Best Life, October 2007Link Two preeminent aging experts are on opposing sides of a bet that someone living today will be alive in 2150. At stake is not only a wager but also the answer to fundamental questions about the biology of aging and the ability we have to stretch our life span.
If he hadn’t been savaged by a lion, Steven Austad might never have discovered the elasticity of aging. Just out of college, he became friends with a lion trainer who rented animals to movie studios. Soon he was in Hollywood, working with exotic felines. One morning, he was walking Orville, a 300-pound lion, when a duck darted out from some reeds. The 2-year-old lion pounced, and Austad disciplined the big cat with a slap on the head. Orville released the duck, but then pounced on Austad. He knocked Austad down and sunk his teeth into Austad’s knee. Austad didn’t struggle because he knew lions are possessive of their food and Orville might lunge for his neck next. So he waited…for 15 minutes…with the lion gnawing on his leg. Finally, another trainer spotted him and sprayed Orville with a fire extinguisher. Austad spent six days in the hospital and realized that he needed to find a safer, more rewarding way to work with animals. He became a biologist and traveled the world, ending up on the remote savannas of Venezuela, studying a less frisky animal, the opossum.
While trapping female opossums, attaching radio collars, and catching them again every month to count the babies in their pouches, Austad noticed something bizarre. “They were falling apart at an incredible rate,” he says. “I’d catch one that would look great, and then I’d catch her a couple of months later and she’d have cataracts and arthritis.” Why, he wondered, did they age on such a fast schedule? Why did they get old at all? As animals age, their cells show increasing signs of damage. But animals also have the ability to repair their cells. So why weren’t the opossums keeping their bodies in good working order until they were killed by a predator or a parasite? “That question doesn’t strike enough people as a mystery on its own,” he says. “Just about everything we are familiar with ages, so people just accept it as a given. But I don’t.”
Austad scoured the scientific literature for ideas about why we age, and he found a hypothesis that explained it: Aging is an inescapable by-product of evolution. Repairing damaged cells may let an animal live longer, but it also requires a lot of energy that could be used for other things -- like maturing faster and having bigger litters. In Venezuela, Austad proposed, living fast and dying young was the best way for the opossums to pass on their genes. Stalked by jaguars, they were likely to be killed anyway, so staying youthful was a waste of effort. If Austad was right, opossums that enjoyed a safer life might also enjoy a slower, longer one.
On Sapelo Island, off the coast of Georgia, Austad found a population of predator-free opossums. They had it so easy that he often found them sunbathing in the road. He tagged and tracked them for the next few years. The chilled-out island opossums, he discovered, lived 25 percent longer than their cousins on the mainland. They also enjoyed better health for a longer time. It was as if Austad discovered an isolated Pacific island on which people regularly lived to 100.
Austad started to formulate an idea that would inform his research for the next 20 years: Aging isn’t set in stone. It’s more like Silly Putty, stretched and squashed as animals adapt to their changing world. In fact, Austad and other researchers found they could make animals live longer, either by changing their diets or tinkering with their genes. These experiments led Austad to a startling conclusion: It might be possible for man to take over where evolution left off and slow the rate at which we age, stretching our life span.
It wasn’t an idea he embraced lightly. As one of the nation’s preeminent experts on aging, Austad, a professor of cellular and structural biology at the Sam and Ann Barshop Institute for Longevity and Aging Studies, at the University of Texas, spends a lot of time debunking the many bogus claims that float around about how to live forever. Yet he could not ignore the possibility that someone would eventually develop a drug that could slow the aging process, adding healthy years to people’s lives. By February 1999, Austad was ready to go on the record. At a gerontology symposium, a reporter asked him if, and when, someone would live to the age of 150.
“I think that person is alive already,” he replied.
That remark caught the attention of another aging expert, S. Jay Olshansky, who had spent the previous 15 years poring over historical data on human longevity. “You’ve got to be kidding,” Olshansky told Austad over the phone. Olshansky didn’t think anyone was going to live to 150 anytime soon. But Austad was quite serious, and so the two men made a wager. They each put up $150, which Olshansky invested in a fund. The winnings will be handed out in the year 2150. If there is a 150-year-old alive on earth -- someone of sound mind and body -- Austad’s descendants will get the pot, which Olshansky has calculated will grow to $1 billion thanks to his shrewd, but secret, investments. If no such Methuselah can be found, Olshansky’s offspring will win.
In the years since the bet, the two scientists have closely monitored new evidence, and, somewhat remarkably, neither has seen any reason to budge on the bet. This fall, they’re even debating each other before an audience of insurance executives like two prizefighters. In one corner, Austad, the swashbuckling adventurer and optimist, points to the accelerating pace of discoveries about aging: Scientists have identified the genes that prolong the lives of animals and discovered ways to switch those genes on, and researchers are launching pharmaceutical start-ups to create the first real antiaging drugs that could slow the cellular damage. In the other corner, Olshansky, the number-crunching realist, sees too many hurdles in the way. In fact, he suspects that any benefit antiaging drugs might bring could be wiped out by a set of rising threats to public health, such as the epidemics of obesity and diabetes. Even with antiaging drugs, the average American life span may shrink over the next generation -- one of the few times since the influenza pandemic of 1918 that this has ever happened. Despite their diverging perspectives on life expectancy, both men share a belief that science is finally catching up with aging, and this has ramifications for us all.
While Austad has spent his career trekking through jungles and capturing animals, Olshansky has spent it swimming in data -- health surveys, actuarial tables, historical records. A professor of epidemiology at the University of Illinois, he is one of the founders of a science called biodemography, which uses biology to explain changing patterns of longevity. He explores these figures to find the rules of aging. When insurance companies and the Social Security Administration want to find out how long people will live, Olshansky is the man they call.
Olshansky, 53, has a trim gray beard and a high bald dome. Somewhat surprisingly, he’s a Cubs fan, and describes himself as an eternal optimist. He even has a bet that the Cubs will win this year’s World Series. “You know what death rates look like?” asks Olshansky. He’s sitting in a booth at Max and Benny’s Restaurant, not far from his house in Deerfield, Illinois. In front of him sits a half-eaten plate of hoppel poppel, a barge of scrambled eggs with chunks of salami the size of Swiss Army knives. (“Rare indulgences won’t kill you,” he says.) He grabs a napkin and draws a falling and rising curve to illustrate how hard it is to make people live longer.
In the past century, the average life expectancy in America has increased dramatically. A girl born in 1900 had a life expectancy of 49 years. A girl born in 2003 can expect to live 80 years. Many demographers think this trend will continue, and within a few decades, the average life expectancy will push beyond 100 years.
Olshansky dismisses such predictions. “I sort of chuckle whenever I see that done,” he says. “The people who come up with these numbers have blinders on.” To demonstrate why these extrapolations don’t make sense, Olshansky once analyzed the world record for the mile. Since the mid-1800s the record has fallen from about four and a half minutes to the current record of three minutes and 43 seconds. If you simply project that trend into the future the way many demographers extend life expectancy, you’d predict that in the year 2580, someone would be able to run the mile in precisely zero seconds. There are fundamental limits to how fast a human can run, argues Olshansky, and there are fundamental limits to how long people can live.
The curve Olshansky draws on his napkin is a graph. It tracks the odds that a person will die at any given age, calculated from the life spans of millions of actual people. From birth, it falls until about age 10, whereupon it begins to climb, soaring exponentially over the decades. In the early 1900s, explains Olshansky, the young end of the curve was much higher than it is today. Babies died of diarrhea and other infectious diseases. Young women died in childbirth. Thanks to clean water, better public health, and medical innovations like antibiotics, many of those early deaths have been eliminated. The increase in the average life expectancy in the United States is thanks mainly to the young lives that have been saved in the past century.
“But we could only achieve that once,” he says. “Once you’ve used it up, you’re done. You then have to focus in on what happens at older ages. At the older ages, it’s no longer diphtheria and tuberculosis. You’ve got aging. You can treat diphtheria and tuberculosis. You can’t treat aging -- yet.”
As we grow older, our bodies change. Our skin wrinkles, our backs stoop, our brains fill with plaque, and our blood vessels stiffen. Changes take place within our cells as well, including damage from environmental toxins and oxygen free radicals, the shortening of telomeres (the tips of chromosomes) as cells divide, and other things that scientists still don’t fully understand. All these changes raise our odds of dying, if not of one disease, then of another. Those odds double every seven years or so. That pace is the same from one culture to the next, Olshansky and his colleagues have found, and from one period of history to another. “No matter where we looked, it’s the same,” he says. Aging, in other words, is deeply etched in our biology. In fact, the same pattern turned up when Olshansky looked at other species. Dogs, for example, live only 10 years on average. But if you draw a dog curve and a human curve on the same scale, they are practically identical.
While the odds of dying have dropped dramatically for babies, they have dropped far less for the elderly. The maximum life span of humans has barely budged over the decades, even as the average life expectancy has soared. Simply attacking this or that disease won’t extend the human life span any further, says Olshansky. “Eliminating cancer would only get about three and a half extra years,” he says. If tomorrow no one ever died of a heart attack again, three years. In fact, the mortality curve suggests that ordinary medical advances would be unlikely to push the average life span of Americans past 85 years. A tiny fraction will live beyond 100.
In the seven years since the bet, obesity has exploded into a nationwide epidemic. Obesity can lead to heart disease, diabetes, and other potentially fatal disorders. Olshansky and his colleagues have built demographic models to project the effect obesity will have on the average life expectancy in the United States. The picture is grim. “We’re losing between two and five years within the next 50 years,” he says, “which is huge.”
Steven Austad, now 60 years old, still has the stocky body of a college wrestler, and there are creases on his face from field seasons in the sun. Although the malaria he contracted in Papua New Guinea still flares up, he rarely finds himself in the jungle these days. He has traded traps and radio collars for microscopes and centrifuges. In fact, he has brought the field to his lab near San Antonio: There’s a colony of naked mole rats in the basement. He and his colleague are now searching for the molecular differences between species that die young and others that live long.
In the years since the bet, Austad has grown even more certain that he’s right. Scientists now have a much more detailed understanding of how shutting down certain genes and restricting calories slow aging.
Scientist Edward Masoro, at the University of Texas, pioneered research in the 1990s that showed that calorie restriction in animals leads to a longer, healthier life span. It turns out that a low-calorie diet switches on a key gene called SIRT1, which controls a network of dozens of other genes. They create an army of proteins that protect a cell from damage. Related versions of SIRT1 trigger the same response in mammals, insects, and even yeast. Scientists in laboratories across the country were performing similar experiments on spiders, mice, and worms. For example, researchers at the University of California shut down a gene called daf-2 in a microscopic worm known as Caenorhabditis elegans and it lived twice as long. The scientists weren’t sure what daf-2 actually did, but the results were undeniable. Researchers at Brown University found that manipulating a gene known as IGF-1 had a similar effect on flies.
Discovering genes like SIRT1, daf-2, and IGF-1 opens up a new way to fight aging. After all, human biology isn’t all that different from the biology of mice or worms. We share many genes, such as daf-2, and they do similar things for us. So if scientists are already figuring out how to slow aging in animals, it might be possible to do the same for people. Instead of going hungry for the rest of your life, you might be able to take a pill containing molecules that are able to switch on SIRT1 in your cells. In recent years, scientists have launched a large-scale search for those molecules. One molecule that switches on SIRT1, known as resveratrol, is produced by grapes and other plants. Harvard University’s David Sinclair, PhD, and his colleagues have found that, as predicted, resveratrol shows signs of slowing aging. They fed resveratrol to 1-year-old mice that ate a high-fat diet that would normally cause them to drop dead after about a year. But with regular doses of resveratrol, the badly fed mice enjoyed a mortality rate as low as mice on a normal diet -- three years.
Resveratrol may turn out to be the first antiaging drug (Sinclair took a purified form of resveratrol for four years but cautions others against doing so until more studies are done), but others are in the running as well. Sinclair and his colleagues have founded a company called Sirtris Pharmaceuticals to search for other compounds that may do an even better job of switching on SIRT1. Elixir Pharmaceutical, another pharmaceutical hatchery, is following up on the discovery of daf-2’s life-extending powers. About a dozen others are pursuing molecular-based antiaging drugs. It’s also possible that antiaging drugs may emerge from other investigations of old age, like the one going on in Austad’s lab. Other scientists are studying aging-linked genes found in all animals. Austad is curious about genes that evolved only in the lineages that gave rise to long-lived species.
Consider his naked mole rats, which usually live in subterranean tunnels in Africa. A mouse lives three years or so. Naked mole rats, by contrast, live more than three decades. He wants to know what the naked mole rat has that ordinary rodents don’t. It may be the same thing that other long-lived animals have as well. Austad and his colleagues are examining the cells of long-lived animals and comparing them with their short-lived cousins. So far, only one thing seems to unite all the long-lived animals: They do a much better job of fixing their DNA. As our cells are damaged over time, tiny patches of our genes become garbled. Some of those mutations are harmful, causing our cells to make defective proteins or even turn cancerous. Our cells manage to repair a lot of this DNA damage, but not all of it. It’s possible that extreme longevity has evolved through the same path each time. Austad is figuring out how each species makes its repairs to understand how that leads to long life. “We hope we’ll ultimately discover pharmaceuticals that can mimic the same thing and repair our DNA,” he says.
Austad didn’t imagine an army of 150-year-olds when he made the bet. People live to different ages, thanks to a mix of good genes and lucky experiences. The current record holder is Jeanne Calment, a Frenchwoman who died in 1997 at the age of 122 -- after smoking for almost 100 years. In the coming era of antiaging drugs, Austad thinks a 150-year-old Calment isn’t too much to expect. “Only one person has to do it,” Austad points out, for him to win.
Despite the fact that Olshansky is betting against any human making it to 150 years, he is impressed with the scientific progress on the biology of aging. “In our lifetime, I think you and I are going to be taking a pill to slow our aging,” he predicts. “No matter when we take it, we will benefit.” Antiaging drugs could, he believes, change the way doctors practice medicine. And on this count at least, he and Austad are in agreement.
Today researchers help the elderly by trying to cure one disease at a time -- a medical Whac-a-Mole approach. But curing any one disease does not change the shape of the mortality curve. “If you pick off diseases one by one, it’s really not a pleasant situation,” says Austad. “You’d just uncover all these other diseases that lay behind them. Imagine a society full of demented people, or people who are incontinent or immobile. Not a pretty picture.”
Rather than curing diseases one at a time, Austad and Olshansky agree that researchers should be focusing more of their efforts on solving the underlying problem of the elderly: being old. When scientists have succeeded in extending the longevity of animals, the animals generally became healthier even at an advanced age. Humans might enjoy the same benefit. A drug that slowed the course of aging might give a 60-year-old the same risk of developing osteoporosis as a 53-year-old, for example. The same goes for Alzheimer’s disease and other diseases of the elderly. Shifting the risks back by seven years would wipe out millions of cases of these diseases, allowing people to enjoy their final years in better health.
Unfortunately, medical research these days isn’t set up very well for this sort of revolution. There’s no pipeline for developing and testing drugs for their ability to slow the course of aging. Sirtris Pharmaceuticals is already running clinical trials on humans to test a form of resveratrol. But they’re not testing it as an antiaging drug. They’re testing it as a treatment for diabetes.
Although the private sector is racing to develop these drugs, Austad and Olshansky believe a true antiaging pill will require a major governmental push, a Manhattan Project of Aging. Together with a group of prominent aging researchers, they’re calling for $3 billion a year to be directed to finding compounds that slow aging. “If somebody found a cure for cancer, they’d get the Nobel Prize,” says Olshansky, “but the fact is that the discovery of a way to slow aging would be the equivalent of finding a cure for cancer and for heart disease and for Alzheimer’s and for osteoporosis -- all at the same time. It makes much more sense to go after the one thing that gives rise to all these things.”
Three billion dollars may sound like a steep price tag, but Olshansky points out that Medicare -- which is what we have to pay as a country to treat the ailments of aging -- costs $408 billion a year. What’s more, the numbers of the elderly and infirm will continue to increase for decades. Consider the coming toll from just one disease of aging: Alzheimer’s. Five million Americans have it today, and by 2050, that number could rise to 16 million. The economic toll of Alzheimer’s and other forms of dementia will rise by a factor of 10 to $1 trillion a year. “If we succeed, it has tremendous potential to reduce costs,” says Olshansky. “Not just today, but for every generation.”
It’s a bet, in other words, that everyone would win.
Copyright 2007 Carl Zimmer