Having It All

The discovery of numerous long-lived worms, mice, and flies has scientists squabbling over whether the creatures sacrifice health or fertility in exchange for their extra time. Now the two sides are close to compromise, say researchers who believe that organisms--including possibly humans--can have extra longevity and good health under the right conditions.

Geneticist Cynthia Kenyon's lab at the University of California, San Francisco, has become a veritable old age home for worms. In 1993 she and her colleagues discovered a mutant nematode with twice the normal life span, and they've since identified a host of genetic changes and other alterations that can prolong survival in these millimeter-long creatures. In September, her group reported the largest longevity increase ever. A normal nematode persists for about 20 days, but the study showed that mutant worms that had been sterilized and dosed with a certain gene-blocking molecule were still alive and wriggling after 120 days--making them the equivalent of 500-year-old people.

Kenyon isn't alone. Labs around the world are crawling with prodigiously long-lived flies, worms, and mice. Many researchers are confident that unraveling the survival tricks of these Methuselahs will guide them to treatments to stretch our own lives. But wait just a Darwinian minute, say evolutionary biologists. Because organisms don't have infinite supplies of food and raw materials, they can't excel at everything. Just as an engineer can't hope to double the size of a car's engine and boost its gas mileage, scientists can't generate organisms that have an extended life span without undercutting their abilities in some other way--usually by reducing reproduction. It's possible, these researchers say, that longevity-extending treatments will impair our fertility or even undermine our health. Scientists have been debating the point for a decade, but they could be inching toward a compromise view that suggests we can add years without paying a hefty price.

Organisms aren't designed, but they face engineering limitations similar to those of a car or a computer. A laptop can't have the number-crunching prowess of a supercomputer, for instance, because then it would fit only on an elephant's lap. Similarly, any creature has only a limited amount of proteins, fats, and other molecules to build and maintain its body and a limited supply of energy to power its activities. Evolutionary biologists argue that because organisms can't escape these constraints, improving performance in one area, say, longevity, hampers performance in other areas, such as making offspring. This idea of "design" constraints undergirds evolutionary biology, says geneticist Marc Tatar of Brown University in Providence, Rhode Island. The standard view, says Tatar, is that longevity and reproduction are like two children playing on a seesaw—: If one goes up, the other has to go down. Experiments in which increased life span goes hand in hand with decreased fertility back the view, he says.

Although researchers have nabbed many types of long-lived mutants, they usually have to look hard to find them. The rarity of these ultrageriatric organisms further supports the notion that the mutants don't breed as well as their normal counterparts do, says evolutionary geneticist Daniel Promislow of the University of Georgia in Athens. If a superorganism could live long and pump out lots of babies, it would gain a huge competitive advantage over its rivals. Such creatures would then be the norm, and what we regard today as typical animals would seem like sickly freaks.

And a decline in fertility is not the only possible side effect of enhanced longevity. Antiaging treatments that mop up harmful oxygen radicals--metabolic byproducts that damage cellular components--could have deleterious effects. Although many scientists blame these toxic radicals for the deterioration that accompanies aging, removing them could impair immunity, because our defensive cells use these caustic compounds to slay invading bacteria, says molecular geneticist Gordon Lithgow of the Buck Institute for Age Research in Novato, California.

The ethical questions about life-extending treatments get trickier if the costs include damaged health, Tatar says. Plenty of us would leap at the chance for a few extra decades, even if it meant we could have only a few children. In developed countries, most people already voluntarily curtail their family size. But, he asks, would people embrace a drug that promised extra years if, for example, it also increased the risk of cancer? (see "Dealing With the Devil").

Kenyon, however, is convinced that we won't have to pay any price for longevity: "Clearly, the idea that there has to be something detrimental is wrong." As evidence, she points to the large number of seemingly vital, long-lived mutants slithering, buzzing, and scurrying around her lab and others. Sure, some of the animals with extended life span are evolutionary losers. One strain of dwarf mouse, for instance, outlives normal rodents by 50% but is usually sterile. However, other creatures don't seem to pay a price for their extra days or month. This spring, for instance, a French team described a mouse strain that grows and breeds normally and lives up to 33% longer than typical mice. Such creatures appear to defy the tenets of evolutionary biology, much as two children on a seesaw who go up at the same time defy the laws of physics, says Tatar.

Not everyone accepts the idea that some animals have achieved long life without a price. The tradeoffs are there, Promislow cautions, but most researchers haven't looked carefully for their subtle effects. To find the hidden, long-term costs of longevity, he says, researchers need to see how the mutant animals fare in competition with their normal counterparts under natural conditions. For example, Lithgow and his colleagues pitted "wild-type" worms against long-lived wrigglers in the same culture dishes. When food was plentiful, both groups prospered. But when the worms had to endure periods of starvation, as they would in the wild, the mutants couldn't compete and their numbers dwindled. The performance difference between the nematodes proved to be small: After food supplies increased, the normal worms resumed breeding slightly sooner than the mutants did.

Lithgow sees his results as a way to reconcile the two viewpoints. Under natural conditions, mutant worms do lose some competitive ability in exchange for their longer lives, as the evolutionists predicted. But if the worms eat heartily, the tradeoffs seem to disappear, confirming many lab findings. And at high temperatures, the mutants prevail. The difference in outcome depends on the worms' environment. "It's possible, with the correct environmental conditions, to uncouple the costs" from the benefit, Lithgow says.

That's just what researchers working on ways to extend human life want to hear. If the costs can be separated from the benefits, scientists might be able to devise treatments to help us live longer and healthier lives. For example, if fertility is an issue, Lithgow suggests that it might be wise to delay antiaging treatments until after people have finished having children.

But figuring out how to live long and prosper will take more work. Researchers have some time to tackle the problem, Promislow says, because they don't yet know how to extend human life. If scientists do solve that conundrum, they'll be looking to long-lived worms and flies to show us how, instead of giving up health or fertility, we might be able to have it all.

Mitch Leslie, a science writer in Albuquerque, New Mexico, won't give up cheesecake even if it means living longer.