Defying the years

Monday, December 02, 2002


OAKLAND, Calif. — Time unravels us. Day by day, it peels away the layers of our lives until nothing is left but the nub of our own mortality.

Human beings are the only animals on the planet capable of contemplating their own demise. We mourn, we memorialize, we philosophize and we pray. And when it happens on that rare occasion that we “cheat” death or “escape” our fate, we believe, just for a moment, in the myth of immortality.

Today scientists are tempting fate in ways never before imagined as they demystify the secrets of longevity. Biochemist Bruce Ames believes that vitamins can repair damaged cells and make them “young” again. Molecular biologist Judith Campisi is studying how to keep cells from aging.

Both believe that while there may be no actual Fountain of Youth, no scientific Dorian Gray in a Bottle, reversal of aging and an extended life span are now on the horizon.

Bruce Ames is a chain-reaction thinker — one thought always leads to another — which may explain why the senior scientist at Children’s Hospital of Oakland Research Institute is so restless. Ames, 73 and wiry, often starts a conversation sitting down but invariably finishes it standing up, practically sprinting across his office to a blackboard to illustrate something about unattached free radicals or mitochondrial decay.

Chain-reaction thinking leads to big ideas, and Ames is a big idea man. Genes. Cancer. Nutrition. Aging. He has tackled them all, publishing more than 450 articles and becoming one of the most frequently cited scientists on the planet.

“I told a colleague recently that I was doing the best work in my career,” says Ames, who is also a professor of biochemistry at the University of California at Berkeley, “and he looked at me and said, ‘Bruce, you’ve been telling me that for 30 years.’ I guess that means my enthusiasm genes are undamaged.”

Ames should know. Damaged genes have been his business for half a century. Ames grew up in Manhattan as the son of a high school chemistry teacher and a mother who wanted him to be a doctor. Instead he became a researcher, graduating from the Bronx High School of Science before getting his undergraduate degree at Cornell and his Ph.D. in biochemistry at the California Institute of Technology.

In the 1950s Ames was a researcher in a lab at the National Institutes of Health, investigating ways to test for genetic mutation. His petri dish protocol ultimately proved that genes damaged by certain chemical substances often gave rise to cancer. By the 1970s, the “Ames test” was the world’s most widely used method for identifying potential carcinogens in everything from clothing to hair dye to pharmaceuticals.

“It’s just problem-solving,” says Ames about his research methods. “If you have two odd facts in your head and suddenly they fit together, you see some new way of explaining something.”

That’s what happened nearly a decade ago, when Ames turned his focus from cancer to aging.

How and why we age has been a mystery since humans first contemplated their own mortality. It is one of the most complex of biological processes: The human body contains more than 250 types of cells, and each type has its own peculiar aging characteristics.

There are scores of different theories about aging, but all of them can be broken down into two broad camps: theories that regard aging as the result of normal wear and tear from environmental insults and metabolic processes; and theories that regard aging as the result of a pre-programmed genetic plan, a process that begins at birth, or even at conception, and continues until our “biological clock” runs down.

As a scientist who loves studying process almost as much as its results, Ames falls in the wear-and- tear camp. His years of watching the cellular chaos created by cancer has given him perspective on the degradation of cells that comes with aging.

“In 6 million years of evolution, we’ve gone from a short-life creature to a long-life creature,” says Ames, “and age-specific cancers have gone up. Thinking about that said to me: A lot of cancer is just about getting old. And that got me interested in aging.”

Two odd events kept jangling about in Ames’ head: the rise in cancer and the increase in free radicals with age. Free radicals are molecular miscreants, compound substances that create havoc inside cells by stripping other molecules of their electrons. Was there a direct link between free radicals and aging? Was it possible that free radicals actually contributed to aging?



Ames began by looking at mitochondria, where free radicals are produced. Mitochondria are tiny structures inside every cell that act like furnaces, manufacturing most of the energy that is used by the body. Some cells with high metabolic rates, such as those in the heart muscle, contain many thousands of mitochondria. Other types of cells may contain as few as a dozen.


As energy-producing machines go, mitochondria are spectacularly efficient. Of the oxygen consumed by an average cell, the mitochondria convert 95 percent of it to help turn food — fats and carbohydrates — into a chemical fuel known as adenosine triphosphate, or ATP. Every time we breathe, in other words, we’re giving an energy boost to our cells.

During that process, mitochondria steal electrons from oxygen molecules in order to function more smoothly. But therein lies the problem. During those acts of larceny, a mitochondrion sometimes “misplaces” the electrons it is stealing. Like money flying out the back of a Brink’s truck careening around a corner, these misplaced electrons — now called free radicals — scatter around the insides of cells, bonding indiscriminately with other molecules.

This mischief is called oxidation, and it allows free radicals to become chromosomal rototillers, breaking and mangling DNA at will.

Too many free radicals create a kind of cellular pollution that stiffens cell membranes and wears down enzymes. Too much damaged DNA results in cell mutations (which can cause cancer). Both are signs of aging.

If not for these free radicals, Ames realized, mitochondria could be a cellular Fountain of Youth.

In 1990 he and his colleagues at Berkeley announced the findings of their study. They’d discovered twice as much free radical damage in tissues of 2-year-old rats as in those of 2-month-old rats. Ames had found a crucial link among oxidation, DNA mutation and age: Free radical oxidation doesn’t just rise with aging, it causes it. The more that mitochondria “leak” free radicals, the more those radicals end up damaging the mitochondria, which in turn leak even more free radicals.

This vicious cycle gets only worse with age. It is the ultimate biological irony: The thing we most need to live — oxygen — is the very thing killing us.

Ames estimates that the DNA in each cell of the human body experiences at least 100,000 “hits,” or instances, of free radical damage per day.

“Living is like getting irradiated,” says Ames. He admits it’s a slight oversimplification, but free radicals created by radiation do the same thing as free radicals created by breathing. “With age, despite the mitochondria trying to keep it all in check, the level of free radicals goes up, which means the level of oxidized protein goes up, which means the level of DNA damage goes up.”

Most scientists believe that mitochondrial health is only one cog in the aging wheel.

“Aging is complex and will not be explained by one gene or mechanism,” says Jerry Shay, who holds the Distinguished Chair in Geriatric Research at the University of Texas Southwestern Medical Center. Shay believes Ames’ research is promising but that other biological processes affecting longevity must be taken into account, since “different tissues may have fundamentally different mechanisms underlying their maintenance and repair.”

To prove that mitochondrial dysfunction actually causes us to age, Ames decided to work backward. If he could find a way to restore mitochondrial health by lowering free radical damage, he could improve cellular function. In essence, he could turn back the cells’ biological clocks.

(Ames is in no hurry to turn back his own biological clock. He likes to joke that he gets his exercise by “running” experiments, “skipping” the controls and “jumping” to conclusions. His wife of 40 years, biochemist Giovanna Ferro- Luzzi, heard the joke for the 50th time recently and exacted her revenge: “She got me a personal trainer.”

Ames says he has time for only about an hour a week with the trainer, but his wife insists they walk the two miles to their favorite Italian restaurant, Oliveto, for lunch at least three times a week.)



It was while visiting his wife’s native country in the mid-1990s — they have a house in Tuscany and an apartment in Rome — that Ames got the idea for how to improve mitochondrial health and perhaps slow, or even reverse, the aging process.


A dietary supplement known as acetyl-L-carnitine, or Alcar, was sweeping Italy. The latest nutritional fad was being marketed as a pick-me-up, and Ames understood why: Alcar is a naturally occurring biochemical involved in the transport of fatty acids into the cell’s mitochondria. In other words, Alcar helps cells produce energy.

When Ames got back to his lab, he started feeding Alcar to his old rats.

And the old rats loved the stuff. Within weeks, they appeared re-energized, and their biochemistry was running more smoothly. There was a problem, however. As the Alcar improved mitochondrial health, it also appeared to increase the level of free radicals. Ames decided to add another nutritional supplement to his rats’ diets, the anti-oxidant alpha lipoic acid. Another naturally occurring chemical, lipoic acid, he thought, should work by tuning up mitochondrial function, thereby lowering free radical oxidation.

The results were staggering. Said Ames earlier this year, after the findings of his research team were published in the Proceedings of the National Academy of Sciences:

“With these two supplements together, these old rats got up and did the Macarena. … The brain looks better, they are full of energy. Everything we looked at looks more like a young animal.”

Some researchers believe the hope offered by maintaining healthy cells or rejuvenating old ones is limited.

“You can achieve immortality at the cellular level, but I don’t see how it would be practical in extending life span,” says Robert Lanza, the medical and scientific director of Advanced Cell Technology in Worcester, Mass. “There’s a wall at 120 years. We can continue to piece things together. But we’re like tires; there are just so many times you can be patched up.”

Ames acknowledges he has not discovered the Fountain of Youth but lays claim to a Fountain of Middle Age. The evidence, he says, lies not only in the physical rejuvenation he observed in his rats, but in their improvements on cognition and memory tests. Says Ames: “It was the equivalent of making a 75- to 80-year-old person look and act middle-aged.”

Ames looks every bit the part of an elderly gent, with his white hair, bifocals and quaint bow tie. While he has a penchant for mixing plaids, his mind is relentlessly mixing and matching ideas.

“I was always sort of a B-student in school, but I loved reading enormously. Still do. I was always a pretty creative thinker. I try to be a generalist. I make my living as a big picture guy, always looking for the next big idea.”

Ames put his current big idea into a pill. In 1999, he and a colleague, Tory Hagen, founded a company to sell the energy formula as a dietary supplement. The pill, available over the Internet, includes 200 milligrams of alpha lipoic acid and 500 milligrams of acetyl-L-carnitine, but Ames says the two nutrients just as easily can be purchased separately at any health food store.

While Ames and Hagen’s company, Juvenon, licenses the supplement, the University of California holds the patent. Juvenon has yet to make a profit. If it does, the university will get a third. Another third will go to the university’s department of molecular and cell biology, where Ames is a professor, and the remaining third will be split by Ames and Hagen, now at the Linus Pauling Institute at Oregon State University.

Clinical human trials are ongoing. Ames, for one, is satisfied enough with the animal results that he takes a dose of his own supplement twice a day. He admits he hasn’t noticed any significant changes in himself just yet.

“Is it a reversal of aging or just a slowing?” he asks himself out loud. “The rats seem to do better on the IQ test as well as the treadmill test, so that looks like a reversal. …

“I don’t want to over-hype it. If you’re an old rat, it looks very good. But we still have to wait for the results from the human trials. There’s every reason to think it’s going to work in people. I’m very optimistic.”



In her basement office in nearby Berkeley, Judith Campisi perches herself on the edge of a chair and speaks with a wide-eyed enthusiasm usually reserved for first-year graduate students. Campisi is a senior molecular biologist at Lawrence Berkeley National Laboratory. An expert in the genetics of aging and a proponent of the “biological clock” theory, the 54-year-old scientist believes that “reprogramming” human genes to extend life span may not be far off.


It is 7:30 in the evening and Campisi is in no hurry to go home. “I have no separation between my work life and the rest of my life,” she admits without hesitation, and the evidence is all around her: three empty yogurt cups in the wastebasket, and on a shelf below a side table, a kind of researcher’s survivor kit — a couple of cans of Progresso hearty chicken soup, a container of Cafe Vienna coffee, a makeup mirror and hand lotion.

Piles of papers rise from the floor like unsteady chimneys, forcing pedestrian traffic to take a serpentine route through the room. The stacks are layered with journals bearing such titles as “Trends in Cellular Biology” and “Experimental Gerontology.” On a nearby table, “Handbook of the Biology of Aging,” a textbook co-written by Campisi, sits atop a tower of paper nearly as tall as the 4-foot-10 biochemist.

Campisi’s research focuses on the telomere, a structure containing a repeated DNA sequence that is found on both ends of every chromosome in the human body. In 1990, Calvin Harley, now the chief scientist at Genron, a California biotech company, discovered that as cells divide, the telomeres of the new cells become shorter.

A few years later, it was shown that in some cells telomeres also get shorter with age. When telomeres become too short, they send a signal to the cell to stop dividing and a natural cellular state called senescence ensues. Campisi believes the primary function of senescence is to fight off cancer.

“Senescent cells are not dead,” she says, “they’re perfectly alive, they metabolize, but what they can never, ever do again is divide. And if you can’t divide, you can’t form a tumor. …

“It’s only in the last .00001 percent of human evolution that we have had the luxury of living in an environment where the food supply is good, infections are pretty much kept at bay, and there are no lions jumping out of the savanna to kill us. But for the vast majority of evolution, we evolved under very hazardous conditions. The life span was probably only 25, 30, 35 years at most. So think about what happens. If all evolution really does is devise a system to keep an organism — keep us — cancer-free for 30 years, well, then it does a pretty good job.”

What it doesn’t do is keep us young.

Campisi’s research has shown that the longer we live, the more senescent cells our bodies accumulate, and it’s those senescent cells, she says, that may play a leading role in making us look and feel old. If she can prove this hypothesis, Campisi will have identified one of the main contributors to aging: We age not because our cells die, but because they stop dividing.

“We reasoned several years ago that because the senescence response is an arrest of cell proliferation, but not cell death, after about age 50 we start to see significant numbers of these cells appearing. And we know from our culture studies that these cells don’t function properly, and so we’re filling up with these dysfunctional senescent cells the longer we live, and so this may be an important reason we age.”



Campisi, like Ames, came to aging by way of cancer research. She came to research, however, by way of a Catholic girls high school.


“When I finally got to college,” she says, “I decided I wanted to take classes with lots of guys. I was good at science and I liked it, but the best part was all those men majoring in it.”

Campisi, who was born in Queens, graduated from the State University of New York at Stony Brook in 1974 and stayed on for her doctorate, which she received five years later. Along the way, she married, divorced and settled into a career in cancer research. In the mid- 1980s, during a postdoctoral fellowship at Boston University, a colleague came calling with an offer.

“He was putting together a project grant on aging, which I wasn’t even interested in at the time,” says Campisi, “and they needed one more scientist. He said, ‘Do you think we could get you interested in a problem called cell senescence?’ The funny thing is, he didn’t think senescence had anything to do with aging.”

Campisi came to see that cancer researchers were looking at one aspect of senescence, researchers on aging were looking at a different aspect of it, and “nobody tried to get those two to come back and talk to each other.”

Campisi didn’t have to. She looked at both aspects herself, and like several other molecular biologists discovered a critical connection among cancer, aging and cellular senescence.

“When the telomere becomes dangerously short but not completely gone, it sends that signal to the cell to stop dividing,” she says. If it didn’t, the DNA tips on the end of the chromosome would become raggedy, and the chromosome would start seeking out other broken chromosomal pieces — and “that,” says Campisi, “is the hallmark of cancer.

“Now, how does a healthy cell know that it doesn’t have a broken piece of DNA? The telomere.”

Telomeres allow cells to senesce, and if such cells stop dividing, they can’t form a tumor. “The question is,” says Campisi, “what happens to an organism that begins to accumulate senescent cells with age?”

Cancer, again, may hold the key.

While normal cells can divide only so many times (known as the Hayflick Limit), cancer cells are essentially immortal, and in 90 percent of them telomerase, an enzyme, can be found. Telomerase replaces the bit of telomere clipped off after each cancer cell’s division.

If telomerase production can be turned on in normal cells, it seems reasonable to assume that normal cells could be immortalized.

“One thing we’ve learned from the mouse model,” says Campisi, “is that you don’t want cells to not senesce at all, because if you do that, you have cancer. What would be great would be to have some of those senescent cells die, so that they don’t accumulate with age. That’s what we’re working on. It’s not going to be easy to do that, but that’s the idea, that’s the long-term goal.”

Campisi credits her scientific creativity to her wide-ranging education, which includes an undergraduate degree in chemistry, a Ph.D. in biophysics and postdoctoral research in the biology of cancer.

“I kind of learned at an early age not to be bound by field or science or even technique. And so I think when you have that kind of broad training, you move between fields very easily.” Moving between fields allows Campisi to keep looking for the next thing she needs to know. “You have to have this fire in the belly to know the answer to something, and then you just go and find out.”

Research, says Campisi, is a lot like one of her favorite pastimes, cooking. A little of this, a little of that — the best of meals are unplanned, the result of intuition and experimentation. “I consider recipes advisory only,” says the microbiologist.

Likewise in her research. Campisi enjoys creating her own path to an answer, pursuing solutions not with a sprinter’s speed but at an ambler’s pace, taking the time to search out familiar territory for missed clues and overlooked details.

“I have this philosophy of I just start doing this random walk,” says Campisi, “and eventually I wind up where I need to go.”

Currently, she is walking her way through the complex problem of aging by trying to identify the molecular mechanisms responsible for cellular arrest, studying the defective genes in premature aging diseases, and determining how telomere length is regulated. The payoff from that research, she hopes, will be a postponement of aging.

Some scientists, such as Jay Olshansky, a professor of public health at the University of Illinois at Chicago, express caution when it comes to the promise of research into aging.

The co-author of “The Quest for Immortality” said last year: “When we survive into old age, just as with automobiles and race cars, things start to go wrong, and unless we can change the structure of the body itself or the rate at which aging occurs, then inevitably things will go wrong as we push out the envelope of human survival.”

Lanza, of Advanced Cell Technology, believes the problem of wear and tear will soon be overcome.

“I think there’s no question that in two or three decades we’ll be able to replace every part of the human body,” says Lanza. “Whole organs, like blood vessels and bladders, have already been grown in the lab.”

Like Ames, Campisi believes the secret to longevity is about maintaining a balance in the biological processes, whether it’s mitochondrial function or the stability of the DNA.

“Eventually you run out of cells, which is why immortality is not on the books,” she says. “But a reversal of aging — as long as you define the aging process segmentally — is within our grasp.

“We really are talking about how to preserve the health of tissues for the maximal period of time, for a very long and healthy extended middle age.”

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