Source: Business Week
Date: 11 October 2004

Aging Is Becoming So Yesterday

Tantalizing new discoveries suggest the possibility
of reengineering the body.

The New England Centenarian Study collects data on people 100 and up, with 1,500 very senior citizens enrolled. It's getting easier to find subjects -- there are 40,000 such people in the U.S., and it's the fastest-growing demographic segment. This could be because the very old are unusually resistant to the ravages of age. Surprisingly, long-lived people don't necessarily make it because of their lifestyle. Dr. Thomas T. Perls, associate professor of medicine at Boston University School of Medicine and chief investigator of the Centenarian Study, reports that many of his subjects spent much of their lives eating fatty foods, drinking alcohol, exercising sporadically -- and, in 20% of cases, smoking. They come from all social and racial backgrounds. Common denominators: They generally are thin, handle stress well, and are female (85%). One role model is Jeanne L. Calment, believed to be the world's oldest person when she died in 1997 at 122. She quit smoking only two years before her death and attributed her long life to port wine, a diet rich in olive oil, and a sense of humor.

Perls's research indicates that Calment may have had something more basic going for her. He believes centenarians live longer because their bodies are particularly resistant to the disorders that kill most people before age 90, such as cancer and heart disease. Perls calls this trait "selective survival," the vigorous ability to overcome health obstacles that defeat the majority of humans. And this ability appears to be heritable, because centenarians tend to cluster in families.


A broad swath of researchers around the world are determined to ferret out the factors that confer this survival advantage. They are toiling in government labs, academic settings, and tiny startups, and have already figured out how to extend the lives of yeast, worms, flies, and rodents by 30% to 40%. This requires new ways of thinking about some of the great unanswered questions in biology. If answers are found -- if people can be reengineered to live routinely to be 110, or 120, or 150 -- it will have an impact on every aspect of society in ways that economists, health-care experts, and social scientists are only beginning to contemplate.

The pace of the research will probably outstrip that of policymakers trying to deal with its implications. Dr. Donald K. Ingram, head of the experimental gerontology lab at the National Institute on Aging (NIA), concedes it could be a decade or more before there is a fundamental breakthrough on life extension, and there may be considerable risks in tampering with the aging process. Nevertheless, he says, "I think the discovery of some agent that would increase life span by 20 to 30 years is not unreasonable."

So far, such an agent is strictly hypothetical. The many potions hawked at "longevity clinics" and health-food stores are so ineffective that 51 renowned scientists published a manifesto in Scientific American debunking them. "No currently marketed intervention -- none -- has yet been proved to slow, stop, or reverse human aging, and some can be downright dangerous," they charged. "Anyone purporting to offer an anti-aging product today is either mistaken or lying."

It makes sense that there is no easy fix, because the aging process is enormously complex. Consequently, scientists are pursuing myriad ways to slow it down. Some are teasing out the dozen or more genes that can protect the body from the ravages of aging, while others are manipulating hormones that do the same. Still other groups devote their time to figuring out how to delay the damage caused to cells by oxygen particles called free radicals, which essentially rust the body from the inside out.

Substances contained in blueberries, red wine, spinach, and other foods are all under investigation for possible life-extending properties. The most publicized approach, the effort to extend life through extreme calorie restriction, has even engendered cultlike groups around the world eagerly hoping to cheat the clock by sticking to near-starvation diets.

All of these efforts are part of the search for a fountain of youth that has been going on for at least 3,000 years (some of the earliest theories are documented in an Egyptian papyrus titled Book for Transforming an Old Man into a Youth of Twenty). But it wasn't until the past 100 years that most people could expect to reach even middle age. In 1900, the average life expectancy in the U.S. was 48; today, it is 80 for women and 75 for men. Virtually all of these gains can be attributed to improvements in public health and safety, such as clean water, refrigeration, seat belts, and routine vaccinations.

In recent years, advances against heart disease and cancer have extended life expectancy by a further seven years or so for the over-65 set. There is a finite number of years to be gained from curing disease, however. To get people routinely living well to 110 or 120, the aging process itself would have to be slowed.

This is no easy goal, because there is no single factor, such as a gene, that directly determines aging. The process is more of an evolutionary byproduct. Nature simply has no need for any organism to live beyond its reproductive age, plus whatever time it takes to raise its young. Once most living things pass their reproductive prime, their bodies fall apart. All the cellular processes needed to sustain life start to wear out, and organisms become slower, weaker, and more prone to disease. Humans, because they have no natural predators, are able to soldier on well past this particular sell-by date, as do household pets, but our parts eventually do break down. Nevertheless, there is no biological switch that demands that life be terminated. We are not programmed to die.

The lack of a "death gene" has caused many scientists to speculate that there is no biological reason why humans could not live to be 150. In reality, age is the greatest risk factor for mortality, because the aging process makes the body more susceptible to heart disease and cancer, the most common causes of death. This raises a knotty dilemma for longevity researchers. Should they try to delay the aging process itself or bolster the body's ability to ward off the diseases of aging?

Caloric restriction, for example, is an effort to slow down the aging process so that deadly diseases will strike much later in life. Researchers have found that worms, mice, and rats raised on diets with 30% or fewer calories than they would normally consume can live 30% to 40% longer than the average, and in better health. A subsistence diet seems to retard the aging process, allowing the animals to resist disease longer.


Similar experiments are under way with rhesus and squirrel monkeys by Ingram at the NIA and a team led by Richard A. Weindruch at the University of Wisconsin. These animals, which share most of their genome with humans, normally live from 24 to 40 years. So far, after 15 years on a restricted diet, the middle-aged primates have lower-than-expected levels of blood pressure and triglycerides, and higher levels of health-protecting hormones. Those readings indicate that the animals should be able to stave off heart disease, diabetes, and chronic diseases once they reach old age.

Few humans, however, could tolerate such a diet. The only monitored human experiment of caloric restriction was inadvertently conducted on the eight occupants of Biosphere 2 when they discovered their food supplies were much lower than expected. Dr. Roy L. Walford, one of the participants, reported that over two years on a diet of between 1,750 and 2,100 calories a day (the recommended daily allowance is 2,500), the occupants showed the same beneficial metabolic changes as long-lived rodents on calorie-restricted diets. However, the participants complained of feeling hungry all the time -- causing one to wonder if centenarians on such a diet would find their long life worth living.

Consequently, a number of scientists in the field of aging are searching for "calorie-restriction mimetics," substances that would trick the body into thinking it is on a drastically reduced diet. One of the most intriguing candidates was first identified in the lowly yeast. In 2000, Leonard P. Guarente, professor of biology at Massachusetts Institute of Technology, discovered that a yeast gene called SIR2 acts as a master switch, activating or shutting down parts of the genome based on how much energy is available.

When food is scarce, SIR2 slows down a yeast cell's energy-processing function to make sure it will survive to reproduce when conditions improve. Guarente's lab has found that yeast cells given an extra copy of the SIR2 gene live longer than normal, while those missing SIR2 have much shorter life spans.


Guarente's lab is focusing on a human gene equivalent to SIR2 called SIRT1, which evolved to protect cells from dying during times of famine. SIRT1 turns off the body's ability to store fat, using it for fuel instead -- making the gene an important target for obesity research. SIRT1 could also explain the health benefits often attributed to red wine: resveratrol, a substance in the skin of grapes, has been found to activate the gene.

Guarente is involved in one of the few companies devoted to anti-aging research. In 1999, he and another leading researcher in the field, Cynthia Kenyon of the University of California at San Francisco, started Elixir Pharmaceuticals Inc., based in Cambridge, Mass. They were later joined by Perls, director of the Centenarian Study, as well as Louis Kunkel and Dr. Annibale Puca of Harvard Medical School. "We talked to a lot of people about commercializing our research, but Big Pharma is not ready to buy into the idea that there are central mechanisms underlying disease," says Guarente.

Elixir's stated mission is to find drugs that target the genes involved in the aging process. Guarente predicts such a drug could be available in 5 to 10 years, though he says it likely will be developed as an anti-obesity or diabetes treatment rather than an aging preventive -- because it could take some 70 years of clinical trials to prove that aging can be delayed.

But even if genes can retard the rate of aging, the body must still contend with the stress of living. Every day, cells are attacked by free radicals, toxic oxidants created when oxygen, fats and carbohydrates combine to produce energy. These particles bombard each cell some 10,000 times a day. Over time, the attacks begin to wear the cells down, leaving them vulnerable to disease much the way rust weakens a car's structure. Many scientists believe that if some sort of biological anti-rusting agent could be found to protect against free radicals, the body would be able to fend off disease much longer.

That agent could be related to superoxide dismutase (SOD), an enzyme produced by the body to break down the most damaging free radicals. By turning up the activity of SOD and an accompanying enzyme called catalase, a number of experiments have extended the life span of fruit flies and worms by a third more than normal.

Significantly, researchers have not had the same luck with mice, raising some doubt about SOD's usefulness in mammals. Scientists at Oregon State University had better results when they fed older rats lipoic acid and acetyl cartine, chemicals that are converted into antioxidants inside the cell. The rats regained agility, looked yournger, and had better-functioning brains and immune systems.

Blocking free radicals could cause some blowback, though. Gordon J. Lithgow, an associate professor at Buck Institute for Age Research, warns that "we need free radicals to protect against infection. By manipulating these genes, we may be introducing a fatal flaw."

There are, of course, some perfectly safe ways to extend life. If more humans lost weight, stopped smoking, exercised regularly, and drove carefully, the average lifespan could easily be extended a further 10 years. But just staggering through another decade wouldn't satisfy most people. As Lithgow points out, "everyone wants another 10 years. But to be quite honest, it's not just the lifespan they want, but a healthy longer life."

That desire ensures that anti-aging research will continue to flourish. Until it produces results, we might all want to start drinking port.
and further reading

Living Forever?
Immortal Youth?
Longevity Genes
Yoda the Ancient
Caloric Restriction
Daf-2 and longevity
Antiaging Drugs 2006
Stress, telomerase and aging
New treatments for aging brains
World's Oldest Supercentenarians
Does caloric restriction significantly prolong life?