TOPICS

COLUMNS

LISTINGS

2002 LISTINGS

HELP

PARTNER LINKS

HEALTH

Taming time: The science of getting older

Maybe some day in the future, our vision of birthdays will change. Scientists investigating the genetics of aging are looking for ways to lengthen the years of vim and vigor or extend the human life span.

By Victoria Stagg Elliott, amednews staff. July 1, 2002.

Mapping Disease
As the results of the Human Genome Project began to shake out into clinical applications, this 2001-02 series detailed progress in the prevention and treatment of a variety of diseases and conditions -- both on the near horizon and possibilities far into the future.

Humans have dreamt, written and sung about living forever -- or at least living longer -- since the beginning of civilization.

There were the Greek gods who occasionally shared their immortality with mere mortals. And Jesus brought Lazarus back from the dead. In modern literature, living longer is a frequent theme, particularly in science fiction.

Links

In science and medicine, the hunt for the genetic basis of aging, and ways to address it, is the long-sought holy grail, the fountain of youth, the sweeping theory that promises to explain everything about human health -- the reasons for immunity, vulnerability, health, sickness, strength and frailty.

"Unlike cancer and heart disease and all the other diseases, everybody ages," said Robert Costa, PhD, professor of molecular genetics at the University of Illinois at Chicago. "And because we're living longer, we're seeing some of the problems with aging, stuff we never saw before."

To a certain extent, American society is already addressing the genetics of aging. On average, Americans have children later in life than those in less-developed countries, weeding out genes more likely to result in death at an early age.

Many believe this phenomenon -- along with improved medical care and better nutrition -- has played a part in the near doubling of life expectancy and the growing population of centenarians that has occurred during the past 100 years. Several studies have also confirmed that living longer has at least some genetic basis.

Americans wait longer than people in developing countries before having children.

Most recently, a paper in the Proceedings of the National Academy of Sciences found siblings of centenarians had lower mortality rates than the population at any age after adolescence. Other studies have found centenarians tend to be healthier at every age.

"Centenarians are not just people who've been able to keep ticking along in a vegetable state and make it to 100," said Evan Hadley, MD, associate director for geriatrics and clinical gerontology of the National Institutes of Health National Institute on Aging. "They are people who have managed to hold off the decline that is more typical of the overall population."

Siblings, however, share more than genetic material. It's also clear that the environment plays a significant role, particularly early in life. Studies of twins that examine aging rates in connection with various factors such as sun exposure and smoking have shown clear links.

But most believe the role played by environmental factors is strongest for those who reach their mid-70s, the current average life expectancy. Studies of those who live to become centenarians indicate that it is more likely that genetics propels them to this mark.

Physicians who treat this population report a wide array of behaviors ranging from the very healthy to such things as smoking, drinking and eating badly -- the very practices that put most people in the grave early.

"The right answer on a test would be to say that longevity is 80% environment and 20% genetics, but it's very complicated," said Nir Barzilai, MD, director of the Institute for Aging Research at the Albert Einstein College of Medicine. "It's the right answer, but it's not the full answer. Medical intervention has really changed life expectancy, but when you go over the age of 95 you find that the genetic effect of longevity is really marked."

Genetics plays the strongest role in people who live to 100.

Despite the strong environmental influence, many scientists prefer the genetic approach because some behaviors and other aspects of the environment that are known to result in longer life for the majority who are not blessed with a centenarian's genes can be tricky to change, particularly if the result is less than pleasant.

Calorie restriction, for example, has long been known to result in a longer life, albeit one of lower quality.

"You're cold, hungry and grumpy," said Leonard Guarente, PhD, the Novartis Professor of Biology at the Massachusetts Institute of Technology. "It's not something that most people will go for."

Dr. Guarente is hunting for a drug that would target the SIR2 gene and mimic the effect of calorie restriction without requiring that people eat less. Many of his studies, however, are still in lower organisms, and there are questions about whether the research will be applicable to humans.

"That is a line of research that could lead to something," said Dr. Hadley. "But there's a lot to be worked out as far as what those genes are doing in people as opposed to other organisms."

Addressing DNA damage

Other scientists are looking at ways to address DNA damage, often considered the root cause of aging, and cell repair. Most are aiming to improve the length of a healthy life, viewing expanding the life span much beyond 120 years as unrealistic -- certainly in the short term.

"I'd like to get the people who are dying at 65 to live to be 70," said David T. Burke, PhD, associate professor of human genetics at the University of Michigan in Ann Arbor. "Talking about getting people to 150 is the wrong issue at the moment."

Genes in a region of chromosome 4 set the stage for centenarians' long lives.

Meanwhile, Dr. Costa is trying to build a better mouse, one that heals itself as well when it grows older as it did when it was younger. He has so far created mice with durable livers by up-regulating the cell repair gene FoxM1B, and he believes his work will result in a better quality of life rather than a longer life.

"You won't get degenerative diseases," said Dr. Costa. "And you'll live a better life."

Still others are looking for drugs that could mimic the physical conditions created by the centenarians' lucky genetic heritage.

In studying the super-old, Dr. Barzilai discovered a pattern. These subjects appeared to be genetically predisposed to high levels of good cholesterol. Would it be possible to create a drug that could mimic this?

"I'm looking for longevity genes," he said. "If I find the genetic component, then I can develop a drug that will prevent age-related diseases."

Other studies have indicated that a region of chromosome 4 contains the genes that set the stage for centenarians' long lives. It remains a mystery, though, what these genes actually do or exactly which are important of the 400 to 500 in that region.

"We may understand why we age," said Duane Superneau, MD, chief of the section of medical genetics at the Ochsner Clinic in New Orleans. "The problem is we understand a lot less about how we age."

The genetics of aging is, however, tricky to research. The two genetic diseases that mimic it -- progeria and Werner's syndrome, both of which are characterized by premature aging and death -- are imperfect models. Scientists are struggling to build animal models that might be better. And to study those with long lives takes a very long time, with human subjects possibly outliving the researchers. Also as time passes, the environment is frequently changing and introducing uncontrolled variables.

"One of our major problems is there's a total failure sometimes to reproduce results," said Dr. Burke, who is working to develop mouse models of aging. "It's extremely difficult to talk about setting up an experiment whose time course is 40 years long. We need to talk about how we're going to construct experimental systems that many investigators can tap into."

Getting to the crux of the issue

The lack of good models means that experiments on aging can often be expensive. And studies of centenarians may not result in useful data because the most important information is not that they are now older than 100 but how they got there. The result of all this is that there are many theories floating around about aging with little proof behind them.

"We're theory-rich and data-poor," said Dr. Burke. "And we've got to change that ratio with some good animal models. If you want to research centenarians and their kids, you've got a 20- or 30-year wait till they become 100."

Many concede, however, that the answer to the question of how we age may be all of the above -- SIR2, FoxM1B, genes that raise good cholesterol, the region on chromosome 4. Little is known about how these different aspects may work together, but most suspect that they do.

"It's extremely unlikely that it's just one gene," said Bard Geesaman, MD, PhD, vice president of informatics at Centagenetix, Inc., a Boston-based biotechnology firm trying to close in on the exact genes on chromosome 4 that can lengthen life. "You could probably implicate nearly all the genes in the aging process."

But everyone is hunting for the one out of many that could change everything by slowing down or even stopping aging. The one gene that when suppressed or highly activated can mean the difference between 65 and 70, or even 70 and 300, a healthy, long life, or one marred by decay in the last couple decades.

There is, however, no clear winner in sight.

"I'm confident that we will break the 120 barrier, but I don't think it's promised by any of the research going on now," said Dr. Barzilai. "It's my goal and the goal of everyone to work within this time limit and live longer with a better quality of life."

But with so much at stake -- any therapy that could address aging would be a blockbuster drug -- several companies including Centagenetix have been set up to pursue it, hunting for the one factor that can make a difference.

"What we want is the gene that has a strong effect on our ability to achieve an extreme age, and then understand how that gene is working," said Dr. Geesaman. "But in terms of market opportunity, if we could even come up with six targets with potential, it would be huge."

Even the most optimistic feel the first drugs won't be available for at least 20 years, and there will be many hurdles before then because there may be unintended consequences of up-regulating or down-regulating certain genes.

"Longer life can be achieved in lower species," said Dr. Barzilai. "But by mechanisms that if they exist in humans will kill them young."

Up-regulate P53, a tumor suppressor gene associated with aging, for example, and you will age rapidly. Down-regulate it and cancer will ravage the body uncontrollably. If FoxM1B is up-regulated, diabetes is more likely.

And it is unknown what everybody living longer could do to society. The United Nations is already warning of an elderly "population bomb," and those who live longer in fiction frequently live miserable lives.

"You've got to watch what you want," said Dr. Costa.

ADDITIONAL INFORMATION:

Project accelerates the genetics revolution

In the two years since the first draft of the human genome was released, a flood of new genetic-related discoveries have been announced.

Scientists found they were no longer limited to analyzing the genome one gene at a time and have discovered new insights into how genes work together. Pharmocogenomics is closer to reality than ever, and numerous genetic tests have been developed. Gene therapy had its first success when the technique was used to treat severe combined immunodeficiency -- "bubble boy" disease.

The Human Genome Project made Francis S. Collins, MD, PhD, director of the National Human Genome Research Institute, and J. Craig Venter, PhD, then president of Celera Genomics, media darlings. But while Dr. Collins remains head of the government's genome project, Dr. Venter is no longer running Celera. He has turned to philanthropy -- forming three nonprofit organizations focusing on ethical and legal issues brought up by the project. He also became the first person to make a medical decision based on the sequence of his own genome and is now taking a statin drug to keep his cholesterol low.

"It's the future of medicine," Dr. Venter said. "Within 10 years every physician will be making decisions based on the genetic code of their patients."

A final draft of the Human Genome Project is due out next year.