The DNA Files:
Unraveling the Mysteries of Genetics
As heard on National Public Radio
The Search for the Fountain of Youth
The Genetics of Aging and Longevity
Hosted by John Hockenberry
2991 Shattuck Avenue, Suite 304
Berkeley, California 94705-1872
For further information about genetics and these programs, as well as the producers who brought you this series, visit the project web site at www.dnafiles.org.
Send your questions about genetics and this project to firstname.lastname@example.org.
Funding for this series was made possible by generous grants from The National Science Foundation and the Alfred P. Sloan Foundation.
Last reviewed for accuracy: February 2002.
JOHN HOCKENBERRY: This is The DNA Files. I’m John Hockenberry. As humans, we learn to accept the inevitable facts of life: we’re born, we get old and we die. You could say that life itself is a process of decay. Americans spend billions of dollars each year trying to postpone the inevitable. And increasing numbers of scientists are spending their lives trying to find the key to extend life, cure age-related diseases, even defeat death.
JUDITH CAMPISI: I do not think that we see in our future going into an embryo and mucking around with enough genes to make an impact on life span; look at how long it took evolution and how many genes evolution had to change to acquire that. It’s a big job.
JOHN HOCKENBERRY: The DNA Files journeys to a place we call “De Nial Lounge” to explore research into the genetics of aging and longevity in, “The Search of the Fountain of Youth,” when we return with The DNA Files.
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As the debate over embryonic stem cell research rages in this country, fuelled by moral quandaries and the hope for miracle cures, scientists working with adult stem cells are making quiet progress. It’s too early to tell whether these cells can reverse the ravages of aging, but they may be able to mend a broken heart, as Sheri Quinn reports.
SHERI QUINN: The heart begins its countdown in the womb. It’s simply a pump driven by tiny electrical impulses in each cell, beating in rhythm as it pushes blood through the body. The fetal heart starts out fast; then the rhythm slows into adulthood.
JANET DIX: I used to ride bikes and I love gold-panning and camping. I can’t do none of that anymore. My body feels like it’s 80, but my mind is still young.
SHERI QUINN: Janet Dix’s heart is a ticking time bomb. At 50, she suffers from a heart disorder, a mutation in her genes that’s turning her heart cells into what she calls mush. Disease is just one of the culprits in the aging heart, says Dr. Jeff Anderson, chief of cardiology at the University of Utah.
JEFF ANDERSON: It can age rather abruptly when damage is done to the heart by blockage of the critical blood supply; that’s called a heart attack. Then there is some general aging and loss of heart function over the years, replacement of heart cells by fibrous tissue and scar tissue as part of the aging process.
SHERI QUINN: By age 20, our bodies are losing millions of cells each year. So scientists are scouring every tissue of the body for fresh supplies. They’re looking for adult stem cells that seem to hide in tissue reservoirs like bone marrow. When triggered by chemical signals of trauma, disease or aging, these unspecialized cells can turn themselves into specialized cell types like muscle, skin and heart cells.
University of Utah molecular biologist Shannon Odelberg and his colleagues work with newts, a tiny green salamander with bright orange spots. Newts can regenerate several limbs and organs, including the heart. Odelberg extracts genes he thinks control this regeneration process in newts, and inserts them into the newts damaged heart tissue. He’s looking to see if this causes the heart cells to start dividing.
SHANNON ODELBERG: The approach we are taking is to induce the cells that are already present in the heart or damaged tissue, to lose their specialized properties and to become stem cells and then to re-specialize into the appropriate cell type, all within the body.
SHERI QUINN: Other studies that extract stem cells from rodents and re-inject them into damaged heart tissue have shown the injected cells will specialize and make some repairs. Scientists believe stem cells might respond to stimuli like a sudden decrease in oxygen when a cell dies, or the release of an enzyme in damaged muscle. When the siren of injury goes off, these paramedic cells rush to the scene of damage. Through adhesive molecules they are able to graft onto injured tissue, mature into heart cells and regenerate the tissue. With their sights on the baby boom generation, large biotech firms are pouring millions of dollars into stem cell studies, despite the economic risks.
ANNEMARIE MOSELEY: … this has been a driving force to look at a product which is going to be able to be implemented in an age of healthcare which is going to be designed around a growing aging population.
SHERI QUINN: Dr. Annemarie Moseley, president of Osiris Therapeutics in Baltimore, hopes to market frozen stem cells like drugs in a pharmacy. Researchers here use sound waves to break cells into pieces for analysis. They work with mesenchymal cells, an adult stem cell found in bone marrow. They grow them like patches of grass, and when injected into the region of a heart attack in pigs, will rebuild the heart tissue.
ANNEMARIE MOSELEY: We believe that is possibly because they are involved in the wound healing process where it wouldn’t make sense for the body to be fighting off these cells. What this allows us to do is generate from a single donor, a very large number of cells, which would then be available off the shelf, so to speak.
SHERI QUINN: But it’s not just older people and heart patients that will benefit from tissue engineering. Biomedical engineer Dr. Robert Langer of the Massachusetts Institute of Technology pioneered the technique used to grow new skin for burn victims.
ROBERT LANGER: Tissue engineering will certainly have an effect on young people, if somebody’s burned the ability to make new tissue, for example it will have an enormous impact on their lives. It’s not clear what effect it will have on old people.
SHERI QUINN: No one knows if the regenerative effects will last, or if enough cells can be generated for therapeutic use in humans. Studies with rodents, newts and pigs are mere stepping stones on the long journey to fixing human hearts… and many scientists are now arguing that the potential of adult stem cells has been overplayed, hyped up by opponents of embryonic stem cell research. What seems certain is that as long as heart disease remains the number one killer in the United States, scientists will continue to purse the potential of adult stem cells for heart tissue repair.
For The DNA Files, I’m Sheri Quinn.
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JOHN HOCKENBERRY: Welcome to The DNA Files; I’m John Hockenberry. And I’m getting older just talking to you. You, too, right? Well, then, join me in a search for the genetic keys to longevity and aging. To understand what makes us tick for as long as we do—possibly to find the proverbial fountain of youth. We’ll visit many possible sources for that fountain, real scientists, molecular biologists, geneticists, endocrinologists—in settings both real and imagined. Let’s go!
JOHN HOCKENBERRY: Ah, Florida! Home of Disneyland, Cape Canaveral—ah, Kennedy! And more old folks than anywhere else in the country. No wonder that it’s also the site of the alleged Fountain of Youth.
TOUR GUIDE: Ponce lived from 1460 to 1521, 61 years old was about 15 years past the life expectancy. To strengthen the hope, maybe Ponce made it to 61 having drank from this location.
[water pouring into paper cup]
JOHN HOCKENBERRY: L’chaim! To life! Ahh.
WOMAN: I drank it all down. It tasted of sulphur, but I drank it anyway.
MAN: I would like to live to my prime, and maybe a little bit past that & I think I’d like to keel over.
WOMAN: I think I’ll enjoy this life & look forward to the next.
WOMAN: Originally I wanted to live to be 80 so I could see the year 2000; well, I made that so I don’t have any long-range goals right now.
JOHN HOCKENBERRY: Hello!
CLEOPATRA: Well, hello.
JOHN HOCKENBERRY: Interesting outfit. Gold metal snakes wrapped around your arms and neck. Tiara, with the horns. That’s quite a combo. You’re not from St. Augustine are you? You’re a tourist, like me?
CLEOPATRA: More a citizen of the world—Actually, I thought you might like a guide to these parts. That is, the sagging bagging parts—and to the elixirs and elucidators of aging—fountains and findings of youth like you’ve never seen or heard—sparkling telomeres, super super-flies, romps in the biosphere where bananas are like gold—visions of a future of eternal youth and eternal life—oh, John, come with me.
JOHN HOCKENBERRY: But, tell me, Cleo, that is your name, isn’t it? That’s the name embroidered on your emerald—green, is it really cotton?—bowling shirt.
CLEO: Bowling, hah, my—asp.
JOHN HOCKENBERRY: What’s your story? I mean why were you at the fountain of youth along with me? I know that red hair came from a bottle! Could it be that you, like me, are also searching for the source?
JOHN HOCKENBERRY: Whoa! Ah—what did you put into that fountain?
Where are we? Slot machines shaped like giant helixes—giant roulette wheels with people as the balls—and, yech, there are bugs here! Rotting fruit with flies hovering and piles of compost with worms—and monkeys—what is this, the monkey bar? Mice running over my feet, there are rats! For rodents I could have stayed in New York! Parents warned me about these kind of places.
CLEO: Hey, they were probably here plenty of times themselves—most of us are—
Welcome to De Nial Lounge. I am your hostess, Cleopatra, the, ahem, Queen of Denial.
JOHN HOCKENBERRY: Oh I get it.
CLEO: Do you? The clues, the keys to aging are much more complex than just drinking the waters from some fountain. It’s not so simple, John, it’s not so simple. Look around, see all those escalators? They lead to mazes of rooms wherein people pursue games of chance—with life. Scientists are in all of them.
CALEB FINCH: Ha, ha, there’s all sorts of chance in each of us! And uh, I would take issue with Albert Einstein’s wonderful remark, “God does not play dice with the universe.” Well, I can’t speak to the universe, but dice are rolled for each of us.
CLEO: Ah, there’s Dr. Caleb Finch, an esteemed Professor of Biology and Neurology from the University Of Southern California.
JOHN HOCKENBERRY: That’s the guy with the fiddle with the fuzzy dice hanging from the neck?
CLEO: Mm hmm, the dice of life. Life on a level unseen by the naked eye. Oh, and peek down that corridor—it leads to the philosophers club: scientists poring over statistics and arguing that gambling is useless, our life-spans are not expandable. Then there are a bunch of real gamblers around here—hard-core scientists who bet their whole stake on a gene, a pathway, an enzyme, a worm.
JOHN HOCKENBERRY: Sounds fascinating—but what’s that mean, anyway—aging?
CLEO: Come on John, let’s go to the convergence lounge for an answer. Shall we just, ah, barge in?
JOHN HOCKENBERRY: Why not? What’s this? A certificate on the wall for completing an Italian wine-tasting course?
JUDITH CAMPISI: Oh, yes, red wine. I love wine dearly.
JOHN HOCKENBERRY: Oh, please allow me: a glass of Chianti perhaps?
CLEO: John, Dr. Judith Campisi.
JOHN HOCKENBERRY: Hi.
CLEO: As a senior scientist at the Berkeley Lawrence National laboratory, she’s been investigating the causes of aging for the past 10 years.
JUDITH CAMPISI: We all recognize it. It’s like pornography; we know it when we see it. The boring definition of aging is, aging is some process that converts a young, healthy, fit organism into a less healthy, fit organism.
LEONARD HAYFLICK: Biological aging results from an increase in systemic molecular disorder after reproductive maturation and in animals that reach a fixed size in adulthood.
CLEO: John, this is Dr. Leonard Hayflick, true pioneer in the field of research into aging—one of the touchstones of the field was discovered by and named after him—the Hayflick limit. That states that cells divide only a certain number of times, and then they die.
JOHN HOCKENBERRY: Who’s the guy hanging out with the fruit flies?
CLEO: He’s U.C. Irvine’s Dr. Michael Rose.
JOHN HOCKENBERRY: He’s swatting flies with one hand and scratching some numbers on a dry-erase board with the other! Looks like, for him aging is some kind of mathematical equation.
MICHAEL ROSE: [reading equation] Well, it’s a partial derivative of little r, the mathogean parameter, with respect to long, the natural logarithm of the a-specific probability rate is equal to a scaling function with respect to age gene action divided by the mean generation interval, and that scaling function has the dramatic feature that it stays high and flat, before the start of reproduction, and once reproduction starts it goes down, down, down, down until it hits zero, toward the end of reproduction. And what that says is that natural selection gives up on you as you get older.
JOHN HOCKENBERRY: Oh, Ma Nature just dumps us once we’ve reproduced—so if we make it to old age, we’ve defied the odds, is that it?
MICHAEL ROSE: Well, aging is one of the things that determines longevity. There are many things that determine longevity. Aging is underlying biological process. Your longevity is determined in part by whether your technician crushes your fruit fly by accident.
JOHN HOCKENBERRY: Wow, to never age, to live forever—to be forever young. Cleopatra - you’re immortal, in a way?
CLEO: Well, yes John—I have managed to live forever—in the mind—and, of course, on film.
CLAUDETTE COLBERT as Cleopatra: They must think we’re funny people, scheming to destroy each other, as if we had forever to live.
VOICE from the Elizabeth Taylor version of Cleopatra: All hail Cleopatra, kindred of Horus & Ra, beloved of the moon & sun, daughter of Isis, and of upper and lower Egypt, Queen!
JOHN HOCKENBERRY: Well, lovely papyrus! Where are you taking me now? This looks like the outdoors. Are those turtles real?
CLEO: They’re real, just like everything here. Reality, possibility, is shifting, John. Take how long we live.
JOHN HOCKENBERRY: So, why is it that we—and nearly everything else—ages at all? And it’s not like everyone—or every species—lives the same amount of time.
CLEO: DR. Cynthia Kenyon’s made a rare trip out of the wormhole just because she heard you were in De Nial.
JOHN HOCKENBERRY: That’s nice, and technically I am. So, why would I live longer than, say, my pet canary, or my dog?
CYNTHIA KENYON: All these animals evolved, we believe, from a common precursor, a kind of primordial animal that gave rise to everything. And this little guy must have gotten old at some rate. And all that happened during evolution is that it just kept having more progeny, more grandchildren, descendants and so forth. As that happened, mutations occurred, which ultimately gave rise to all of the different species that you see now on the earth, including the differences in lifespans. So it suggests that life-spans are encoded in the genes or the predicted lifespans, the aging rates are encoded in the genes somehow, and that maybe there’s a way in evolution for certain genes to be changed in such a way that different life-spans result, you see?
JOHN HOCKENBERRY: Not yet—Of course since the beginning of time, there’ve been people trying to reverse aging, stop it, or certainly as I try to do—ignore it.
CLEO: People have always told legends of the immortals among us—or above us—and looked for ways to be them.
S. JAY OLSHANSKY: The gland grafters were very popular in the early 20th century. They would cut off the testicles of goats and insert them in, graft them on to older men. And these older men claimed that they had… no, I’m not going to say it—they had some benefit associated with it. Bruce will claim that—
BRUCE CARNES: They didn’t live any longer but they had an insatiable desire to eat tin cans.
JOHN HOCKENBERRY: So, who are you two comedians?
BRUCE CARNES: My name is Bruce Carnes and I’m a researcher at the National Opinion Research Centers—Center on Aging at the University of Chicago.
OLSHANSKY: I’m S.—‘S’ stands for Stewart—Jay Olshansky, Professor at the School of Public Health at the University of Illinois at Chicago:
JOHN HOCKENBERRY: You’ve got quite a sheaf of papers there.
CLEO: Those are actuarial tables, John. Doctors Carnes and Olshansky are biodemographers who use charts to forecast the life—and death—of species.
They hold that what most everyone else in these lounges here is gambling on—that we’ll live to be one hundred and fifty—is bogus. Can’t be done.
S. JAY OLSHANSKY: The rise in life expectancy during the 20th century was about 30 years for humans. From about 47 to the high 70s. But the majority of that rise in life expectancy was associated with reductions in early age mortality—infant, child and maternal mortality. Those kinds of gains can be achieved only once for a population.
We think life expectancy for humans can realistically rise to about 85, which is about 10 years higher than it is now. It just seems pessimistic relative to those who are suggesting that it can go to 100 or 120 or higher.
ROY WALFORD: Aging is just a problem in biology and it’s solvable.
JOHN HOCKENBERRY: Wha—what’s that? Where is that sound coming from?
Oh, there’s the door—it’s an enclosed glass pod—and there’s a skinny guy in there, shaven head, really long mustache. Let’s see, there’s a book rack just outside: “The 120 Year Diet, How to Double Your Vital years, “ by Roy Walford, M.D., Professor Emeritus, UCLA Medical School.
ROY WALFORD: Well, I think that many people who are now alive maybe live throughout the next century and on into the other because of the advances being made in gerontology and regenerative medicine and so forth. They could do this by caloric restriction, also, if they started young enough. They could extend their life spans, at least some of them, throughout the entirety of the next century. If humans behave the same as rodents.
JOHN HOCKENBERRY: Rodents?
ROY WALFORD: There’s good evidence that they do so behave in terms of caloric restriction. I collected that evidence in Biosphere 2. That was the first well-conducted and controlled human experiment.
JOHN HOCKENBERRY: Caloric restriction is just another way to say eating a whole lot less, right? Besides, that batch of humans just figured on being locked up in a self-contained environment in the desert doing experiments for a couple of years.
ROY WALFORD: Well, I told the other Biospherians that eating an 1800 to 2000 calorie diet, would leave them hungry, but they would be very healthy because the diet that they could eat was a super nutrient dense diet and it was deficient only in calories. So this was exactly like what I had worked out very much in mice and other people worked in many other species.
JANE POYNTER: Yeah, that means that were we to have the same power to stick with this diet for the rest of our lives, we could apparently live to 120. But I have to say I don’t think I could do it. It’s a jolly strict diet.
JOHN HOCKENBERRY: Hmm, I hadn’t noticed all the computer screens. It’s a bit Orwellian around here. You, on the big monitor up there, you are?
JANE POYNTER: My name is Jane Poynter. I was one of the first eight people to close ourselves up inside Biosphere 2 from 1991 to 1993.
JOHN HOCKENBERRY: I guess that’s why you’ve got a burrito in front of you now. A couple of years without much to eat would do—wonders for my appetite later...and for my imagination during.
JANE POYNTER: Some people thought we were highly masochistic because I would provide expensive dinners for people in Tucson on the proviso that they would take along with them a video phone which was able to take still photographs of the food they were eating and the wine they were drinking just so we would feel like we were participating in a dinner. (Giggles.)
JOHN HOCKENBERRY: I’d call that extreme.
CLEO: Talk about voyeuristic—Actually, that made me hungry.
ROY WALFORD: I got interested in caloric restriction since it was, and remains actually, the only method that can prolong life span, at least in mammals so far discovered.
CLEO: That’s incredible, since Clive McKay figured that out back in, what, 1935? He was a veterinary nutritionist at Cornell University, who got rats to live more than half again as long as their normal life span.
JOHN HOCKENBERRY: Wow, like you’d want rats to live longer.
CLEO: Dr. Walford used mice.
ROY WALFORD: A maximum life span of mice normally is about 38 to 39 months. That’s equivalent, let’s say, to 110 in humans. So they’re all kind of dead by then, or on their way to dying. A caloric restricted mouse will live, that is a cohort or colony, some of them will live to be 53 or 54 months of age, not 38 months. But if you take a 38-month-old caloric restricted mouse and compare him with a normal mouse, well there’s no comparison. The restricted mice looked great. And he will perform better. The restricted mouse will run a maze, for example, with the same facility as a six-month-old normal mouse.
CLEO: So if you take that as a marker of intellectual capacity, that’s like a 100 year old man being mentally sharp.
JOHN HOCKENBERRY: Now you’re talking. I’d like to look good and be a brilliant debater as a centenarian—but what if I’m spending my life in the doctor’s office—you know, heart trouble, arthritis, the works?
ROY WALFORD: The diseases of aging on calorie restriction are postponed. For example, in mice they still get lymphomas if they are calorie restricted but they occur at 55 months of age or something like that instead of 40 months. So you’d still maybe have your heart attack but instead of getting it at 60 you would get it at say, 90. That’s how the diseases of aging pan out.
JOHN HOCKENBERRY: It’s the knowing how the diseases catch up with us in old age that’s the catch, eh? What are the chances that one of the scientists here in De Nial will find a key?
CLEO: What’s the fun in betting on a sure winner? You know, Dr. Walford’s played nearly all the games here—caloric restriction figures in so many of them.
JOHN HOCKENBERRY: Okay, but, there’ve got to be scientists looking at creatures that are more like—me.
CLEO: How about we—process—over to the monkey bar?
JOHN HOCKENBERRY: Great! In this place, the monkeys are actually at the bar. What a lovely couple over there, picking nits out of each others’ coats.
CLEO: Lustrous coats they are, too!
JOSEPH KEMNITZ: I think for many people, perhaps most people, it would be difficult to pay as detailed attention to your daily intake as it is for us to control the monkey’s food intake.
JOHN HOCKENBERRY: No, kidding! I understand it’s a voluntary cutback of around 30 percent. I’d have to be caged! It’s clear you know your way around this bar. You are?
JOSEPH KEMNITZ: My name is Joseph Kemnitz; I’m the director of the Wisconsin Regional Primate Research Center. I don’t think there is going to be a single pill or some other fountain of youth that will be discovered from this line of research or any other. But I think there is the very real potential to improve the every day well being of many people through this work, and that’s what we’re trying to accomplish.
CLEO: As if it’s possible to have well-being on a restricted diet!
JOSEPH KEMNITZ: This room houses several of the males that have been on the study for more than ten years.
LAB TECH: Snippy here is a DR guy. While Val, here, he isn’t.
JOSEPH KEMNITZ: You can see both of the animals look good, they’ve got good hair coats; they’re very alert and so forth. You may be able to see more body fat on the control animal than on the restricted animal. Although they’ve both got a little bit of a paunch.
CLEO: Hmmm. He looks good!
JOSEPH KEMNITZ: Thank you for saying that. That’s a restricted animal. It’s kind of...a subjective judgment, although, there’s a lot of individual variation of the animals of both groups. Just like people, they seem to age at different rates and they have different physical characteristics. Some of the older animals develop little spots, age spots on their faces and on other parts of their body.
CLEO: I may be able to help out here. Let me check my bag. [rummaging through purse] We Egyptians—well I’m Macedonian Greek, but still—in Egypt, we developed the very first wrinkle creams. Care to try some, gentlemen?
JOHN HOCKENBERRY: You didn’t want this jar back, did you?
CLEO: You really are in denial, aren’t you John.
JOHN HOCEKENBERRY: I’m getting depressed. Or maybe it’s hungry. Oooh, what’s that fine smell? Like bread baking! Can’t be; a bakery seems so wholesome for place like this.
I should have known—it’s a rock and roll bakery. I wonder what’s fresh here?
CLEO: That black haired young guitarist looks pretty fresh to me!
JOHN HOCEKENBERRY: Try to behave!
CLEO: U.S.C’s Dr. Valter Longo—a former student of Roy Walford’s. That’s his band. Music in his off hours, yeast his on.
JOHN HOCKENBERRY: Excuse me?
CLEO: Yeast, he studies yeast. Got a problem with that?
JOHN HOCKENBERRY: Mice I get. Monkeys, sure. I can relate. But—why yeast as a means to study aging?
VALTER LONGO: So I figured if I find out the rules of aging in a simple organism then we might go much, much quicker, by knowing exactly what to look for. And so I started working with baker’s yeast.
JOHN HOCKENBERRY: Yeast?
CLEO: Yeast. Check it out: according to Valter Longo, more than 50% of yeast proteins are similar to those in—mammals.
VALTER LONGO: We age because of wear and tear, molecules in cells can damage with time, just because they lose their ability to protect themselves, and cells lose function and then the organism loses function.
CLEO: You mean the cell’s DNA gets damaged and everything starts to break down?
JOHN HOCKENBERRY: That sounds like regular, human stress. Right? You’re talking about stress?
VALTER LONGO: Right, it’s an accumulation of damage caused by stress. We refer to stress as any form of insult, such as heat is a stress, oxygen can become a stress. And so there are various insults that we refer to as stress, such as oxidative stress. For example what we call free radicals.
[chorus of voices, chanting “ Don’t free the Radicals, don’t free the radicals!”]
JOHN HOCKENBERRY: And all the time I thought that was a political movement.
CLEO: Hmm, nice body on that demonstrator over there. The shaven headed man in the muscle T? That’s Dr. John Tower, a biologist at the University of Southern California. He’s more of a fly guy himself; he’s here at the bakery to show solidarity.
JOHN HOCKENBERRY: Uh, excuse me. Got a minute to tell us about the free radicals?
JOHN TOWER: They are oxygen species with an unpaired electron.
And these molecules will interact with and damage all the other classes of molecules in our cells. Damaged molecules appear to increase in concentration with age.
JOHN HOCKENBERRY: Hold on a nanominute here! Oxygen—we need it for life. You’re saying it can also be poison? Is this a case of when good oxygen goes bad?
JOHN HOCKENBERRY: Oh, another baker to the rescue.
CLEO: It’s MIT’s Dr.. Lenny Guarente. He keeps his gym bag by his desk—could be why he’s not out of breath.
LEONARD GUARENTE: So whenever we breathe, okay? [inhales] The oxygen is doing a good thing, okay? We’re respiring but at a very low level we’re producing these toxic byproducts, okay, so-called oxygen radicals that do damage.
JOHN HOCKENBERRY: That’s—oxidation, right? Oxidation—rust. That’s what happens to my car. My car—my cells? My body? So what we’re talking about here is finding a way to slow down human, cellular rust. We’re looking for Rustoleum. The gene for Rustoleum. The anti-oxidation gene.
LEONARD GUARENTE: Many years of work have lead us to the notion that there is a particular gene that we’re quite interested in at this point and that seems to be a key regulator of aging in yeast and very likely in animals.
JOHN HOCKENBERRY: And that gene would be?
LEONARD GUARENTE: S-I-R-2, or sir2.
JOHN HOCKENBERRY: I’m assuming it’s not an honorific.
LEONARD GUARENTE: SIR stands for Silent Information Regulator and the gene was thus named because it controls a process in yeast cells that’s called silencing. And in that process genes that are in particular regions in the chromosomes are rendered silenced, they’re turned off, they’re not expressed. So it’s really the guy that seems to be indispensable for yeast cells to turn off blocks of genes in their chromosomes.
CLEO: And by turning them off, some of those genes responsible for aging are stopped from continuing their—debilitating work. Then anti-oxidants that we produce go to work doing repairs.
JOHN HOCKENBERRY: But if there are scientists who’ve already figured out the answers, why is this place so packed? So many lab rats, so many crawling, flying, leaping—budding things!
CLEO: Oh—it’s that demonstrator again, John Tower.
JOHN TOWER: We’ve really seen a big transition in our ability to study this question and the number of people that are interested in it. And I think some of that has to do with the fact that our society is rapidly becoming much older than it was so the diseases of aging and questions having to do with aging are becoming more important to our society as a whole and so this type of research is becoming more and more important.
JOHN HOCKENBERRY: I read recently, that by the year 2100—not so very far away—the percentage of the world’s population over 60—will increase from the 10% it is today to—ready for this?—as much as 34%. And by then, who knows? 60 may be relatively young.
ALAN GINSBERG POEM: Pull my daisy, tip my cup, all my doors are open, cut my thoughts for coconuts, all my eggs are broken.
JOHN HOCKENBERRY: When we return with The DNA Files—why having babies in your forties may extend your life!
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JOHN HOCKENBERRY: Welcome back to The DNA Files, I’m John Hockenberry, in De Nial Lounge with my guide, you remember her, Cleopatra. We’re exploring how DNA research is helping us understand and possibly defeat aging.
CLEO: I tell you, I’m ready for a facial about now.
JOHN HOCKENBERRY: I want to stop in a vitamin shop; I mean there’s got to be something I can take right now to bud again like the young yeast I’ve got in me! You get your facial; I’m going to pop in here.
VOICES: Can you slow down the aging process, recapture youth and be younger again? Scientists are on the brink of… Would you love to have beautiful, youthful, more touchable skin?… He’s been eating yogurt for a hundred and five years…
JOHN HOCKENBERRY: You have anything that just stops aging all by itself?
SALESMAN: Nothing’s around to stop aging, but there are many…
JOHN HOCKENBERY: I’ll bet if you had it there would be more people in the store.
SALESMAN: There certainly would.
VOICES: …New cocktail is easy, it’s complete, and it combines the very best of what anti-aging science has to offer… Once we learn how to transfer memory from the old body to the new young clone, man will truly reach the status of gods.
JOHN HOCKENBERRY: With all the ads and hype on TV and radio and in magazines of alleged cures for aging—from hormones to gizmos to freezing… to cloning…
VOICES: …become immortal… financial future, you have to plan for your health future as well…
JOHN HOCKENBERRY: …it’s confusing. And kind of creepy. And potentially expensive. I’m in the wrong business.
CLEO: Hello, John.
JOHN HOCKENBERRY: Hello, gorgeous!
CLEO: How’d you make out in there? I can’t really see a difference. Or maybe these eyelashes are getting in the way.
JOHN HOCKENBERRY: I think I’m going to have to live with this aging body for now.
[sings:] Shoo fly, don’t bother me, shoo fly don’t bother me—
CLEO: [sings, too]
John, why are we singing that silly children’s song?
JOHN HOCKENBERRY: Could be you bring out the child in me? Which reminds me. Doesn’t behavior have something to do with youth? Being active and involved; doing exercise, all of that?
CLEO: Sure, sure—all of that makes you feel better, and can definitely extend your life—to a degree. For now, care to join me for a journey through the wormhole?
JOHN HOCKENBERRY: As if I have a choice.
CLEO: Hold on.
JOHN HOCKENBERRY: Wow, what a view! We can see over to Mount Olympus! And on you my traveling companion, now can see a whole lot. Your attractions have become transparent. I mean for someone a couple of thousand years old, you have aged remarkably well. Can I say that? Where are you leading us in this slithery ensemble?
CLEO: To the worm lady, John, to Dr. Cynthia Kenyon. You met her earlier.
JOHN HOCKENBERRY: Oh, yeah, all-life-spans-aren’t-created-equal lady.
CLEO: She works up here on Mount Parnassus, at the University of California, San Francisco.
JOHN HOCKENBERRY: The worm lady: you trying to scare me?
CLEO: Hardly. Molecular geneticist Cynthia Kenyon works with a tiny dirt worm named “C. Elegans.”
CYNTHIA KENYON: It is quite beautiful. It’s a simple animal, and yet it has all the tissues of a human, pretty much. It has a brain, muscles, everything. Working on aging with C. Elegans is particularly beneficial because it has a very, very short life span. It gets old and dies in just a little over two weeks.
JOHN HOCKENBERRY: How convenient. But how can you tell if a worm is getting old?
CYNTHIA KENYON: Young worms look young and old worms look old. It’s in the nursing home. It’s obvious, obvious. So we just ask, you know, can you change genes and make the worms live longer? And sure enough you can.
JOHN HOCKENBERRY: Great, a bunch of wrinkly old worms weakly slithering about.
CYNTHIA KENYON: What happens when you double the life span is that you double the time at which it’s youthful, so it’s as though you’re looking at a person who’s 90, but they look 45. It’s almost miraculous.
CYNTHIA KENYON: We believe there are hormones in the worm that control aging, and in fact, these hormones actually make the worms get old. These hormones are not the friend of the worm. So what we do, when we change the gene that makes the receptor, it’s like you have baseball glove that doesn’t have any fingers on it anymore, so it can’t catch the baseball. So basically the hormone is still there, but it can’t do anything to the worm, and the worm stays young longer, and that tells us that the normal function of the hormone is to make the worm get old. It tells us that aging is controlled by hormones, which has always been a theory, but this is the first case in which it’s been really demonstrated to be the case.
JOHN HOCKENBERRY: So, that’s dirt worms?
CYNTHIA KENYON: What we’re made of is all very similar. It’s just put together slightly differently, but the building blocks are all the same, and so it’s not surprising that the genes that control things, very fundamental processes like growth and differentiation, are the same genes, and they are.
JOHN HOCKENBERRY: That’s out of C. Elegans total what, 19,000, right? These genes have names?
CYNTHIA KENYON: It’s called the DAF II regulatory pathway in the worm because the name of the receptor is DAF II, but we also call it the insulin IGF-1-like signaling system. So yeast seems to have these genes, and it looks like the fruit flies also have it. People who work on fruit flies have been asking themselves whether the same genes that control aging in the worm also control aging in the fly, and so they’ve changed these same genes in the fly and asked do they live longer, and the answer is yes they do. So that’s very exciting because worms and flies are really different. So it looks as though possibly the system that we’ve been studying in the worm may have arisen in evolution very early.
JOHN HOCKENBERRY: You know, I think I’ll be gardening differently from now on. Our compost heaps, ourselves. But it’s a bit difficult to accept that what governs aging in an organism that only lives two weeks is just like what made it possible for the late Jeanne Calment of France to make it to 122 and a half—and that’s as old as we have proof it gets. Quite a range.
CYNTHIA KENYON: Let’s suppose there was another species. Let’s suppose chimpanzees could live to be 200. If they could, wouldn’t you think that humans could? If we could see chimpanzees that could live to be 200, then we would think there’s a lot of hope. For example if we were dogs, if we had the life span of dogs but were smart like humans and we could study aging, and we saw humans, I know that we would have already solved aging.
JOHN HOCKENBERRY: You know, I read something once—I think it was in one of those parenting magazines that get delivered to our house. The article stated that women who gave birth later in life lived longer. I wonder why that is? Will those later child-bearing, baby boomer moms be the ones who’ll be around to babysit their great-great grandkids?
CYNTHIA KENYON: One thing that’s interesting is that centenarians, apparently, women have a 19% chance of having reproduced when they were in their 40s. Whereas your typical person who dies at 70 has only like a 2% chance. And so either it’s because they had children late that they lived long or it’s that these were the people were capable of having children. So maybe we right now in society are actually pushing back the aging process by inadvertently selecting for reproductive fitness and just general fitness at an older age, which could correlate with longevity. As a matter of fact, we might be evolving right now toward a 200 your life span without any drugs. With no company. No molecular biology. Just by doing this. That’s what Michael Rose did when he looked for his long lived fruit flies.
MICHAEL ROSE: The little trick of this whole thing is I actually work on immortality. We’re doing genetics. So genetics is like Christian theology. You’re allowed to do whatever you want, only you pay a price at the end, ok? So what we do is, we set the situation up, where the flies that have genetic self-restraint, so they are not over-doing the eating, fornicating, whatever else it is they’re doing that is killing them early. So they arrive at a later age, healthy, they get to reproduce and start the next generation, all the others get wiped out.
JOHN HOCKENBERRY: Flies, eh?
CLEO: Drosophila Melanogaster, to you. Fruit flies. And not just any fruit flies—these are superflies.
MICHAEL ROSE: Since February of 1980 I’ve had these flies, specifically selected to live a long time, and then to be able to reproduce, once they’ve lived a long time. And these are the O flies, sometimes called the superflies. And you actually would be hard-pressed to see any difference between them and regular flies, but that’s because what they do inside their bodies has been redone, through evolution.
JOHN HOCKENBERRY: You’re trying to get them to stop—dropping like flies, right?
MICHAEL ROSE: Say your normal fruit fly as an adult might 20-30-35 days. And our fruitflies live 60-80 days as an adult. It’s more than a doubling now, of their life-span. And very significantly, this is a doubling or more of life-span with a great increase in vigor throughout most of adult life including toward the later stages of life.
JOHN HOCKENBERRY: So you’re talking the equivalent of a, say, 150 year old person, at least! How do you do it? Do you starve them? Avoid insulting them?
MICHAEL ROSE: The way we do this is simplicity itself. We just deny them the opportunity to reproduce when they are younger, generation after generation after generation. So a minimum of 10 generations, and we’ve now got this experiment to around 100 generations, which is a very long time in evolutionary time. In human terms you’re looking at millennia for this experiment. Which is of course why we do it in fruit flies, we don’t have millennia, to work in our labs. So, basically what you are doing is setting the stage for evolution to focus on enabling these little fruit flies to live long enough to reproduce at a later age and to be healthy enough to reproduce at that late age. There’s a lesson in there.
JOHN HOCKENBERRY: But, can you really apply this lesson—evolutionary genetic engineering to humans?
MICHAEL ROSE: You can achieve those same results earlier by other kinds of inventions, like pharmaceuticals.
CLEO: Drugs, ha, I knew it! I think that calls for another drink, John. Care to try the Evolve Inn?
JOHN HOCKENBERRY: Sure. Well then, here’s to your health!
[clip from They Might Be Giants song: “Time is marching on & time is still marching on!”]
JOHN HOCKENBERRY: No kidding, time is marching on! Hey, Cleo, you know those warped clock paintings by Salvador Dali? He re-set the clocks!
CLEO: Odd you should mention that. Let’s go down the hall—see the cinderblock wall? Here in denial, we call what’s behind it, “ the museum of the face of the future.” That’s where we’ll find Dr. Calvin Harley, the Geron Corporation’s Chief Scientific Officer.
CALVIN HARLEY: I have the Salvador Dali clock picture on my wall in part because I just liked the painting ever since I first saw it probably 30 years ago. But also the metaphor for flexible clocks, and the ability to perhaps manipulate time or the timing mechanism—the chronometer—has relevance to our understanding of the mitotic clock or the cell division clock of aging.
CLEO: John, Dr. Titia De Lange at Rockefeller University has been working for the past decade to figure out the mechanism that drives that clock.
TITIA DE LANGE: Clearly the cells can count the number of cell divisions they’ve gone through which was an enormous puzzle. How would a cell count the number of cell divisions, remember that its gone through 50 or 60 cell divisions, pretty precise counting too. Now its clear that they count through their telomeres and what they’re actually counting is the loss of telomeric DNA, every cell-division there is a little bit of the telomere that’s lost and there’s a point where the cells take note that the clock has run out. Exactly how that happens we don’t know, but it’s very clear that the telomere is the molecular basis of this clock.
JOHN HOCKENBERRY: A telomere?
CLEO: You can see them in the microscope, John
TITIA DE LANGE: Isn’t that nice? We have such fun!
CLEO: They sparkle! It’s almost celestial.
TITIA DE LANGE: It was pretty exciting for us 5 years ago when we saw them for the first time. I still find it beautiful.
JOHN HOCKENBERRY: So the little red things that stick out at the end of the chromosomes are the telomeres and each time the cell divides, they break off until there is no more—and whap, it’s over? We age.
JUDITH CAMPISI: Think of the telomere hypothesis of aging as having two parts.
JOHN HOCKENBERRY: Ah, our friend from the Convergence Lounge, Dr. Judith Campisi from Lawrence National Labs.
JUDITH CAMPISI: Telomeres as they shorten, cause cell senescence. If the telomeres get too short, nature abhors a broken piece of DNA and nature can now no longer distinguish the end of a chromosome from a broken DNA so it sticks them together. And it sticks them together and the next mitosis, you got to pull them apart, but there’s no natural telomeres so it rips them apart. Now you’ve got another break that you’ve got to stick together, and this is what we call genomic instability, a very important step in cancer. So nature wants to be sure that when the telomeres get too short, that cell undergoes this voluntary sterilization and will not divide, too dangerous. So we now know that it is certainly true: short telomeres does cause cellular senescence.
CLEO: Oh, you mean they’re—resting.
JOHN HOCKENBERRY: Not dead?
CLEO: No, resting. Actually, the cell knows it’s becoming neoplastic, cancer-like, and just stops-dividing. It’s not dead.
JUDITH CAMPISI: That doesn’t mean that short telomeres causes aging. Here’s the problem with the so-called telomere hypothesis of aging. The second part of the hypothesis, then, is that cellular senescence causes aging. I work on cellular senescence. I am the first to admit; we still do not know the extent to which cell senescence contributes to aging. It is still hypothesis, very much in the process of being tested. So I would have to say there really is no “telomere” hypothesis of aging; there is a “cellular senescence” hypothesis of aging, still a hypothesis, but that is the link between telomeres and aging, and until we have shown that cellular senescence impacts aging in some significant way, the telomere hypothesis is, it’s nowhere.
JOHN HOCKENBERRY: Hmm—I wonder what Geron’s Cal Harley would think of that.
CLEO: Yeah, what Dr. Campisi’s saying could throw a wrench into Geron’s philosophy—and potential cash flow.
CALVIN HARLEY: Geron in fact is Greek for Old Man and is short for gerontology - the study of aging. The company was not founded around telomere biology. It was founded around the concept of trying to use an understanding of cellular aging to develop medicines for the treatment of disease.
CLEO: Actually, Geron’s more focused now studying an enzyme on the tips of the telomeres: it’s called telomerase. And while there are direct applications for disease, there are potentially lucrative offshoots-
JOHN HOCKENBERRY: Like?
CLEO: One of my favorites—anti-wrinkle creams.
CALVIN HARLEY: And that’s an area where in fact telomerase activation may play a role. Aging of the skin is not just a cosmetic problem it’s a health problem as well. And that might translate to some cosmetic applications down the road once the safety is fully worked out with respect to manipulating telomeres. We’ve also filed patents on methods of uses and methods of measuring telomere biology, telomerase activity, telomere length and so on. And the reason we did that is we want to survive long enough to actually get these products into the marketplace.
CLEO: Therapeutic beneath the surface—and there’s the rub. Like oxygen back at the bakery; telomerase is both good and bad.
CALVIN HARLEY: Telomerase is the key enzyme that synthesizes telomeric DNA. Certainly in terms of cancer, the only key difference that we can tell in telomere biology between cancer cells and normal cells is that telomerase is turned on.
JOHN HOCKENBERRY: Ah, the big C- Claims nearly everyone, if they live long enough. I wonder if you could turn this telomerase business into a cancer treatment, too?
MICHAEL SHAPIRO: There are no magic bullets. There are no therapies without adverse effects.
CLEO: John, this is Michael Shapiro. He’s on the law faculty at the University of Southern California. He’s written a book on bioethics and the law.
JOHN HOCKENBERRY: Great, okay, so I assume you’ve considered the problem of haves and have nots, of people who can pay for this life enhancement and extension stuff and those who can’t. The curing cancer, the erasing aging—it’s not so simple. There are going to be effects on society—already we’ve got more and more truly old people. Are people going to be working when they’re 150? Are they going to be working when they’re 90? What are the job prospects for younger people—what does it even mean to be younger in a society like that? Are people going to be having affairs with partners a quarter of their age? I mean there’s a lot of going on here.
MICHAEL SHAPIRO: And even if it were introduced rapidly and all those science fiction scenarios had a chance to play out, sooner or later the chances are the economic and social system would stabilize. We don’t know what it would look like. But to say we shouldn’t do it because we don’t know what it would look like is to say that we know the way that we are now is the only right way. There is no reason to dismiss this out of hand.
JOHN HOCKENBERRY: But, I need to think about this a bit more. Cleopatra, all these guys are saying it’s ok to really seriously tinker with Ma Nature.
CLEO: Isn’t that what all medicine does? You don’t remember the pre-penicillin days when people dropped like—flies. If messing with mother—nature—gives me a healthier life, what’s wrong with that?
GREGORY STOCK: The environments around us are not the stomping grounds of our Pleistocene ancestors. They’re not the natural environments in which we emerged. And now our technologies are becoming refined and more powerful and we’re turning them back upon ourselves.
JOHN HOCKENBERRY: Well, that is a point. And you are?
GREGORY STOCK: My name is Gregory Stock and I’m the director of the program on medicine, and technology in society at the UCLA School of Medicine and I’m also a visiting professor in the Department of Psychiatry.
JOHN HOCKENBERRY: I’m going to need a shrink when I get out of De Nial. So you think we’ll turn our bodies into these well-manicured golf courses? Mow down mountains, excavate, fill, shape- shift?
GREGORY STOCK: I believe that we’re going to reshape our own biology to the same extent that we reshaped the natural environment around us. And that it won’t come quickly. But it’s very clear to me that in a hundred years or a thousand years when future humans look back on this era, they’re going to see it as this incredibly challenging, and difficult, and turbulent moment in time, because we’re doing all these things that we don’t really know where they’re going to take us, and they’re very challenging to who we are.
CALEB FINCH: We are just really in terra incognita here.
CALVIN HARLEY: I don’t want to die.
ROY WALFORD: I get mildly hungry a lot.
GREGORY STOCK: Immortality is a very, very long time.
CALEB FINCH: I never miss lunch if I have the chance.
CYNTHIA KENYON: I’m 300.
JOHN HOCKENBERRY: I’ve got a joke for you. What did the Buddhist say to the hotdog vendor?
CLEO: I give up. What?
JOHN HOCKENBERRY: Make me one with everything. [laughs]
CLEO: Well. That’s not as silly as you may think, John. It’s a continuum.
JOHN HOCKENBERRY: You gonna start calling me grasshopper in a minute?
CLEO: The Vietnamese Buddhist master, Thich Nhat Hanh can help you out on this.
THICH NHAT HANH: In our tradition we try to learn and to see that body & spirit are manifestations of the same reality, sometime the same thing manifest itself as body, and sometimes sprit.
JOHN HOCKENBERRY: Then how do we see ourselves, our aging corpus?
THICH NHAT HANH: So we learn to look at the body as the object of our consciousness and also our consciousness as object of our consciousness. And if you look deeply into your body you find that every cell of your body can represent the whole of your body and your consciousness. There is a heritage you get and that can be found in each cell of your body, not only physical, but mental, everything. The suffering, the happiness, the wisdom, everything undergone by your ancestors can be found there in every cell of your body, so your body is not just physical matter, it is also consciousness.
JOHN HOCKENBERRY: So there’s biology, and psychology and chemistry. It’s all one big happy, and hopefully balanced, family of ideas.
CLEO: Pretty good John, you’re getting closer.
JOHN HOCKENBERRY: Thanks.
JOHN HOCKENBERRY: Now I don’t know if I’m just an aging fruit fly or one with the universe—and I’m probably in trouble if I don’t get out of this De Nial lounge. I’m pretty sure I’ll take better care of myself now—just in case I’ll be around a whole lot longer than I ever expected. Let’s take a peek into the souvenir shop before I go, gotta take home gifts for the family. We’ve got packages of yeast of course and a bread maker.
CLEO: Oh, John. The worm earrings are quite attractive, don’t you think?
JOHN HOCKENBERRY: Yeah, but they only last a couple of weeks.
CLEO: How about these rubber clocks? They never wind down—or keep accurate track of the time.
JOHN HOCKENBERRY: Yeah, that’s perfect—the rubber clock with the De Nial lounge motto: life is a chance operation. Guess I can check out now.
CLEO: See you around, John. It’s been—a pleasure to cut the rug with you.
JOHN HOCKENBERRY: There you go again. I’m John Hockenberry. Thank you for listening to The DNA Files.
This series, The DNA Files, was produced by SoundVision Productions, with funding by the National Science Foundation and the Alfred P. Sloan Foundation.
This program, The Search for the Fountain of Youth: The Genetics of Aging and Longevity, was produced by Karen Michel, and engineered by David Goren. The program editor was Catherine Stifter, and our host was John Hockenberry. Cleopatra was played by Elizabeth Stifter.
The opening feature, “Tissue Regeneration,” was produced by Sheri Quinn, and edited by Gemma Hooley.
The DNA Files is: Managing Editor, Rachel Ann Goodman. Science Consultant, Sally Lehrman. Research and Production support by Adi Gevins and Noah Miller. Technical and Music Director, Robin Wise.
Original music composed by Jesse Boggs and performed by the Stanford Woodwind Quintet, Anton Schwartz, Tom Hayashi, and Jesse Boggs.
Project Director, Jude Thilman. Marketing by Murray Street Enterprise. Legal services by Walter Hansel and Spencer Weisbroth.
You can visit our website at www.dnafiles.org. Send your responses and letters to email@example.com. For tapes and transcripts, call 866-DNA-FILES (866-362-3453).
The Executive Producer is Bari Scott.
This has been a SoundVision Production, distributed by NPR, National Public Radio.