Sci. Aging Knowl. Environ., 3 July 2002
Give Me Liberty or Give Me an Early Death
Lolling on a soft rug by the air conditioner, a pampered poodle is a far cry from its cunning, hardy wolf ancestor. Domestication has taken the wolf out of our dogs, and it has similarly robbed lab mice of genes that slow aging, according to a new study. Wild mice not only outlive their lab-dwelling cousins but also show hormone concentrations associated with slower aging, report Richard Miller, a gerontologist at the University of Michigan, Ann Arbor, and colleagues in the July issue of Experimental Biology and Medicine. The results suggest that studying only lab-adapted strains of rodents might hamper understanding of the molecular mechanisms that make us grow old.
Most of today's lab mice descend from wild rodents captured by mouse fanciers, says Miller. They fancied striking fur colors, oddly shaped ears, or other novelties, and they wanted tame animals that were loath to escape. As they mated favorites to enhance these qualities, the connoisseurs were also inadvertently selecting for animals that grow faster and larger, mature sooner, and bear more pups. When scientists inducted these mice into the lab in the early 1900s, they continued selective breeding, changing the animals further. The result, after hundreds of generations under artificial conditions, is the frumpy, docile, often inbred lab mouse (see figure). By comparison, wild animals are lean, mean, and athletic, says Miller: "These mice can jump from your shoes to your shoulder in a single bound, bite you, and then be out under the door before you have time to react."
To add experimental heft to these anecdotal observations suggesting that life in a cage had adjusted the rodents' physiology, development, and aging, Miller and colleagues compared three wild strains with a lab strain. One wild lineage came from animals captured in barns and fields in Idaho, and the other two hailed from the balmy Pacific islands of Pohnpei in Micronesia and Majuro in the Marshall group. The researchers cultivated the lab rodents by crossing four commonly used strains, thus avoiding inbreeding, which can truncate longevity. Using blood samples from young adults in all four lines, the team gauged two physiological markers: the concentration of the fat-regulating hormone leptin and the amount of glucose-bound hemoglobin, an indicator of blood sugar values. They also tested for thyroxine, the thyroid hormone that fires up metabolism, and IGF-1, a middle manager in a biochemical pathway that regulates growth and metabolism (see Bartke Viewpoint). In addition, the researchers determined when females reached sexual maturity.
The Idaho mice outlived their lab counterparts by about 25%, and one Methuselah from the group survived for 1450 days, a record for a fully fed nonmutant mouse (see his obituary). Compared with the lab strain, the Idaho mice also had much less leptin, which correlates with low body fat, and IGF-1, but their thyroxine readings didn't differ. IGF-1 and thyroxine quantities are meager in long-lived Snell and Ames dwarf mice and in mice that are calorically restricted, a regimen that also promotes longevity. In addition, the Idaho mice were, on average, about 75% lighter than the lab mice--although the wild rodents were still about one-third heavier than long-lasting Snell and Ames dwarves, and females from Idaho weren't ready to mate until they were twice as old as the lab Lolitas.
The Majuro animals also outlasted the lab group. That observation surprised the researchers, because the island mice had whopping values of glucose-bound hemoglobin. Calorically restricted animals and some dwarf mice harbor particularly small quantities of blood glucose, and some scientists think that this characteristic presages long life. The longevity of these sugar-saturated mice argues that we need to learn more about the connection between blood glucose concentrations and life-span, Miller says. Unlike the other wild groups, the Pohnpei rodents weren't long-lived. The mice might be suffering ill effects of inbreeding due to a small initial population, the researchers speculate.
The results suggest that during their captivity, lab mice have lost genes that promote long life, Miller says. Nobody is sure about the identity of these misplaced genes, he says, but the study points to genes that control the rate of maturation. The Idaho mice grew slowly and bloomed late, and their low IGF-1 values reflect this pokey rate of progress. But the energy they save by ambling early on could be funneled into, say, better mechanisms for repair or maintenance, which might confer a longer life. Miller and colleagues plan to start looking for chromosome segments that differ between wild and lab mice, and researchers might eventually be able to track down the genes responsible for the differences in longevity, growth, and metabolism.
But David Harrison, a physiological geneticist at Jackson Laboratories in Bar Harbor, Maine, argues that the difference could come down to appetite. In captivity, Idaho mice might be eating less than their lab counterparts, even when they encounter an endless buffet of tasty mouse chow. Their dainty appetite might be an adaptation for the food scarcity they often face in nature. The animals are calorically restricting themselves, he suggests, and their slower maturation and low IGF-1 quantities reflect their self-restraint. "The Idaho mice look like the result of a successful food-restriction experiment," Harrison says. Although the researchers didn't measure food intake in the animals, previous work by co-author Steven Austad of the University of Idaho, Moscow, suggests that even in captivity, wild mice eat less than lab rodents do (see Austad Perspective).
The study doesn't invalidate all we've learned about aging from studying mice, says molecular biologist Caleb Finch of the University of Southern California in Los Angeles. But it does deliver an important message for researchers who use animal models. The large differences between lab and wild mice demonstrate that details of aging in one strain might not apply generally. Broadening the range of model organisms is particularly important, says Finch, if we hope to transfer discoveries made in animals to humans. Like wild mice, we are not an inbred, lab-adapted population. "If you want to develop a model for an outbred species [like humans], you would want to pick an animal that hasn't been selected for artificial conditions," he says.
Evolutionary geneticist Daniel Promislow of the University of Georgia, Athens, concurs. The same pattern shows up in fruit flies: Lab varieties breed earlier, squeeze out more offspring, and die sooner than their wild counterparts do, he notes. The abbreviated lives of lab animals raise the possibility that genes that supposedly extend longevity could instead be restoring "sick" animals to a normal life-span, Promislow says: "As we get closer and closer to finding the genes that are important for the aging process, we need to know if they are important only in lab organisms or in all members of the species." One test would involve mating long-lived lab rodents with wild ones to determine if the putative life-extending genes add time.
Don't expect animal rooms to be teeming with wild mice in the near future, Miller says. The rodents create a slew of headaches for their keepers, because they bite hard and escape as readily as Houdini. But to ensure that their results don't just apply to lab mice, researchers need to go a little wild.
July 3, 2002
Mitch Leslie, a science writer in the rodent playground of New Mexico, prefers the gamey taste of wild mice.
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