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From The Genomics Age

Read interviews with some of the scientists working hard to extend our healthy life spans, reprinted with permission from Gina Smith's The Genomics Age: How DNA is Transforming the Way We Live and Who We Are.

Copyright © Gina Smith

Eighty and Loving It!

"Sixty Is the New Thirty" reads a cover of the AARP magazine, the one with the beautiful (and at the time of the photo, fifty-nine-year-old) Lauren Hutton on the cover. It is a breathless cover story and hardly scientific, but it makes you think. Thirty has been a magic number. Aristotle once said "the human body is at its best between the ages of 30 and 35." So if age 60 is the new 30, is 110 the new 80? Will it ever be? "It remains to be seen," says Leonard Poon, director of the University of Georgia Gerontology Center, "if you pass the threshold of, say, 120, whether you could be healthy enough to have a good quality of life."

To point, Madame Jeanne Louise Calment, the world's record-holding oldest person, lived to 122. But in the end, her family members were literally propping her up for interviews. Calment, however, lived independently well into her hundreds. Most centenarians, in fact, are even driving into their nineties and keeping up with lifelong hobbies. Is there a genetic reason for this? What do these old folks have that the rest of us may not? And is there a secret to prolonging youth, and not just years?

Old "youth" just seems to run in families, says Thomas Perls, a Boston University geriatrician who has been heading up the New England Centenarian Study, the largest DNA study ever of people age 100 and older. He is also a founder of Centagenetix, a Boston company that is hoping to find medicines to retard aging. He points to a photo of Sarah Knauss who, before she died in 1999, held title to being the oldest woman in the United States. She is pictured, at age 119, alongside her 95-year-old daughter, her grandson, her great-granddaughter, her great-great-granddaughter, and her great-great-great grandson. In all, six generations of Knausses sat still for a single snapshot. Pictures such as this will be increasingly common. The U.S. population now includes more than 40,000 souls age 100 or older. (In 1950, there were fewer than 2,300.) It is the country's fastest-growing demographic group.

"We are not trying to find the fountain of youth," Perls says. "If anything, we're trying to find the fountain of aging well." Most of the 750 participants in his centenarian study have aged well by any measure. "We have a small number of people, particularly guys, who do everything short of throwing an atomic bomb at their bodies and still live to 100," Perls says. They eat lots of fat and sugar. They never exercised. Some have been smoking multiple packs a day for half a century. (France's Calment had smoked filterless cigarettes for more than a hundred years of her 122-year life.) They even seem to age more slowly. If you look at pictures taken throughout their lives, you will notice that centenarians generally look younger than their peers at every stage.

Perls and fellow scientists say they are sure that these oldsters have genes that allow them to get away with things that would send most of us to early graves. But what are they, and where are they? In all likelihood, there is a vast network of genes that helps people live to extreme old ages, he says. Some genes may slow aging throughout life. Those genes have not been located, says Perls. However, a few age-related genes have turned up, according to his research. One lies smack in the middle of chromosome 4. Called the microsomal transfer protein gene, it appears to control how much cholesterol clogs up your veins. If you have this gene - one of the "genetic booster rockets," Perls calls them - you are more likely to live longer. While it isn't a switch that goes on and off, the mere presence of this gene does seem to appear in centenarians more often than in the general population. The gene may have the effect of limiting, or at least delaying, the onset of such age-related diseases as Alzheimer's, stroke, heart disease, and cancer, Perls says.

Jumpstarting the Search

"When we finally are able to add significantly to our lifespans," says Cambridge University geneticist Aubrey de Grey, "we will look back and ask the moral question, why did we not do it sooner?"

De Grey is perhaps the most outspoken biologist in the world. His Rasputin hairstyle and beard and his formal English demeanor belie his relative youth in this field - he is just forty years old. And he is an international rabble-rouser, a ruthless critic of the medical establishment's overly conservative approach to anti-aging. De Grey has made headlines with his claims that, outside of the fringe, venture capitalists and pharmaceutical companies aren't investing enough in anti-aging research. He says that's primarily because there's no short-term profit in it. "The funding isn't there," de Grey says. "But if we can do it in mice - significantly increase the years they are alive - this would be a result so impressive that it would trigger an immediate war on aging."

To this end, de Grey and colleagues have created the Methuselah Mouse Prize, named for the biblical figure claimed to have lived 969 years. In a prize potentially worth tens of thousands of dollars, scientists hoping to win must come up with the longest-lived laboratory mouse. (An alternate Methuselah prize will go to the late-intervention longest-lived mouse-that is, the mouse scientists waited until adulthood to treat.)

Getting a mouse to live to at least five years of age, instead of the normal two years, will be the first hurdle. Andrzej Bartke of the Southern Illinois School of Medicine managed to get his mouse, a genetically engineered critter named GHR-KO 11C (11C for short), to live 1,819 days, just short of five years. That is the equivalent of 150 to 180 human years. To accomplish this, Bartke engineered 11C with a gene that would limit the animal's production of insulin, leading to less age-related damage to the cells.

Once imaginations are captured, de Grey says he is optimistic about extending human lives to age 120 or even 130, within decades. "We now know all the processes that make up aging well enough to target aging," de Grey says. "And when you want to manipulate a complicated system, you only have to understand it a limited amount. You don't have to understand all of it. If we manage to triple the life expectancy of a fifty-year-old," he says, "we are pretty much there." That is, typically a fifty-year-old could expect to live another thirty years. If we could triple his or her remaining years, then science would have ample time to catch up with even better, longer-lasting treatments. The trick, he says, is going to be "repairing damage as it occurs."

An Engineer's Approach

Essentially, de Grey is advocating an "engineer's approach" to aging. Rather than trying to slow down the process of deterioration, you simply get better at fixing damage as it happens. This is the same as how you would keep an old house in good repair. You fix the roof when it has a leak; you paint the house when it needs it; you upgrade the wiring every few decades.

"This means that we should, in due course, be able to take people who are already middle-aged or more and rejuvenate them," says de Grey. "We will, in the first instance, only be able to do this imperfectly and incompletely, but that will be long enough to extend life span a bit. As time goes on, we will get progressively better at that. In fact, we will get better at an accelerating rate [as with all technology]. This means that eventually we will be getting better at fixing aging at a faster rate than time is passing. We will be encountering new things that go wrong with us at older ages, but we'll be fixing them faster than they arise." De Grey, to this end, has identified seven "strands," or areas of aging, that aging engineers might focus on in the future. They range from modifying genes to reduce the incidence of cancer to finding ways to replace cells that are lost to heart disease and Parkinson's.

"This might be difficult if it weren't for monkeys. They're fabulously similar to us and prone to age at least as twice as fast as us," de Grey says. "So we don't yet know what 200-year-old humans will die of, but we don't need to until we have some people that old-and by that time, we will for some time have had 100-year-old monkeys that we've been treating in just the same way that we treat ourselves: bad diets, no exercise, but all the life extension technology that we use on ourselves. And because those monkeys will have exhibited the same symptoms 200-year-old humans would, we'll have been working for a long time on fixing [those symptoms] in monkeys by the time humans get them. And when that occurs, we'll already know how to fix them well. By the time the first humans reach [age] 300, the same will be true by an even greater lead time. This all [depends] on the monkeys getting the same problems that we get, but at under half the age, but that's a pretty safe assumption," de Grey says.

According to de Grey's vision, eventually scientists will reach a kind of "escape velocity," at which point anyone with access to the latest medical care could live almost indefinitely. "At that point we will die only from accidents, wars, homicide, et cetera."

Slowing Aging Indefinitely

Richard Miller, a biogerontologist at the University of Michigan, has another perspective. "Most kids, when they are growing up, go through a phase where the idea of getting old and dying is really scary. . . . I did, too. And most people grow out of it, and I didn't. . . . If you're interested in scientific mysteries, things that aren't yet solved, where people really need to use their intuition to discover what the important cracks are, aging is right up there at the top of the list as cancer biology was fifty years ago or infectious disease was 200 years ago." While he agrees with de Grey that most scientists are too pessimistic about longevity research and more funds are desperately needed, he doesn't think fixing things that go wrong may extend life by enough of a margin. Research shows, he says, that the average woman would only live to age 95 if cancer, stroke, heart disease, and diabetes were fixable. But if you could slow down her aging - as some scientists have done with mice by restricting their calories to the level of a near-starvation diet - she'd probably survive to the age of 115, and would be basically healthy up until the end.

The idea that people can live longer as a result of a severely restricted diet is based on work done in 1935 at Cornell University. There, scientists discovered that calorie-restricted rats lived longer than rats fed regular diets. In the last sixty-five years, there have been hundreds of other studies showing similar results, and such organizations as the National Institute on Aging (NIA) spend several millions of dollars a year on related research. The calorie-restriction longevity technique may work because it lowers blood sugar levels, but scientists say they don't advise it for humans: It tends to make people miserable. However, a drug that duplicates the effect of lowering blood sugar is an oft-cited goal among anti-aging specialists.

"In general, I like the idea of fixing things," says Miller. "If someone has a broken arm, a cast is in order, and if someone has cancer, taking it out is a good idea. But in my view, none of this has much to do with aging research. So many things go wrong, more or less at the same time, in old individuals [such as two-year-old mice, ten-year-old dogs, and seventy-year-old people), that the notion that one can somehow fix all of them seems wrongheaded to me, particularly because at this point we don't have any really good ideas about how to stop any of the key problems-cancer, Alzheimer's, diabetes, heart attacks, hip fractures, and many other problems."

"The nice thing about anti-aging interventions," Miller continues, "is that, like caloric restriction and some genetic mutations, in unknown ways these postpone or retard nearly all of the adverse effects of aging at the same time. So I think it would be a good idea to learn more about how aging works to produce the diseases and disabilities of old age so that we could, potentially, figure out how to delay this process and stay alive and healthy for longer."

Miller agrees with de Grey that one of the biggest problems facing aging research is a lack of funding. "I think that if it were politically feasible to devote to aging research the same kind of funding that has gone into Alzheimer's disease research, or into AIDS, or into breast cancer, or 10 percent of the money that goes into the purchase of cosmetics - $45 billion per year in the United States - we would, in twenty to thirty years, have some pretty good ideas about how to delay aging in people," says Miller. "Actually testing these approaches in people would take a generation, though testing them in pets [dogs, for example] would be a good deal quicker."

An Unexpected Obstacle For Anti-Aging Research

As you've seen, biogerontologists are all over the map in their theories for what exact treatments will work to delay aging and lengthen human life. But one of the biggest obstacles they face is the attitude people have toward the research. Biogerontologist Richard Miller calls it "gerontologiphobia."

"There is an irrational public disposition to regard research on late-life diseases as marvelous, but to regard research on aging, and thus on all late-life diseases together, as a public menace bound to produce a world filled with nonproductive, chronically disabled, unhappy senior citizens consuming more resources than they produce," Miller says. The same arguments were made 200 years ago, against penicillin, surgical anesthesia, and plumbing systems, he adds.

According to Aubrey de Grey, "[T]here's the plethora of arguments why curing aging might not be a good idea . . . but that's just a crutch to help people not get worked up about the perceived infeasibility. They'll be forgotten overnight when big progress is realized . . ."

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