Reality Check

A new program run by the National Institute on Aging seeks to standardize how researchers study longevity in laboratory mice. The initiative aims to provide definitive answers about which interventions prolong survival.

When gerontologist Richard Miller decided to test claims that the testosterone precursor DHEA extended life, he did something a bit unusual. Instead of feeding the hormone to inbred mice--animals generated from pairing brothers and sisters--he first mated a couple of different strains to stir up his subjects' gene pool.

Miller, at the University of Michigan, Ann Arbor, wanted to test DHEA in animals that more closely represented the genetic diversity found in populations of wild mice--not to mention humans, who rarely marry close kin. Researchers usually work with laboratory animals that have been bred so that each individual has the exact same set of genes. That way, the scientist can feel confident that she is testing the effect of one variable against a uniform background.

But the practice has its drawbacks. In studies that assess antiaging therapies, detractors can argue that any intervention--whether vitamins, hormones, or diet--might take advantage of "the Achilles' heel of a particular strain," says gerontologist George Martin of the University of Washington, Seattle. By testing his drug of choice on a population of mice with a mixed bag of genes, Miller took the first step toward untangling decades of sometimes inconsistent or inadequate data on animal longevity.

Many of the longevity studies that have been conducted over the past 20 years are peppered with minor flaws, notes biochemist Huber Warner of the U.S. National Institute on Aging (NIA) in Bethesda, Maryland. Scores of researchers working in different laboratories, with many species, under varied conditions have drawn up a slate of genes and treatments that appear to retard aging, or the diseases with which it is associated, in their favorite laboratory animals. Unfortunately, the variability in this Whitman's sampler of data makes it hard to compare the results of one study with those of another to determine which treatments work consistently--and how those interventions extend life. Before humans try an antiaging therapy, researchers want to know that it isn't a flash in the pan. With the exception of a draconian diet known as calorie restriction, none of the interventions studied to date appear to slow aging in multiple animal species, says Miller. Although mutations in certain genes enhance longevity in a variety of species, treatments that mimic them have yet to be identified.

To tame the experimental inconsistency, NIA has launched a new type of research program. Typical government grants dispense funds to individual research labs to test their favored supplements and regimens. Instead, NIA has named three labs that will conduct the same set of experiments simultaneously in mice. The officials in charge of the new Interventions Testing Program (ITP) are soliciting ideas, and a committee will decide which strategies to pursue. Researchers with promising proposals will collaborate with the three labs to outline protocols--deciding how much of a drug to give, for instance--and they will be co-authors on the resulting publications, but they won't perform the experiments. ITP will not "give people money. It will give them research data," says Miller, whose lab is one of the three experimental sites.

The program focuses on mice because these animals serve as a model organism for the study of mammals--including humans--and scientists can manipulate them to reveal the physiological means by which treatments work. The critters are also attractive because calorie restriction--the closest thing to a gold standard for life extension--boosts their longevity (see Counting Up the Calories, Holding Back the Years?).

The mice used in the ITP labs will be housed under identical conditions and receive standardized quantities of food and water. Like Miller's mice, they will share a kaleidoscopic gene pool. Such mice suffer from a range of ailments as they age, similar to humans. Thus, an intervention that extends life in the ITP populations should be more relevant to humans than regimens identified by studies in inbred mice, says Martin.

The experiments will be performed in laboratories designed to bar unwanted germs. "Many life-span studies have been conducted in less-than-ideal situations, for example, in labs that aren't guaranteed pathogen-free," says endocrinologist William Sonntag of Wake Forest University in Winston-Salem, North Carolina. Exposure to deadly viruses or bacteria could skew the results, he says, by killing the animals in a way that is unrelated to aging.

In addition to studying life span, the ITP researchers will delve into the physiological mechanisms that underpin successful interventions. Such understanding is key to designing safe life-extending treatments for humans. Furthermore, if investigators discover that different regimens work the same way, they can focus on the more palatable and inexpensive treatment when attempting human trials.

For example, supplementing food with antioxidants or cutting calories increases mouse life span. Unfortunately, some studies aimed at assessing the antiaging properties of antioxidant supplements didn't measure the caloric intake of the animals, says Martin. "If you put a bunch of nasty-tasting stuff in their food, they're not going to eat as much," he adds.

The search for strategies is on. "We are canvassing the whole [aging research] community to see what interventions to test," says NIA's Warner. Besides antioxidants and compounds that might mimic calorie restriction, ITP researchers are also considering chemicals that prevent metabolic byproducts from damaging molecules inside cells. Also up for nomination are drugs that interfere with the biochemical pathway that responds to insulin and related molecules; mice with mutations that inhibit this pathway tend to live longer than normal.

No single intervention is likely to ameliorate all of the afflictions associated with aging, says Martin. With any luck, however, the ITP program will harvest a cornucopia of curatives that will prove useful not only for a wide range of mice and their kin but also for the rodents' more distant mammalian relatives.

Mary Beckman is an aging writer based in southeast Idaho who sees the benefit of ranking mice among her kin.