A Methodical March Toward Immortality

Over the next few years, researchers will troll through the DNA of yeast, worms, and mice in hopes of generating a comprehensive list of genes that grant long life.

For gerontologists at the University of Washington (UW) in Seattle, the magic number is 800,000. No, that's not how many baby boomers will turn 65 today. It's the number of baby yeast cells that these researchers will pry away from their mothers in an attempt to identify every gene that might make these creatures--and maybe even people--live longer.

Stealing children from their parents isn't generally considered a noble pursuit, but in this case the kidnapping is the first part of a five-year project, funded by the Ellison Medical Foundation, that will begin by scouring the entire yeast genome for genes that regulate longevity. The researchers will then take these life-extending genes and search for their counterparts in worms and mice. Finally, they'll determine whether any of these genes bestow on these animals long life.

"It's the first time someone's tackled the problem of going through every gene and trying to develop a comprehensive list" of those that retard aging, says biogerontologist Richard Miller of the University of Michigan, Ann Arbor. "It's a big thing to bite off." It's so big that the project, called the Consortium for the Determination of Public Pathways Regulating Longevity, will employ investigators from at least four UW laboratories, each with its own area of expertise.

Looking for genes that regulate life span in multiple species, the scientists hope, will maximize the likelihood that they will identify biochemical pathways that are relevant to aging in all animals--including humans. "When you think about worms and yeast, they're very different from each other. So anything that regulates aging in those disparate systems is likely to also regulate aging in mammals," says molecular biologist Brian Kennedy, a Consortium member.

Kennedy and his UW colleague, molecular geneticist Matt Kaeberlein, have begun measuring life span in 4500 yeast strains, each of which has had one gene deleted, representing two-thirds of the genes present in yeast. The researchers will assess how the loss of each gene alters a yeast cell's life span in two different ways: First, the team will measure how long each strain survives when grown under conditions in which the yeast cells are metabolically active but no longer reproducing. Then, in separate cultures, the researchers will gauge replicative potential by counting how many daughter cells a single mother cell can produce.

The approaches not only provide two separate measures of yeast longevity, but each also serves as a model for the way different types of human cells undergo aging. Genes that influence chronological life span could yield insight into the aging process in human tissues that no longer reproduce, such as muscle cells. And discovering genes that keep yeast cells reproductively fit could help researchers better understand aging in cells that continue to proliferate throughout the life of an organism, such as those in blood or skin.

Because the chronological studies are fairly simple, these tests can be performed by robots programmed to scoop up a bit of yeast-laden broth and determine whether the cells within it are still alive or not, says Kaeberlein. Measuring replicative aging, however, is a bit more labor-intensive. Researchers must use needles to carefully remove each daughter cell as it buds off its mother so that they accurately track how many offspring each yeast cell produces. Kennedy estimates that they'll be disrupting roughly 800,000 mother-daughter pairs in their efforts to analyze all 4500 strains. Robots aren't capable of performing this delicate--and tedious--operation, but Kennedy and Kaeberlein have already forged through almost 600 strains in 6 months. In so doing, they've come up with 13 genes that lengthen yeast life span by at least 20%. "The chance of discovering new genes is enough to get you motivated," says Kennedy.

Next, they bring in the worms. So far, half of the newfound longevity-boosting yeast genes have counterparts in worms, a discovery that Kaeberlein finds encouraging. The researchers will then use a technique that interferes with the functioning of individual worm genes to determine whether the candidates also lengthen life span in the squigglers.

And then come the mice. According to mouse pathobiologist Warren Ladiges, another Consortium member, the team will generate 20 to 30 strains of mice, each one missing the mouse counterpart of a gene that promotes longevity in yeast and worms. Genes that stretch yeast life span by 20% should add six months or more to the 2.5 years that mice normally live. In addition, the team will examine whether these genes influence the animals' susceptibility to heart disease, cancer, diabetes, or other maladies, he says. Assessing how the candidate genes affect the health of mice is important, says UW biogerontologist George Martin, who is not involved in the work. "The physiological functions have to be addressed," he says, because scientists are interested in genes that keep animals healthy longer, not merely alive.

A huge advantage to beginning with an exhaustive search to find aging-related genes, the scientists say, is that the process is unbiased. "The real benefit of this is our naivete," says Kennedy. Rather than starting the investigation with a particular protein or pathway in mind, he says, "we're going to let the yeast and worms tell us what to look at in mice."

Members of the Consortium expect to come up with genes that have already been shown to be involved in aging. They also expect complete surprises, perhaps entirely new biochemical pathways. And they might pick up some genes that have already been discovered in labs that study phenomena other than aging, in which case the Consortium hopes to set up collaborations.

For other scientists who wish to explore their own favorite genes, the Consortium will provide the tools--mutant yeast and worm strains and genetically engineered mice--to do the necessary studies. "The infrastructure part is important to the Ellison Foundation. It's meant to be an open process, to include rather than exclude other researchers," says gerontologist Peter Rabinovitch, a Consortium scientist.

In addition to increasing the research community's understanding of the basic biology of aging, Ladiges says he hopes the work turns into real interventions that enhance health and longevity in people. "We are laying the groundwork for clinical trials in the not too distant future"--a foundation that will require a lot more plodding work and prodding yeast.

Mary Beckman is a writer in southeast Idaho who gets exhausted just thinking about all the work these guys are in for.