COLUMN ONE : Unlocking the Secrets of Aging : Scientists are deciphering genetic codes they say will lead to keeping people alive much longer. But the social and ethical implications of sharing the Fountain of Youth are impossible to ignore.

In his laboratory at the University of Colorado, molecular biologist Thomas Johnson is studying a translucent worm no bigger than a printed comma. In this simple animal, composed of just 959 cells, Johnson believes he may find the answers to complex questions that have eluded scientists for centuries:

What makes us grow old? Can we stop aging, or at least slow it down?

By breeding tens of thousands of these nematodes, Johnson has created a strain that can live for about five weeks--about 70% longer than the worm’s average three-week life span. It appears that the difference between the elderly worms and their shorter-lived counterparts lies in a single gene. Now, Johnson is trying to isolate that gene, and he says he is close.

And if genes can be manipulated to extend the lives of worms, the 48-year-old researcher asks, might not the same be true of people?

“Maybe there are major genes in humans that, if we alter (them), we could project a longer human life span,” Johnson said. “This would be an absolutely tremendous sociological finding. It would affect . . . every aspect of the way we live our lives if we all of a sudden had average life spans of 120 years instead of 70 years.”

Tremendous indeed. Johnson’s work is on the cutting edge of a fascinating scientific sojourn, a modern-day quest for the legendary Fountain of Youth. He is among a growing corps of 2,000 molecular biologists, geneticists, immunologists and other researchers across the United States who are trying to unlock the secrets of aging.

They are tinkering with genes, human growth hormones and new drugs, and with strategies of diet, nutrition and exercise. They are studying patterns of survival in worms, fruit flies, mice and people. They are examining the links between aging and illness--cancer, Alzheimer’s, Parkinson’s, osteoporosis, heart disease, stroke--as well as the effect of environment on aging.

Their strides in recent years have been so significant that a startling new body of thought has emerged, one that says humans may one day live much longer than anyone dreamed possible. Some go so far as to say that the maximum life span, now at 120 years, and average life expectancy, about 75 years in the United States, could double or triple.

“The ideal of all of our work is that sometime in the future, we would take pills that would slow or postpone our aging,” said UC Irvine biologist Michael Rose, who is breeding fruit flies that can live up to three times as long as the average fly. “That’s the ultimate goal, the man on the moon for all this research. We’re not going to have that in five years. But someday it will happen.”

Michal Jazwinski, a Louisiana State University biologist who has isolated “longevity assurance genes” in yeast, said: “In the next 30 to 50 years, we will in fact have in hand many of the major genes that determine longevity in humans. What we have been able to see with our yeast is a doubling of the life span. So that could be something that we might aim for in the future.”

Scientists are pondering the social and ethical implications of their work. They raise a litany of questions: If the research is successful, what would happen to the nation’s overburdened health care and Social Security systems? Would the work force be so crowded with elderly people who have postponed retirement that young people will not be able to find jobs? Would a population boom cause a housing crunch? What would be the effect on our fragile environment?

And, perhaps most important, will living longer also mean living healthier?

“If we are able to produce 150-year-old people but those 150-year-old people spend the last 40 years of their life in a nursing home, we would have created a disaster,” said Dr. Richard Sprott, a top official at the National Institute on Aging. “The big public worry is that by increasing the number of people who make it (to advanced ages) we will produce this huge increase in the amount of disease.”

In some respects, that is occurring. As the population has grown older, the incidence of age-related diseases such as Alzheimer’s and osteoporosis has skyrocketed. The Alliance for Aging Research estimates that it costs the nation $90-billion a year to treat people with Alzheimer’s, which affects at least 2 million and possibly 4 million Americans. As these costs continue to rise, experts say, society has a vested interest in finding ways to keep older people healthier.

“What we have to do as a society is come to the realization of how much money is going into the medical care of the elderly,” said Raymond Daynes, a cellular immunologist at the University of Utah. “We are becoming incredibly sophisticated in preventing individuals who have some acute, devastating illnesses from dying. But we are way behind in providing preventive measures so that (illness) doesn’t happen in the first place.”

Life expectancy in the United States has increased dramatically since 1900, from 47.3 years to 75.4 years. The greatest gains occurred during the first half of this century, largely because of dramatic reductions in infant mortality and infectious diseases. More recently, as Daynes notes, smaller gains have resulted from progress against major fatal illnesses, such as heart disease, cancer and stroke.

Improvements in sanitation and living conditions have also made a big difference, and are likely to continue to do so, said James R. Carey, a medical demographer at UC Davis whose recent work with fruit flies has been cited as evidence that there is no arbitrary cap on human life span.

“The people that are 100 years old today were born in 1892,” Carey said. “Think about all the things they went through, in terms of lack of medicine and nutrition. They were working hard to make it to 100. Now think about a newborn of today, with the emphasis on nutrition and exercise and medical advances. I would bet that we are going to find 125-, 130-year-olds by the 22nd Century just because of these changes in conditions.”

Whether the pace proceeds more quickly than Carey suggests will depend on the outcome of the research being conducted in laboratories today--particularly in the area of genetics, scientists say. Few researchers, however, are willing to make predictions about how soon a breakthrough might come.

Yet as demographic shifts create an older society, and as scientific advances continue, the study of gerontology is enjoying an unprecedented boom. Once suspiciously regarded as the province of charlatans and snake-oil salesmen, longevity research is gaining attention and respect. Now, top-flight scientists are flocking to a field that, as little as five years ago, failed to draw the best and the brightest.

“Aging,” said Daynes, “is finally coming of age.”

This trend is reflected in funding: The federal government’s National Institute on Aging is among the fastest-growing branches of the National Institutes of Health, with a budget that has nearly doubled in the past three years--from $222 million in 1989 to $402 million this year. However, the budget is still small compared to that of some other arms of NIH--the National Cancer Institute has an annual budget of nearly $2 billion.

Much of the growth in aging research has been fueled by intense interest in Alzheimer’s and other age-related diseases. The media have lavished much attention on the subject, particularly since a highly publicized 1990 study in which doses of a synthetic form of human growth hormone were reported to restore youthful vigor to elderly people.

Within the past decade new technologies--such as the ability to conduct transgenic experiments, in which a gene can be transferred from one organism into another--have become available to biologists, making possible certain types of gene research that used to be unthinkable.

“For the last 20 years, a lot of the research has been simply trying to characterize aging in a descriptive way,” said Huber Warner, deputy associate director of the NIA’s Biology of Aging program. “Now people are beginning to find out what the mechanisms of the aging process are so that they can then try to develop interventions that will slow the process down or prevent it altogether.”

Judith Campisi is among those whose work is funded by the National Institute on Aging. At UC’s Lawrence Berkeley Laboratory she is studying cellular senescence, the process by which cells keep dividing until they grow old and die. When she entered the field five years ago, she said, science had barely begun to examine the basic mechanisms that control aging.

“Before,” she said, “nobody quite knew how to ask critical questions about aging. That has changed dramatically in the past five years. The field has now reached a level of maturity where . . . we are beginning to see a path to at least dream about approaching some answers. Until recently, that dream was not a very viable one.”

The answers remain elusive. Aging is an extraordinarily complex puzzle--affected by genetics and the environment and individual habits, such as cigarette smoking and diet and exercise--and Campisi said she and her compatriots each hold only one small piece of it. “We all need each other terribly,” she said.

Research is proceeding on many different--albeit interwoven--fronts:

At Bemidji State University in Minnesota, biochemist Gary W. Evans recently reported that dietary supplements of the metal chromium can extend the life span of rats by one-third, and may do the same for humans. At USC, noted gerontologist Caleb Finch is exploring new terrain with his studies on how aging affects the brain.

In Irvine, biologist Rose is breeding red-eyed fruit flies that can live 80 days--double the life span of an average fly--by mating selected flies that are able to reproduce late in life. Rose theorizes that these elderly flies, some of which live six months, are passing longevity genes to their offspring. But a key question remains: Which genes are responsible?

At the University of Colorado, Johnson, the biochemist who is breeding round worms, is taking a slightly different tack. He is mating long-lived nematodes with short-lived ones in an effort to follow the worms’ DNA trails. Through a process by which he marks the DNA of the elderly worms, Johnson can see which genetic patterns reappear in the offspring. He has narrowed his search for a “longevity assurance gene” down to a 50-gene region of a single 3,000-gene chromosome.

In Kentucky, pharmacologist John Carney has learned that when a synthetic compound known as PBN--phenyl butyl nitrone--is injected into gerbils, certain proteins in the brain that deteriorate with age are restored, resulting in improved short-term memory for the animals.

PBN works by combatting the effects of “free radicals”--damaging oxygen byproducts that occur naturally in the body, destroying fats and proteins that are crucial to the way cells function. In certain diseases such as Alzheimer’s and Parkinson’s, researchers believe, these free radicals run amok.

In addition, scientists at the National Institute on Aging say they have evidence that free radicals speed the aging process. The theory is that if free radicals can be controlled, so too can aging. Researchers are also exploring the effects of “dietary antioxidants”--foods and vitamins including Vitamins C and E, and beta-carotene, a compound that turns into Vitamin A in the body--that may help combat free radicals.

Soon, Carney hopes, PBN will be tried in humans. He and his partner, a biochemist at the University of Oklahoma, have set up a pharmaceutical company to manufacture the drug and are hoping to gain government approval for testing within the next two years.

While Carney studies how a synthetic drug might slow the aging of the brain, Dr. Daniel Rudman of the Veterans Administration Medical Center in Milwaukee has spent the past five years examining how human growth hormones, which occur naturally in the body but decline in secretions as people grow older, affect aging.

Rudman has administered a synthetic form of the hormones to 42 men, ages 60 to 90, and the results have been nothing short of dramatic. Some signs of old age--the shrinking of certain organs, such as the spleen and liver, and the increase of fatty tissue in the body--were reversed by the hormones. After a few months of therapy, Rudman said, 70-year-old men looked as though they were 55.

But a growth hormone is not a cure-all. Given in doses that are too large, it can cause carpal tunnel syndrome, a repetitive stress disorder that commonly affects the wrists of computer users, breast enlargement and a rise in blood sugar. Moreover, it failed to curb other factors associated with aging, such as memory loss and softening of bones. “This,” Rudman said, “is by no means a total reversal of the aging process.”

Another promising hormone is DHEA, a steroid whose natural secretions decline with age. At the University of Utah, immunologist Daynes has discovered that when laboratory mice are given small amounts of DHEA-Sulfate--a water-soluble form of the hormone that had been thought to be irrelevant to the functioning of the body--their immune systems work better and their skin looks more youthful.

Over the long term, Daynes hopes that the hormone might be used as a sort of vitamin for the elderly. “I believe that over the next few years, we are going to prove beyond a shadow of a doubt that some of the physiological changes which are used to define old age are totally preventable,” he said. “They don’t have to happen.”

In the Arizona desert, meanwhile, UCLA Prof. Roy Walford is trying to delay the onset of old age through his diet.

Walford and seven other scientists who are living in a glass-enclosed three-acre greenhouse known as Biosphere II are engaged in the first human version of a well-known study in which Walford found that a severely restricted, low-calorie diet could double the life expectancy of rats and mice.

Now, Walford and the other biospherians are subsisting on 1,800 calories per day, compared to the usual 2,500. According to Walford, the group eats only what is grown in the dome--grains, vegetables, fruit and one serving of meat per week.

According to the 68-year-old Walford, who has been following the diet for more than five years, the group is exhibiting the same changes as the rodents. Each has dropped an average of 14% in body weight since the experiment began 13 months ago. Their cholesterol is lower--an average of 130, down from 200--and their blood sugar has declined.

“This is the first well-monitored human application of the idea,” Walford said, “and it indicates that humans respond the same as animals.”

But be it gene manipulation, hormones, drugs or nutrition, researchers agree that if their work proves anything, it is that there is no Fountain of Youth, no single elixir that has the power to stop or even slow the aging process.

Instead, they say, advances that come in disparate arenas will over time be put together to create a greater understanding of the aging process. And only when the age-old mystery of aging is unraveled will scientists figure out ways to stop it, or slow it down.

“There is no silver bullet,” said Edward Schneider, dean of USC’s Andrus Center of Gerontology. Instead, Schneider likens the state of aging research to the decades-old search for a cure for cancer.

“Picture cancer research 30 years ago,” he said. “People thought it’s simple, we’ll give one drug and it will cure all cancer. Well, it didn’t work. In the next 10 or 20 years we’ll have specific therapies for specific cancers, because cancer is a complex process.

“Imagine cancer being a 1,000-piece puzzle and we have a third of the pieces. Aging is a 100,000-piece puzzle, and we maybe have a tenth of the pieces.”

The Oldest Old

Even without major breakthroughs in aging research, the population of the United States is growing older. The Census Bureau projects that by 2040, the population of the so-called oldest old, those over age 85, will be at least 12.3 million. Other researchers, as the chart shows, go further.

Percent of U.S. population over 85

Oldest Old Total Population Oldest Old as % of Total 1960 .9 million 180.7 million .49% 1970 1.4 million 205.1 million .68% 1980 2.2 million 227.8 million .96% 1990 3.3 million 249.9 million 1.3%

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2040

The Census Dept.’s conservative estimate: 12.3 million people -- or 4% of a population of 301 million -- will be age 85 or over.

Some at the Census Dept. go further: 19.9 million people -- or 5.3% of a population of 338 million -- will be age 85 or over.

Jack Guralnik, an epidemiologist with the National Institute on Aging, estimates: 23.5 million people -- or 6.9% of a population of 338 million, will be 85 or over

Kenneth Manton, a medical demographer at Duke University, goes the furthest: 42.3 million people -- or 12.5% of the population, will be among the oldest old.