And yet, at a recent meeting here, most agreed that science might be on the brink of being able to stretch the human life span, perhaps significantly.
Scientists have had astonishing success in recent years in increasing the life spans of laboratory species like worms and fruit flies. The time was ripe to review these discoveries and discuss what might lie ahead, said Dr. Gregory Stock, the conference organizer, who is director of the program on medicine, technology and science at the University of California School of Medicine at Los Angeles. "Given adequate funding, given lucky breaks, how far could we go?" Stock asked.
"We know we can extend the life span of mammals," said Dr. Judith Campisi, who heads the department of cellular and molecular biology at the Berkeley National Laboratory. "There is no reason to believe that we couldn't do the same today in humans."
"It is probably possible," said Dr. Cynthia Kenyon, a professor of biochemistry and biophysics at the University of California at San Francisco. "The lights are green everywhere you go," she added.
And if their expectations bear fruit, the scientists said, and humans live to be 150, 200 or even older, these latter-day Methuselahs will not creak along, riddled with disabilities and disease, for decade after decade. The goal is to allow people to be vigorous and healthy as they age, to stretch out the good years rather than elongate the bad ones.
It is, said Dr. Kenyon, 45, as if someone who looks as she does were actually 90. Just imagine it, "I'm 90," she said, challenging the scientists as they turned to stare at her, a tall, vibrant, honey-blond professor.
Fundamental questions remain unanswered, but, the scientists say, the general direction is clear. For now, what they have is a proof of principle and a staggering vision of the future.
"It is going to be very hard for us to deal with," Stock said. The idea of expanding the human life span to 150, 200 or more years, "puts a distance between ourselves and all of our history," he said. And it puts humans in uncharted waters. "All of human wisdom on how to live a life," no longer would apply, Stock said.
Dr. Jan Vijig, the director of basic research and a professor of physiology at the University of Texas Health Science Center in San Antonio, added: "We have a few small starting points now. We have never been in a position like this before."
There are a variety of hypotheses to explain aging, but this group, whose members had a range of specialties, was especially impressed by one that held that the secret of aging was in the genes.
They noted that with just a few genetic alterations, scientists had created worms and fruit flies with lifespans twice the norm and that die healthy and vigorous -- the worm or fly equivalent of being 90 and looking 45. Even mice have lived twice as long as normal with a simple genetic mutation.
Dr. Michael Rose, a professor in the department of ecology and evolutionary biology at the University of California at Irvine, said there was nothing like creating one of these long-lived organisms to make someone a believer.
"I've created postponed-aging with my own hands," he said. "I know what it feels like to see one organism on its last legs and another organism that is the same age doing fine."
In the workshop sessions and in private discussions scientists explained why they were so impassioned and why they came to believe that genes controlled life spans.
Dr. Kenyon started her quest to postpone aging with a fact that used to seem surprising: Many of the fundamental biological processes that occur in the simple roundworm, C. elegans, also occur in humans. She was a postdoctoral student when the revelation occurred, in the early 1980s.
Scientists had discovered a small collection of genes that choreographed development in simple creatures like fruit flies and, they soon discovered, in mammals as well. By making a single change in a single gene, development could be profoundly deranged: A fly's antennae could turn into legs, for example. Worms, once thought too primitive, also turned out to have these genes.
So Dr. Kenyon began pondering the genetic control of aging. Perhaps the same genetic approach that worked with development might crack the problem of aging, she reasoned and worms might show the way. After all, she decided, there was every reason to believe that life spans were written in the genes.
She cites, for example, the life spans of three small mammals: the mouse, the canary and the bat. Mice live 2 years, canaries live 13, and bats live for 50 years.
"I don't know why evolution selected for different life spans, but it did," Dr. Kenyon said. Because evolution acts on genes, that means that scientists can ask whether they can deliberately stretch an organism's life.
To test her hypothesis, Dr. Kenyon began looking for simple genetic alterations that could extend the life of C. elegans. It did not take her long to find one: mutations in a gene, called daf-2, that allow the worms to live for a month instead of two weeks. And unlike other mutations that seemed to increase the worms' longevity, the worms with mutated daf-2 genes were fine -- healthy and vigorous.
When they near the end of their two-week lives, "normal worms look horrible," Dr. Kenyon said. A young worm has a certain body posture, Dr. Kenyon explained, it moves vigorously and its body makes a nicely shaped wave as it wriggles along. An old worm, by contrast, has a pockmarked body and cells that are filled with gunk. It lies around listlessly.
But old worms with the daf-2 gene mutation "look great," she said. It is as though they have a perpetual youth. "Even a dead daf-2 looks better than a dead normal worm," Dr. Kenyon said.
Others found that the worm daf-2 gene was closely related to genes that cells used to respond to several hormones, including insulin, raising questions of whether there might be a simple hormonal treatment to retard aging substantially. The next step, Dr. Kenyon said, was obvious: "Check in mice" to see if the mouse version of the daf-2 gene controls life span.
Rose came at aging from a different direction. It was 1976 and he was 21 years old, trying to decide whether to do his graduate work at Harvard University or at the University of Sussex, when he got a letter from Dr. Brian Charlesworth of Sussex. It said, "I want you to work on the evolution of aging because I've solved the problem of aging," Rose recalled.
"I wrote back saying I didn't believe him."
Rose hesitated even to think about studying aging, realizing that it was "famous as the rocks on which scientists dashed their careers." But Charlesworth convinced Rose of the merits. Rose went to Sussex and worked on the problem.
Charlesworth's idea was that in the time before the age of reproduction, natural selection would insure that those who survived would be very healthy. But once an organism reproduced, natural selection no longer mattered, meaning that there would be no advantage to good health.
To show how this plays out in human genetics, Rose points to two genes. Both kill with absolute certainty. One, which causes a disease called Hutchinson-Gilford progeria, makes children age so fast that by 5 they lose their hair, become wrinkled and develop cardiovascular disease. They look like little old men and women. And they die at about 12.
The other is Huntington's disease. Symptoms begin when people are in their 30s or 40s, after they have finished reproducing. They, too, die grisly deaths.
But, says Rose, there are only a few dozen children in the world with progeria. There are tens of thousands of people with Huntington's disease.
As Rose thought about Charlesworth's theory of aging, he realized he could test it. He would force fruit flies to reproduce at an advanced age, by throwing away their eggs when they were young. The only ones that would survive would be those that could stay youthful and healthy to advanced ages. He would make natural selection work to his advantage.
Just by doing that experiment, Rose said, he has bred flies that live twice as long as normal and that, like Dr. Kenyon's worms, stay healthy and vigorous as they age. "I think I have produced a better fly," Rose said. "They are athletically superior, they have a greater ability to do work and a greater ability to survive under stress."
The only thing they do less well is reproduce at early ages. But, Rose said, "we probably don't care about how well we can reproduce at age 15 to 20, which is what these organisms are giving up."
Now he is analyzing the fly genes that make it possible, finding that only about 100 of the 14,000 fruit fly genes are involved. Three to 8 of the 100 genes are most important, Rose said, and he has identified two of them, both common genes that are found in humans.
One instructs cells to make superoxide dismutase, proteins that "take charged molecules that cut through DNA and RNA like buzz saws and turn them to water." He will not reveal the identity of the other gene because he has applied for a patent on it.
The final piece of the new aging evidence comes from studies with mice, said Dr. Richard A. Miller, a pathology professor at the University of Michigan School of Medicine and associate director of the university's geriatrics center.
Scientists long ago discovered two mouse strains that were interesting because they were small. Recently, Dr. Andrzej Bartke at Southern Illinois University in Carbondale asked how long the mice lived and found that they lived 50 percent to 75 percent longer than normal. They are "fat little mice," Miller said, but they are not entirely normal.
The gene mutations knock out cells of their pituitary glands, preventing the animals from making hormones like growth hormone, thyroid hormone and prolactin. These dwarf mice grow to just one-third the normal size and are not fertile.
But, Miller and others emphasized, the point is that a pinpoint genetic change in mice lengthened their life spans.
Now, Miller said, another scientist, Dr. William Atchley of North Carolina State University, has bred 15 lines of mice, looking for variations in body size. Six turn into giant mice, six into small mice as adolescents but some grow larger by adulthood, and three turn into medium-sized mice. The mice that remain small live on average 941 days and the large ones live a shorter time, with one living just 344 days. Atchley has asked Miller to look for the genetic changes that make the difference.
The same thing happens with dogs, Miller said, noting that small dogs live much longer than large ones. Even small grasshoppers live longer than bigger ones, Miller said. Is the same true for people? "We don't know," he replied, explaining that properly controlled studies have not been done.
Even as the scientists spoke of what might lie ahead, some drew back, nervous about public reactions and stung by their experiences when they voiced their opinions.
Dr. Campisi of Berkeley said she recently gave a public lecture on aging on her campus. Afterward, she said, "a number of people came up to me and said, 'How dare you do this research? The earth is already being raped by too many people, there is so much garbage, so much pollution."'
"I was really quite taken aback," Dr. Campisi said. "It was a small group but they just about nailed me to the wall."
Not only did they fear hostility if they spoke out, but the scientists also feared being tainted with the stain of hucksterism.
"This group is sensitive to the inflated claims that have been made in the past," said Dr. Steven Austad, a professor of zoology at the University of Idaho. "That makes us hesitant. We don't want to follow in this long line of people who say, 'Take this potion and do my exercises and you can live to be 150."'
And yet, most of the scientists at the meeting said, the question no longer is "Will it happen?'' but rather "When?" "There's nothing bigger," Austad said. "If we could do it, there's nothing bigger. It's the big enchilada."
After designing long-lived worms and flies, experts turn to people.
Ten scientists attended the two-day meeting. Future generations, they said, may be able to avail themselves of scientifically established techniques to stretch the human life span like a piece of taffy until it reaches 150, even 200 years.
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