MILWAUKEE - Two years ago, 65-year-old Fred McCullough and 27 other volunteers began a journey to the frontier of medical science - and back to their youth.
"I started feeling the changes after three months," said the retired Waukegan, Ill., factory worker as he recalled how his body regained 20 years of lost vigor with weekly injections of genetically engineered human growth hormone. The hormone normally is produced in the body, but the levels gradually decline with age and stop altogether in one-third of men - those who age the fastest.
McCullough's flabby skin became taut. His soft muscles hardened. Fat melted away. Internal organs shrunken by age resumed their youthful size and vigor.
"The main thing was I felt much stronger," McCullough recalled. He paused, his eyes turning wistful. "I mean, I never felt so strong in my life."
Doctors had never seen anything like it: The hands of the clock that inexorably ages all living things had stopped and begun to tick backward for McCullough and the 27 others.
Their experience, remarkably similar to the rejuvenation of the elderly characters in the film "Cocoon," highlighted an experiment at the Milwaukee and North Chicago Veterans Administration hospitals - the first bona fide scientific attempt to reverse aging.
Now, in hundreds of laboratories around the world, scientists are pressing the quest for youth and longevity, mankind's oldest dream, using the tools of genetic engineering and guided by fresh insights into how our bodies age. Interviews over the last year with nearly 200 researchers show they have made astonishing progress:
-- Drugs that prolong youthfulness, like human growth hormone, are already moving through the regulatory pipeline toward government approval. They include DHEA, a hormone that also declines with age. In tests, DHEA keeps animals lean regardless of how much they eat, reduces cholesterol levels and cuts risks of cancer, diabetes and stroke.
-- A massive effort is being mounted by mainstream science to develop revolutionary strategies of nutrition and exercise that will maintain the body's rejuvenative systems and stave off disease.
-- Root causes of the classic disorders of aging - cancer, osteoporosis, Alzheimer's disease - are being understood for the first time, and new methods for prevention and cure are being developed and tested.
-- Startling increases in longevity - as much as twice the normal life span - are being produced in animals when their food intake is sharply restricted. Such dietary restrictions seem to enhance the body's anti-aging chemistry. Many scientists believe the regimen will work in humans, and the National Institute on Aging will spend $30 million over the next several years to see whether they are right.
Some strategies to postpone or reverse the aging process, like the human growth hormone being tested at the VA hospitals, may be available in two or three years.
"We're at a turning point in history," declared Richard Sprott, associate director of the biology program for the Institute on Aging in Bethesda, Md. "Five years ago, I never would have guessed that growth hormone had any effect on aging. Now we can actually use it as a therapeutic intervention."
In McCullough's case the hormone shots have given him a "second wind" that allowed him to enjoy his retirement more fully - traveling, taking long walks with his wife, working in his yard.
Doctors stopped the hormone shots after a year as part of the VA experiment, and the elderly volunteers' bodies began to age again - although some of the benefits have lingered. McCullough and the 27 others are being followed to see whether the hormone has any after-effects. More volunteers are being recruited for the next phase.
"It was wonderful while it lasted," McCullough said, the wistful look flickering again. "Maybe someday I can try it again."
He noted that the first trial involved only male veterans, no women. "I think they should have a chance to feel like we did," he said.
A RARE MOMENT IN HISTORY
Such research reflects what scientists call a paradigm shift, a fundamental change in understanding that occurs only at rare moments in the history of science - theories clash like cymbals, and then all that was confusion suddenly comes into focus.
Where aging once was considered beyond human understanding, there now appears a startling simplicity: Aging is not programmed in us like a doomsday clock or an inescapable result of life's wear and tear. Rather it is a combination of related events governed by our genes. And, for the most part, aging is reversible.
The VA experiment illustrates the new approach to aging ushered in by three decades of genetics research. Scientists now think some of the genes involved in aging are controlled by hormones, which act as chemical messengers to the genes; when the hormones are depleted, aging sets in.
Under this theory, the elderly volunteers regained some of their lost youth because the injections of growth hormone reawakened certain anti-aging genes, including those that convert fat into muscle.
Thanks to the growing understanding of the molecular mechanisms of life - the bustling microcosmos of genes, proteins and cells - a palpable sense of excitement pervades the field.
"There's a feeling of promise in the air now," said biologist Huber Warner of the Institute on Aging.
In some scenarios being proposed, biological clocks could be reset with drugs and hormones. "Lazy" genes could be kick-started into action to protect cells against the ravages of living. Deterioration could be delayed by exercise and diet. Mother Nature could indeed be fooled. Father Time could be put on hold.
The goal of aging research is not to achieve eternal life, but to avoid infirmity as long as possible until we die from truly natural causes - to retard the aging process and extend healthy, vigorous life.
And for some scientists, that's a powerful motivation.
"I'm 65 and trying to save my ass," admitted oncologist and microbiologist William Regelson of the Medical College of Virginia in Richmond, who is studying hormone rejuvenators. "I can't wait around for some graduate student to save it for me."
So far there is no indication that science can reverse the aging process in the sense of transporting us back to infancy. But advances in research have been so profound that even the most unlikely development can't be ruled out. Consider this: A University of Texas researcher has found two genes that control aging in cells, and he can switch these genes on or off like a light bulb. When they're on, cells age and deteriorate; when they're off, the process reverses, and cells grow younger.
While those engaged in research on aging can barely contain their enthusiasm over recent developments, not everyone embraces the prospect of an extended life span.
Government planners worry about the viability of Social Security and higher medical costs; ethicists wonder whether longer life necessarily means greater happiness; some scientists believe the technology to prolong life is being thrust upon a society ill-prepared to deal with the consequences.
Will there be a nightmare of overpopulation? Will access to life-prolonging treatments be restricted? Should people be allowed to live only to a certain age? Will couples need licenses to bear children? What happens if one spouse, disenchanted with life, decides to age and the other doesn't?
Despite our ambivalence about aging, the desire to live forever - or at least to live much longer in full health - has endured from ancient myth to modern science fiction. Yesterday we begged the gods, hounded the alchemists and bribed the stargazers in pursuit of the dream.
Today we look to the scientists. And they are telling us that there may be no immutable biological law that decrees human beings have to get old and sick and die.
"There is no clear reason why aging starts to occur," said Stanford University biochemist Elliott Crooke. "By design, the body should go on forever."
Why then do we age? The new research has convinced many scientists that aging is mechanistic - that it involves merely the relationship between the destructive and repair mechanisms of tissues, cells and molecules of the body. If those mechanisms are kept in balance, they believe, aging may be controlled.
The science that specializes in studying those processes - biogerontology - has entered its heyday.
Just a few years ago, biogerontology occupied a remote outpost of scholarship. It was peopled largely by mavericks and crackpots with lots of bizarre notions and magical nostrums.
"Being called a kook was no fun," remembers a seminal theorist, Richard Cutler, a research chemist at the National Institutes of Health's Gerontology Research Center in Baltimore. In 1972, Cutler's work was singled out at scientific meetings as the type of research that scientists ought not be doing.
Traditional gerontologists pooh-poohed his studies of how the varying life spans among animals might depend on their ability to repair damage to their genetic material. Also dismissed was his idea that the body made special enzymes to protect genes from all of its chemical changes - particularly the damaging byproducts of breathing oxygen.
OXYGEN'S DARK SIDE
Since then, the dark side of oxygen, which keeps us alive but also releases destructive particles known as free radicals, has come to light. So-called oxidative stress is under intense study to determine its role in the aging process.
Hormonal manipulation also extends life, new research shows. When scientists castrate Pacific salmon to excise the genes that give them the overpowering urge to spawn, the fish's life span is tripled.
How animals respond to changes in their genes is significant, because humans and animals share nearly the same genetic material, or DNA.
"If there really are `longevity determinant' genes, we might intervene and change whatever they do," Cutler said. "We wouldn't have to go in there and rebuild the whole machine. Then we'd really have a breakthrough in controlling aging."
The strategies being designed for such intervention are not directly aimed at eliminating the common diseases of later life. Even if those illnesses could be wiped out, recent studies show, the average American's life expectancy still would not exceed 85 years. The reason is that different diseases probably would take their place.
The point for researchers is that aging is not the same thing as disease, although aging makes us more vulnerable to disease.
3 WAYS TO PREVENT AGING
Basically there are three ways of staving off the aging process.
-- The simplest is to make behavior changes that are known to further life expectancy: better diet, more exercise and healthier lifestyles. Perking up the body in these ways could enable most people to live to be about 85 - although some scientists believe a calorie-restricted diet combined with exercise could push average life span to 120 years.
-- The second option, which thousands of researchers are pursuing, involves replacing the body's hormones, growth factors and chemical-defense systems that lose their guardianship over youth as they decline with advancing years. Periodic tuneups to bodies and brains may let people routinely live at least 115 years.
-- The most far-reaching option is to change the very genetics of aging - to intervene with drugs and gene therapy at the most basic nkind. If it proves feasible, such genetic manipulation has some scientists predicting life spans of 200 years and beyond.
This new understanding of aging stems from new ways of looking at how genes function.
Genes are found in the nuclei of most of the 100 trillion cells that constitute the adult human body.
In each cell are 46 squirming threads of DNA and supporting protein - the chromosomes - that are tightly wound collections of about 100,000 genes. These genes determine everything about each cell - and the masses of cells that grow into tissues, organs and, ultimately, a person.
Scientists find that genes are responsive to their environment and their primary mission seems merely to endure long enough to be passed on to offspring.
Genes perform their roles in two phases. The first occurs when the human embryo develops. The embryo goes through changes that reflect the history of human evolution from lower animals, and many organs we no longer use are shut off - the appendix is a notable exception. Genes kill cells that otherwise would form gills, or a tail or the webs between the fingers of a fetus, while promoting the growth of other essential cells.
When the body attains maturity, many genes change their function to replacing, repairing and maintaining cells. Such remodeling, called protein degradation and turnover, replaces proteins damaged by metabolic byproducts and other environmental hazards.
Contrary to previous belief, the deterioration of the body is not built into every cell, new research indicates. Many body parts show no ill effect at all with age.
One piece of recent research produced the startling finding that each protein that goes into the cell's membrane and inner workings is replaced every three days on average, as genes repair and maintain cells damaged by metabolic byproducts and other environmental hazards like sunlight.
"Protein replacement is an effective and faithful system that is designed to last forever," Stanford's Crooke said.
WE CAN'T LAST FOREVER
So, why doesn't it? Why does nature protect a species such as Homo sapiens for only 30 years, and wipe out half of us by age 76, the average U.S. life expectancy?
"The answer is that aging is unnatural," Cutler said. "There are no such things as `programs' that age us for our own good, or for the good of the species. Aging really results from random changes in the normal processes that maintain us and keep us alive."
The way biogerontologists see it, nature didn't waste time worrying about aging. All energy went into creating an array of creatures to fill every conceivable ecological niche without caring about what happens to them after they pass on their genes to their offspring.
One reason for this view is that scientists can't find many animals in the wild that show signs of old age. All creatures - predators and prey alike - get eaten, die of starvation, suffer fatal accidents or perish from disease long before time catches up with them.
To Cutler and his colleagues, nature's plan is plain: "Nature gives us 30 good years. After that, it's up to us."
Life spans in nature's kingdom are incredibly diverse. For 1.2 billion years, bacteria and protozoa have never aged, for instance, because they reproduce by splitting in two. Fruit flies live for 25 days, human red blood cells for 120 days, elephants for 60 years. Some things - sponges, sea anemones - appear not to age at all.
How long can we live? Cutler believes that longevity is related to an animal's rate of development, the length of its reproductive period, its maximum caloric consumption, and the size of its brain. He calls this combination the mean lifetime potential of animal species and estimates the current human potential at 110 to 115 years.
While most of humanity expires well short of that potential life span, many of us are enjoying a considerably greater life expectancy than our recent ancestors. In less than 100 years, Americans increased their average life expectancy from 49 at the turn of the century to 76 today.
The big increase in life expectancy can be credited in part to better maternal, prenatal and medical care at birth, the eradication of many infectious diseases, better nutrition and hygiene.
This may seem obvious, but it's a development that took many biologists by surprise. No one suspected human life was so flexible. Many classic theories of aging have been overturned as scientists observed the numbers of people reaching old age.
Until recently the view about aging has been ambivalent - hoping we would live long enough to get old, yet being nagged by dread that we might.
But in 1986 the first Baby Boomers turned 40, and their fitness-conscious lifestyles show their determination to make their later years youthful ones.
More than 10,000 runners (42 percent) who finished a recent New York Marathon were older than 40 - and 56 of them were older than 70.
Two decades ago, 57,000 babies were born each year in the United States to mothers 30 and older. At latest count, the figure had risen to 250,000 annually, and first-time brides and first-time mothers older than 40 are increasingly common.
These changes reflect new attitudes about living and aging, scientists believe. Humans didn't become the longest-lived mammalian species by accident, and the Baby Boomers' quest for fitness and longevity may be a biological imperative brought about by our ability to think and to learn.
TOMORROW IN THE TIMES
They're called "oxygen-free radicals" and they possess the power to sustain life by fueling the body's chemical reactions. They also have the power to destroy it when they get out of hand.
DIET DESIGNED FOR LONG LIFE
Dr. Roy Walford has developed a diet that, if it works in humans as well as it does in laboratory mice, may increase the average lifespan to 120 years or longer. The following is a sample of one day's menu.
All weights are in grams .
1/3 cup buckwheat (35) .
Yeast (5) .
1 glass skim milk (244) .
1/2 cup strawberries (75) .
. LUNCH .
Vegetable curry x .
Indian brown rice x .
1 glass skim milk (244) .
. DINNER .
3 1/2 oz. black sea bass (100) .
Zucchini and tomatoes x .
1 glass skim milk (244) .
1 cup peas .
1 cup beets, cubed (140) .
. DESSERT .
1/2 cup low-fat yogurt (122) .
1/2 cup blueberries (70) .
1 tbsp. sunflower seeds (10) .
1 cup skim milk .
x 1 SERVING .
. NUTRITIONAL INFORMATION FOR ABOVE MENU . IN GRAMS .
Total calories 1,284 .
% calories from fat 11 .
Total protein 88 .
Total carbohydrates 220 .
Total fat 16 .
. SOURCE: CHICAGO TRIBUNE, "THE 120-YEAR DIET," BY ROY L. WALFORD .