A conversation with the director of MIT’s Glenn Laboratory for the Science of Aging

Question: What attracted you to biology?

Leonard Guarente: I was actually more inclined towards chemistry, maybe mathematics, than biology. In fact, in high school I never studied biology at all because I found it much too soft as a science. Then it was characterization of taxonomy and species and phyla and stuff that I found totally boring. But in college, at MIT, when I was a freshman I was planning to major in possibly chemistry, but I learned that there was this new thing called molecular biology that was just emerging, and it was very exciting. So I decided to try it out. And I ended up majoring in biology while taking a lot of chemistry courses. And I think it was probably a very good decision, because I think the life sciences really have blossomed tremendously in the past 10, 20, 30 years, and this is really the golden age now for biology.

Question: What made you want to specialize in aging?

Leonard Guarente: That came a little bit later. So I had been on the faculty at MIT for about six, seven years. I had tenure, and it gave me an opportunity to think about doing something a little bit risky, sort of high-risk, high-reward. And I spent several years thinking what are some problems out there in biology now that would fit into that category? And I thought about a lot of things, including learning and memory. And I thought aging was interesting because obviously it's extremely important. And it wasn't being studied systematically. It was being studied from the point of view of comparing old and young, and mainly in the medical community. But in terms of the aging process itself, and moreover what might control the aging process, there wasn't very much known. There was a little bit known, but not much. So it looked like a perfect opportunity, but one that had considerable risk.

What made me decide to actually get into it is, it turned out -- so my lab was at that point studying the organism yeast, and I was a yeast biologist. And we had studied various aspects of cell and molecular biology in yeast, and that's really what gained me tenure at MIT. And it turned out that yeast cells get old; they age. So this was for me a perfect entry point to the problem. We could begin by studying how yeast cells get old, and that's what we did.

Question: So you studied yeast?

Leonard Guarente: We started bashing away at this problem in yeast with the idea that we could find genes, single genes, that could confer extra longevity to yeast cells that are dividing. So when yeast cells divide -- this is baker's yeast that I'm talking about, the kind of yeast you would use to make bread or wine or spirits -- and it turns out they're a very, very good system to study in the laboratory to look at cell biology. Now, when these cells divide, what you get -- interestingly, of course, you get two cells from one cell, but they're different. One is called the mother cell, and it's big; and the other is called the daughter cell, and it's small. And it turns out the daughter cell is all newly synthesized; all the material in the daughter is new. But the mother cell retains the old stuff. So that mother cell will then give another daughter and another daughter, and every generation it will be getting older. And it does that about 20 times, and then it hits the wall, and senesces, okay?

So it really -- there really was aging, albeit in a very baroque system. So we thought we would be able to make some headway potentially in identifying at least what controls this process in this exotic system. And that's really what intrigued me. I had at that point no plan to study aging more generally than yeast. That came as we got deeper and deeper into the problem.

Question: Are there trends in your field that concern you?

Leonard Guarente: Well, I think the problem -- yes -- I think the problem with this field, and what has bedeviled this field over the years, is false claims. And there are all kinds of things that have been claimed about ways you can slow down or stop aging. And what I would say they have in common is that, you know, until -- anything that was claimed that's not based on very recent science is not true; it's baloney. And so I wouldn't believe any claim of an anti-aging procedure, and would really look at claims that are grounded in current science, because I think the science of aging has really only taken off in the past decade and has reached a level of quality that you can trust it, and that it would lead to interventions that would actually work. That's only happened recently. So the thing to look at in any claim -- like this vitamin or that treatment or that bath, whatever it may be, or cream -- is, is it based on the recent science of aging or not? And if it's not, I would tend not to believe it. Even if it is, I would look at whether it's based on good science or not. But there is some good science now in the area of aging.

Question: Do you agree with Aubrey de Grey that people may soon be able to live forever?

Leonard Guarente: No. No, I think that what they're saying is -- it's a good example, I think, of something that's not based on recent science in the field of aging. And so, you know, I don't think that there's any reason to believe that it's true. I mean, it may turn out that it true. I mean, his basic idea is, we're going to make incremental discoveries in aging that will make us live a little bit longer and give us a little bit more time to make the next discovery, which will make us live still longer, and then we'll make more discoveries, and so on and so on and so on and so on. And you know, that would be great, but that's certainly not scientific thinking, and that's not based on current science. So I think that we're talking about -- if you look at all the genetic interventions that have been described -- and we should really get into discussing some of that in a few minutes -- and all the dietary interventions that have been described that promote longevity, what you're looking at is something like 50 percent as a maximum extension, I would think.

So it's nothing to sneeze at, and it's, we think, accompanied by an increase in the number of years we stay healthy. And if we can tap into that and even develop it so that we get some of the benefit -- let's say 10 years of healthier living. So instead of having to retire and stop functioning at a high level at age 70 or 75, you push that back now 10 years -- I think that's a major change in our society.

Question: Can you define the aging process for humans?

Leonard Guarente: Aging process -- you can describe it statistically in terms of mortality curves, and what that means is that the probability of dying increases with your age. And the reason is that there's a degenerative process that's occurring in cells and tissues that makes you increasingly less robust as you get older, and opens up the doors to diseases of aging, the major diseases -- diabetes, Alzheimer's disease, cancer, cardiovascular disease, osteoporosis -- and eventually will kill you. So it's a very pervasive process that has many, many things going wrong all at the same time.

Question: What have been the key breakthroughs in the last decade in understanding aging?

Leonard Guarente: Well, you're talking to somebody who is not unbiased in this area. And you know, I think the sirtuins have really been, to my mind, the completely unexpected new thing to come along. Now, this came from the studies in yeast that I described a few minutes ago, where we were looking for anti-aging genes. And after about nine years of doing this , the first nine years -- we started working in this area about 19 years ago -- the first nine years were spent in yeast, trying to find the right gene. And we came upon a gene called SIR2. And the SIR2 gene was an anti-aging gene. And what I mean by that is, when you made it more active, the cells lived longer; they divided more times. When you made it less active, they lived less long. So this looked like a really interesting gene, and it was the only gene that we came across that did this. And so we thought it was interesting.

Then we carried out a similar kind of study in a different organism that people study in the lab, the roundworm, C. elegans, and again we're looking: are there any genes in the genome of C. elegans that are anti-aging genes? And we got the same gene; we got a gene that had the same sequence, similar sequence, as the yeast SIR2. So that's an amazing finding, because what it means is, if the SIR2 gene is counteracting aging in yeast and in worms that it's doing that universally. And that would include mammals, and it would include us. So it really right away speaks to a universality of this process. So I think that's one thing that's highly significant about this, is that the gene is conserved, and we think its effect on the aging process is conserved.

Now, the piece of this that makes it, I think, particularly exciting is, you say, well, okay, there's this gene that makes you live longer if it's more active. Why should that be? What does this gene actually do? Okay? And what we know is, genes, of course, are the blueprint to specify proteins, and the SIR2 genes encode particular proteins. The proteins are called sirtuins, okay? And we were really, really eager to find out what the sirtuins actually did in cells. And just almost exactly 10 years ago, a little bit more than 10 years ago, we discovered it. And they have an enzymatic activity in cells that enables them to modify other proteins in cells. And that can really change the metabolism, the physiology, of a cell and then by extension, of entire tissues and an entire organism. But the critical thing about this activity is that it was completely coupled to this small metabolic molecule in cells called NAD. No NAD, sirtuins are dead, okay? So NAD links sirtuins to diet and metabolism, because diet and metabolism affect the availability of NAD in cells.

So we came up with a hypothesis 10 years ago, when we discovered this activity, that sirtuins might really be the link between how diet affects how long you live and how diet affects your predisposition to diseases. And this was a, I think, radical idea. I think there are a lot of people out there still critical, don't believe it. But I think the data is mounting, in mice particularly, that says that this may actually be true. And so the idea would be that on a low-calorie diet, a diet that's been termed calorie restriction, we know that rodents live longer, and they resist diseases. They're disease-free under this diet. And we suggest that the reason for that, at least one of the reasons, one of the main reasons, is that this low-calorie diet activates sirtuins via this molecule NAD, and that the more active sirtuins then promote better survival and better ability to ward off diseases. So that's a very simple hypothesis that came from identifying this activity that I mentioned. That's one.

The second thing that came out of that is, once you have an understanding of what a protein does -- and you can actually measure that in a test tube now that just has that protein and, in this case, NAD -- it enables you to screen for drugs, for small molecules that can enhance that activity, and an open door for looking for small molecules that could up-regulate the activity of sirtuins. And that's led to sort of a flood of interest, I think probably the part of the story that's gotten the greatest notice in the press. So the first screens that were done identified a molecule found in red wine called resveratrol that's of a class of compounds that plants make in response to stress -- they're called polyphenols -- and these compounds could activate a sirtuin in a test tube, and they also could make cells live longer, yeast cells, and could make worms live longer. So the remarkable thing seemed to be that not only are sirtuins able to do this, but we might actually be able to influence their activity from outside with drugs.

And that really is, I think, where the excitement began and is still building, because I think that this is still not completely appreciated yet. So that was -- these are natural products, the resveratrol and the polyphenols, the things that are found in wine. But a company was started by David Sinclair and Kristoff Westfall called Sirtris about six years ago to try and look for new kinds of molecules now that are not natural products -- they're not found in nature -- by screening through libraries of different chemical compounds that have been synthesized. And there are new kinds of activators now of sirtuins, new chemicals, that can activate them much more potently than resveratrol. And it's going to be extremely exciting to test these molecules and see what they'll do.

So so far what we know is, both resveratrol and some of these new compounds have beneficial effects in mice. And what they do in mice -- they've been tested against various diseases. So what we would expect is, if these molecules are really activating sirtuins and can protect against diseases of aging, then we should be able to demonstrate that in a mouse. So it turns out if you feed a mouse basically a bad diet, the opposite of a calorie-restricted diet, so a diet high in fat, high in calories, the mice get diabetes, okay? Now it turns out these molecules, resveratrol and the newer compounds that activate the sirtuins, they can protect the mouse against diabetes. So the mouse will still eat a lot; the mouse will still even get fat, okay, but will stay metabolically healthy. So that's a pretty good demonstration that this idea is not so far out, but that there really is an opportunity here to use drugs to keep metabolism strong and intact in the face of caloric excess, okay?

But even more importantly for many of us like myself, who already -- I don't calorie restrict, but I don't eat to excess either, so I'm in good shape -- but even someone like myself would be able to get benefit from these molecules by activating sirtuins in addition to the benefit that I'm already getting by keeping myself in good shape. So I think it's a very promising area of research. And this company, this small company called Sirtris, was bought by one of the giants in the pharmaceutical industry, GSK, for something like three-quarters of a billion dollars a year ago. So obviously there's at least some validation in big pharma that these ideas are realistic and will be brought to fruition.

Question: What is the next frontier in understanding aging?

Leonard Guarente: Well, I think -- well, you know, my lab work's really on sirtuins, and I think there's so much to be done. So what we know now is just the tip of the iceberg about sirtuins. So first of all, there are seven of them in people, okay, and so far most of the studies have been focused on just one of those seven. Second of all, there are many tissues that have to be studied so we know what the sirtuins are doing in each and every tissue, so that we know what the effects of the drug are going to be, tissue by tissue. And that's going to take a long time, so we're deeply involved in that. The third thing is, will these sirtuins really protect against many diseases, or will they just protect against metabolic diseases like diabetes? So my lab is really focused now on nerve degenerative diseases, and we're testing the effect of activating the major human sirtuin, which is called SIRT1 -- it's also been called the survival gene -- and we're interested in what if we activate this in the brain? Will it protect the mouse against Alzheimer's disease, against Parkinson's disease, against Huntington's disease? And I think these are extremely important questions because they'll define the scope of what we're able to think about here and what we can start to attack pharmacologically.

Question: Have there been any studies on humans when it comes to calorie-restricted diets?

Leonard Guarente: Yes, there's a center in Louisiana called the Pennington Center that has been doing such studies. It's been a long time since there's been good data on humans on calorie restriction, and part of the problem has been that humans tend to cheat on the diet, so controlled studies end up not being so controlled. But recently there have been six-month studies done, and what you can do in six months -- you can't ask if it's making people live longer; you can't even ask if it's protecting them against diseases -- but you can ask if it's eliciting the kinds of physiological changes that you expect in calorie restriction, which would be a loss of body fat, a lowering of blood glucose, so anti-diabetic effect, a rendering of sensitivity to insulin, the action of insulin -- these can all be measured. And six months on calorie restriction in humans does roughly the same thing that it does in mice.

Now, just one footnote on one of those studies: so in rodents what we knew is that some of these sirtuin activators could activate muscle to process glucose better. And it was doing that at least in part by activating the synthesis of mitochondria. These are organelles in cells -- it's called the powerhouses of cells -- that make energy for cells. And by activating mitochondria you sort of drive metabolism, and you drive the uptake of glucose from the blood into the muscle in the processing of glucose. So it's a good thing; it's an anti-diabetic thing. And this process can be driven by SIRT1, the survival gene, in muscle in rodents. Now, it was done first with resveratrol, but it turns out calorie restriction in rodents does the same thing. You activate the synthesis of mitochondria in muscle, okay, and that makes them more metabolically active, and it's a good thing metabolically, okay?

Now, to get back to the humans, what they were able to show in this trial is, they took punch biopsies of muscle from the people that were on the calorie restriction diet for six months, and what they found in their muscles was an increase in mitochondria and an increase in the levels of the SIRT1 protein; the protein was actually increased in the muscle in response to calorie restriction. So that says that the congruence between mice and humans may be quite profound with regard to calorie restriction. So we can't say any -- there's no direct evidence in humans about diseases; certainly not about lifespan. But at least basic physiology looks like it might be similar in humans, so that might make a good prediction about the effects of calorie restriction, but nobody want to practice calorie restriction because it's so unpleasant. And so what everybody would like is a mimetic, a drug that would elicit at least some of the benefits of calorie restriction.

Question: What are the five worst things people can do in terms of aging?

Leonard Guarente: Well, I would say smoking would be one. Eating to caloric excess would be another. Being sedentary, not moving around, not exercising would be a third. We didn't talk about exercise, but there's ample evidence that exercise is beneficial. I think the other thing is what we were just talking about: your attitude and mindset. I think, you know, being focused on negativity would be a fourth. And I think the last one, which again would be more or less in this lifestyle area, would be stress level, level of stress that you maintain on a day-to-day basis. So I believe, and others believe, in something called hormesis. What hormesis means is that a lot of stress is a bad thing, but no stress is also a bad thing. And the optimum is something in the middle, so that you're engaged on a daily basis, you're revved up, you're functioning, okay, but you feel as though you're in control. And I think finding that balance, that hormesis, is probably very important in maintaining mental health and physical health. So that would be my big five.

 Well, I mean I think a low-calorie diet is probably a good thing. I think in humans we don't know; there's no data on what a low-calorie diet does in terms of diseases and longevity, as I said before. By analogy to rodents, you would think it would be a good thing. On the other hand, if it made you really miserable to eat 1,000 calories a day -- and people who are on that diet tend to be cold; they tend to have very low sex drive; they tend to in some cases be irritable -- and so if you're not happy, then that gets back to what we were saying earlier. You may be undoing some of the good that that diet would otherwise produce. So my feeling is to live sensibly.

I mean, a word of advice that I think is good -- it's hard to follow -- but I think what everybody should do, if everybody could do this, it's the best you can do right now -- is decide what is your perfect weight, body weight. What's perfect for you? And I think what most people do is rifle through the past and decide on when they were most happy with themselves -- and do everything possible to get to that weight and keep to it. And I think that that would necessarily make you healthier, most people healthier than they are now. Beyond that, I, you know, I take a vitamin supplement, a general supplement. I take Vitamin D. I do not take resveratrol, though a lot of people do. And the reason is, I'm waiting for a 100 percent pure and reliable source of it, and then I will take it. And I drink a little wine, and all the data says, again, there's an optimum. I think the data says that too much wine is bad, but no wine is not optimum. The right amount of wine is optimum.

Question: What do you find frustrating in your field?

Leonard Guarente: I think that at least for the aging field, one disappointment I would say that I've had is that aging is fundamental to so many diseases, yet I really think it's underfunded in terms of an approach to treating these diseases. And to give you an example, I think the past 10 to 20 years has been an amazing time in the field of aging. But the fraction of the NIH budget that goes to research on aging hasn't changed over that period. And to me that's disappointing, because I think that this is one leverage point to really improve human health.

Question: What type of research is over-funded?

Leonard Guarente: I'm not sure anything is overfunded, to be perfectly honest. You know, I think at least most major areas of research that I know of are meritorious. And you know, if you review grants, usually the number of grants you see that are worthy of funding far exceeds the number that actually get funded. So you know, I'm not saying -- I realize it's ultimately a zero-sum game, but I do think that aging in particular probably is a little bit underfunded now.

Question: Which countries are best at encouraging medical innovation?

Leonard Guarente: The U.S. has always been the best country in terms of encouraging innovation. And I think, you know, the rise of the NIH and the granting system after World War II to now is a really good example of that. And I know when I was a young scientist, you know, people would apply for grants, and they weren't so hard to get. The fraction funded maybe was 25 percent, something like that, and so that you could propose things that were a little bit out of the box and have a chance of getting funded to do it, which encourages innovation. I think now, once things become so tight, and instead of 25 percent you have 10 percent of grants funded, then I think, you know, any grant that seems the least bit risk is not going to be funded. And I think you tend to encourage sort of precise, calculated science at the expense of creative science. So historically this country has been the best. I think -- I'm a little concerned now that that might be trailing off, although I can't offhand tell you that it's better any other place.

Question: Who are your heroes?

Leonard Guarente: I think one hero I would mention is Galileo. The reason for that, and the reason I think at least to my mind he's the greatest scientist, is the way we do science now is to actually have ideas that we can test with experiments. And it's -- this is called the scientific method, so critical to making science more than philosophy. And I think in earlier civilizations -- the Greeks, the Romans -- the greatest minds, the philosophers, they just sort of intuited things. You know, here's the way things must be. And of course that's a recipe for making a lot of mistakes and for having a false impression of the world. And what Galileo did was to say, okay, I have an idea, but I think the way to go is to do experiments and to test the ideas. And that, I think, is the bedrock upon which modern science is built. Also I mean he took a lot of heat for what he did in his lifetime from the Catholic Church, and he was operating under pretty extreme circumstances. And given those circumstances, I think he performed pretty darn well

Question: What is an ethical dilemma you've faced in your profession?

Leonard Guarente: I think one dilemma you always have is, our profession really depends on our being able to publish our work in peer-review journals, so what gets published has really been gone over with a fine-tooth comb. And so we review each other's papers. And you have to decide when you have a conflict of interest or not, and if someone's work is too close to yours -- they're a competitor -- I think you have to stay away from it because there's an obvious conflict of interest. A little bit less obvious if you have people whose papers -- who wrote the papers -- are from your lab, they're former post-docs or students. I think that's also a conflict of interest. And I think it's a -- there are gray areas, work that's sort of close to your work, but I mean where do you draw the line when it's okay to review someone else's work, be it a paper or a grant, and when is it not? And when is self-interest creeping in? And you know, I think it's very important that the peer review process -- as it's the best thing we have -- that it be as pure as possible. It's never going to be perfect, but I think it's worth thinking about, and it poses dilemmas on a regular basis.

Recorded on November 9, 2009