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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.

Recorded on November 9, 2009

More from the Big Idea for Saturday, November 19 2011

 

Anti-Aging Genes

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