about how these anti-aging genes work and the prospects of marketable anti-aging drugs.

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  • 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.

  • 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.

  • 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).

  • 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…

  • 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.

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