Aging

AGING

PBS Airdate: January 9, 2007

NEIL DEGRASSE TYSON: Hello, I'm Neil DeGrasse Tyson, your host for NOVA scienceNOW.

First up: at one time or another, each of us wonders, "How long will I live? Seventy, 80, 90 years?"

The average American lifespan is now about 78 years, but a few people live much longer, 100 years or more. They don't seem to age like the rest of us.

Correspondent Chad Cohen met up with a few of them and the scientists who are trying to sort out why.

MAN # 2: We don't feel old. We feel young.

WOMAN # 5: We don't feel old.

CHAD COHEN (Correspondent): There aren't many of them out there.

WOMAN # 1: I'm 96.

MAN # 1 : ...ninety-seven.

WOMAN # 2: ...ninety-eight.

CHAD COHEN: How old are you?

MAN # 2: A hundred, one.

CHAD COHEN: Only one in 10,000 of us, in fact, will defy all the odds and live the long, healthy lives that these folks have. What's the secret?

WOMAN # 3: I really don't have any clue.

WOMAN # 4: I don't have a secret.

MAN # 2: You'll have to ask upstairs.

CHAD COHEN: Well, down here, biologists are having a go, studying every aspect of these long-lived people to see if their elixir of life might be available to the rest of us.

MAN # 2: Let's hope!

CHAD COHEN: Nir Barzilai, of the Albert Einstein College of Medicine, in Bronx, New York, has worked with this genetically distinct population of Ashkenazi Jews for the last eight years, wondering, "What do they have that the rest of us don't?"

NIR BARZILAI: They are born in the early 1900s; many children are dying in epidemics of childhood diseases. So they survive already that. And then they get to middle age and there are all the middle ages diseases. There is the cancer, and the cardiovascular, and they don't get touched by that. And then they have to survive getting to 100. It's an incredible journey against odds.

WOMAN # 3: It wasn't really milk and honey, my life, but here I am.

CHAD COHEN: But none of them have exactly been following doctor's orders.

NIR BARZILAI: I would say the opposite.

WOMAN # 3: ...every day, French fries.

WOMAN # 1: ...roast beef.

MAN # 1: You can drink, but no mixed drinks, just Scotch.

NIR BARZILAI: There is no yogurt eater, there is no vegetarian.

CHAD COHEN: Forty-six years of cigarette smoking?

MAN # 2: Yah.

CHAD COHEN: And you still 101 years old?

MAN # 2: I'm still one-hundred-one-and-a-half years old.

NIR BARZILAI: All the things that we tell our patients to do, they didn't do, and it didn't bother them, they got there anyhow.

CHAD COHEN: Do you feel lucky that you've lived as long as you have?

WOMAN # 3: Of course.

CHAD COHEN: They did have help though, as Barzilai discovered.

NIR BARZILAI: There is an unusual history of longevity in their family.

WOMAN # 2: The youngest sister of my father was 98, and my mother was 92.

MAN # 1: I still have an aunt, my mother's side of the family who's alive; she's a hundred and one.

WOMAN # 4: This is a picture of my husband and this huge kiss. After that we got married.

CHAD COHEN: Something very special was protecting them from the environment and their own excesses.

WOMAN # 4: We have good genes. We owe it all to our mother and father.

CHAD COHEN: And when the team peered into their blood, it became clear what it was.

NIR BARZILAI: The initial thing that was striking is that many, many people in the study had very high HDL cholesterol. HDL cholesterol is the good cholesterol.

CHAD COHEN: Good because it cleans up the bad cholesterol by schlepping the bad cholesterol away, so, the more the merrier.

But something else was going on with the HDL cholesterol. We saw that they were amazingly large at our...with our centenarians.

It seems the bigger the HDL, the better. Perhaps because bigger HDL hauls away more bad stuff than smaller HDL does. Sixty percent of the centenarians had these larger HDLs.

NIR BARZILAI: So this became a major marker of exceptional longevity and also directed us to several of the genes that we tested.

CHAD COHEN: Barzilai smeared our centenarians' DNA onto chips loaded with cholesterol genes.

NIR BARZILAI: This chip contains 500,000 variations that humans can have on their DNA.

CHAD COHEN: Barzilai found that three particular mutations in three different genes distinguished many of their DNA from the general population. And all those changes play a role in making HDL bigger and protecting against age-related disorders like diabetes and cardiovascular disease.

NIR BARZILAI: So then we feel more comfortable in saying, "You know what? This is a longevity gene."

CHAD COHEN: The idea of a small number of longevity genes flies in the face of scientific wisdom, which has long held that aging involves hundreds, even thousands of genes all running amok. But that's never sat well with MIT's Leonard Guarente, thanks to one bizarre, but confirmed, finding.

Cut just about any organism's food supply by 30 to 40 percent, and it will live up to 50 to 60 percent longer.

LEONARD GUARENTE (Massachusetts Institute of Technology): If aging is complicated, multi-factorial, so on and so forth, how could a simple dietary change make an organism live longer?

CHAD COHEN: To find out, Guarente started simply, with a simple organism: baker's yeast, the stuff of beer and bread. In their brief lifespan —about two weeks—yeast cells typically divide a total of 20 times. Every once in a while though, a yeast lives longer than that, dividing, say, 25 or 30 times. Those are what Guarente looked for, the yeast equivalent of our centenarians.

Well, it took them about eight years, but Guarente's group finally found that these long-lived yeast also have life-extending mutations in their DNA in a specific family of genes, called "sirtuins." Yep, genes have names too.

Delete the most powerful of these genes, called "SIR2," from a yeast cell and it will die earlier. Add extra copies back in and it will live up to 50 percent longer.

LEONARD GUARENTE: Okay, we know this is important for countering aging, but what does the gene do?

CHAD COHEN: Ah, well sirtuins, as the scientists soon discovered, are part of an intricate stress response. When times are tough, they kick an organism into survival mode to beef up DNA repair or stop cells from dying. And it turns out, nothing sets these sirtuins into action like a shortage of food.

LEONARD GUARENTE: And that's why our finding with SIR2, I thought, was an epiphany, because it gave a possible explanation for how a reduction in calories in the diet could be equated with a long life.

CHAD COHEN: People have sirtuin genes too, although we don't know how important they are yet. But the more these scientists experiment in yeast, and then in worms and flies, the more they realize how vital this calorie-sirtuin connection is.

David Sinclair, once a post-doc in Guarente's lab, now runs his own at Harvard Medical School.

DAVID SINCLAIR: What my lab and others have found is that when you get rid of the SIR2 gene, the diet doesn't work anymore.

CHAD COHEN: So put them on a calorie-restricted diet, they live longer. Take away this gene, put them on the same diet, they don't live longer?

DAVID SINCLAIR: Exactly.

CHAD COHEN: Amazing as that sounds, sirtuins aren't the only genes that do this.

For more than a decade, Cynthia Kenyon of the University of California, San Francisco, has been making these microscopic worms, called "C. elegans" live far longer than believed wormly possible.

CYNTHIA KENYON (University of California, San Francisco): You just change one gene and the whole animal is fine, it's incredible.

CHAD COHEN: By damaging a single gene, this one's called daf-2, these worms live twice as long. Daf-2 helps makes insulin work. When it's mutated, you get less insulin, and that brings us back to calorie restriction because it has the same effect.

CYNTHIA KENYON: You limit food intake, that leads to a decrease in the level of insulin, so that should lead to life span extension.

CHAD COHEN: It turns out, low insulin levels kick on survival genes too, just like the sirtuins. So by damaging daf-2, the wormly life is longer.

CYNTHIA KENYON: You can see why they call it elegans—they're very beautiful.

CHAD COHEN: These squiggly squirmy guys are about four days old. But in two weeks...

CYNTHIA KENYON: They look terrible. They're in the nursing home. They look like they're falling apart. Their heads are moving, barely, but that's it. And now, prepare yourself for something amazing. This is the mutant worm. We changed just one gene, the daf-2 gene, at that same age, and you can see it's moving around. It looks great. It's equivalent to looking at someone that's 90 and thinking that they're 45.

CHAD COHEN: And the best part, when the equivalent genes were tweaked in flies and then in mice, their healthful properties were also preserved.

CYNTHIA KENYON: These long-lived animals are resistant to a whole range of age-related diseases. The worms have muscle deterioration that happens later. The fruit flies are more resistant to heart failure. The mice are more resistant to cancer. This is a whole new way of thinking about disease, a whole new way.

CHAD COHEN: But hold on a minute. If all of this research is so tied to cutting calories how do we explain these guys?

WOMAN # 1: I always had breakfast; I always had lunch.

MAN # 2: I eat whatever I like, and I do what I like.

DAVID SINCLAIR: It could be that they have different variants of these longevity genes, allowing them to experience the effects of calorie restriction without really having to do the diet.

CHAD COHEN: So what about the rest of us then, who may not be so blessed? Can we live longer by eating less? Well, it's not proven in people yet but the answer, to many scientists, is "probably"—if we eat a lot less, 30 to 40 percent less to be exact, which means the food someone like me might take in a day would shrink from about 2,500 calories to 1,500 calories. Hey, it's no fun, but people do it.

DAVID SINCLAIR: I did try calorie restriction for about a week and gave up. It's not a pleasant way to exist.

CHAD COHEN: Perhaps it was pangs of hunger that lead David Sinclair towards his next venture: finding drugs that offer the benefit of calorie restriction without the drastic diet.

He's off to a good start. Sinclair found that resveratrol, the molecule that has been touted to make red wine healthful, stimulates the sirtuin genes and allows everything from yeast to worms to flies to live 30 to 40 percent longer. And it's looking good for mice.

Barzilai, Guarente and Kenyon are also seeing their gene targets make their way into the pharmaceutical arena.

DAVID SINCLAIR: I'm hoping that, within my lifetime, we'll see the benefits of this research. Being very optimistic, we could see these in the next five to 10 years.

WOMAN # 4: That would be wonderful.

CHAD COHEN: In the meantime, none of the scientists are exactly waiting around for this to happen.

CYNTHIA KENYON: I eat a diet that is predicted to keep my insulin levels lower.

LEONARD GUARENTE: I don't calorie restrict, but I don't gorge myself.

DAVID SINCLAIR: I drink more red wine than I used to.

NIR BARZILAI: My HDL is good, because I'm taking two different drugs to increase that.

CHAD COHEN: Would you recommend living this long to everyone?

MAN # 2: Why not?

MAN # 1: Yes.

WOMAN # 1: Of course.

WOMAN # 2: Yeah. Life is wonderful.

MAN # 2: When I am 110, I want to see you here again.

CHAD COHEN: It's a date.

MAN # 2: You shake hands with me?

CHAD COHEN: I'll shake hands with you. It's a date.

Aging

Edited by

Stephen Mack

Produced and Directed by

Chad Cohen

NOVA scienceNOW

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Longevity Study Participants

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This material is based upon work supported by the National Science Foundation under Grant No. 0229297. Any opinions, findings, and conclusions or recommendations expressed in this material are those of the author(s) and do not necessarily reflect the views of the National Science Foundation.

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Image credit: (hands) © CORBIS

Nir Barzilai

Yeshiva University

Chad Cohen

Correspondent

Leonard Guarente

MIT

Cynthia Kenyon

University of California, San Francisco

David Sinclair

Harvard University www.hms.harvard.edu/dms/bbs/fac/sinclair.html