Fast Track to Longer Life

Scientists have developed a new way to rapidly screen thousands of potential antiaging drugs in worms. Although faster doesn’t always mean better, the technique could accelerate our understanding of the basic biology of aging.

Anders Olsen felt he had spent too much time mastering molecular biology to be stuck with grunt work. After 8 years of undergraduate and graduate study in Europe, the postdoctoral scientist was spending more than 20 hours a week bent over the microscope, sorting tiny worms. As a veteran of molecular geneticist Gordon Lithgow's lab at the University of Manchester, U.K., Olsen had studied the biology of aging in the nematode Caenorhabditis elegans for years. To prepare the experiments, Olsen had to separate each generation of worms from its progeny--a task that requires a microscope, a tiny platinum wire, and lots of patience to painstakingly tease adult worms from a gooey mess of larvae and eggs. Sorting takes so much concentration and steadiness, says lab colleague Matthew Gill, that some people can't do it after drinking coffee.

Few scientists question that such drudgery has revealed surprising details about how worms--and possibly humans--grow old. For example, molecular geneticist Cynthia Kenyon of the University of California, San Francisco, and molecular biologist Gary Ruvkun of Harvard Medical School in Boston have shown that aging in the creatures is regulated by a worm version of a hormone that helps spur growth and cell division in people.

But results like these may no longer require backbreaking stress for laboratory rank and file. Olsen and Gill, now working for Lithgow at the Buck Institute for Age Research in Novato, California, have devised a faster way to sort and characterize worms. For roughly a decade, scientists in many fields have reaped benefits from techniques that allow testing of hundreds of compounds or genes in a single experiment. Now, Olsen and Gill's souped-up worm-sorting scheme will let nematode investigators join the revolution that has made the phrase "high-throughput" a fixture of biomedical papers. Some researchers caution that the new methods might reveal little about human aging or lead to harder choices about where to invest research dollars. But assessing thousands of potential life-extending drugs--and perhaps finding fundamental clues about aging along the way--could be a worthwhile payoff.

Olsen and Gill's technique starts with a commercial worm sorter: a 1.2-meter-tall machine that winnows worms from eggs, larvae, and detritus. Then, using a fluorescent dye that enters only dead worms, the scientists count how many worms remain alive by measuring the amount of light with a machine called a plate reader. Lithgow says that adding robots to move the dishes of worms from one machine to another will let labs simultaneously evaluate the effect that hundreds of potential age-retarding compounds have on the life span of Caenorhabditis elegans. "This allows you not only to try many drugs but to try many concentrations," says Gill, co-author of a paper outlining the new approach in the May issue of Free Radical Biology and Medicine.

Scientists who are weary of sorting worms aren't the only beneficiaries of high-speed methods. Other researchers in the field of aging are starting to reap the benefits of automated techniques. In a widely publicized paper published last month in Nature, Harvard molecular geneticist David Sinclair and colleagues from the biotech firm Biomol Research Laboratories in Plymouth Meeting, Pennsylvania, showed that 17 plant compounds stimulated the activity of sirtuins, enzymes that extend life span in worms and yeast. To figure out which chemicals worked, the team tested hundreds at once, using plates that each had 96 tiny wells, and ended up evaluating more than 10,000 compounds. "The reason [the work] was feasible was the high-throughput assay," says Sinclair. Drugs discovered with high-speed methods are advancing into clinical trials, says Will Kuijpers, a chemical engineer at Dutch drugmaker Organon. For example, a handful of compounds Organon identified with mass screening have reached initial human testing.

But some scientists caution that faster methods don't bring solid answers immediately. In the 1990s, for example, pharmaceutical industry experts touted the potential of speedy drug screening combined with new, giant collections of compounds. "High-throughput screening was thought to be the magic tool," says Kuijpers. It remains crucial, he adds, but computer modeling and traditional drug design--processes by which researchers engineer a molecule to match a particular target--also contribute. DNA chips, which gauge gene activity, underwent a similar maturation. Daniel Promislow, an evolutionary biologist who studies aging at the University of Georgia in Athens, says that the introduction of the chips in the last decade spawned some unfocused studies. Now, says Kuijpers, the chips not only uncover potential drug targets for specific diseases, but they help establish the functions of those genes.

Other researchers worry that the new technique will distract scientists from the ultimate goal: understanding the fundamental basis of aging. The new method will be helpful, says molecular biologist Leonard Guarente of the Massachusetts Institute of Technology in Cambridge. But diverting scarce funds to pursue new mechanisms of aging that have yet to prove their potential might divert the focus from studies of known mechanisms that require further investigation, he warns. Lack of money is always a concern. "Absolutely, there's an issue of limited resources," says Huber Warner, associate director of the Biology of Aging Program at the National Institute on Aging (NIA) in Bethesda, Maryland. Of the $120 million to $150 million of its billion-dollar budget that NIA devotes to the basic biology of aging, for example, Warner estimates that the agency will allot only $15 million to studying nonmammalian organisms. The sum does not leave much wiggle room if researchers will be applying for these funds to characterize a slew of possible new antiaging compounds.

Lithgow agrees that the new tool won't give instant answers on worm physiology, but he's still enthusiastic, saying that "blue-sky" research for new targets can coexist with studies on familiar mechanisms. For years, he says, colleagues have been sending him potential antiaging compounds to try on his worms. Before, he didn't have the resources to test them. Now he will. Even more exciting, he says, is that by testing tens of thousands of random compounds, labs might discover novel molecular pathways that govern aging. Promislow agrees that new mechanisms deserve investigation. "We still know little about the basic biology of the targets we have," he says. "But it behooves us to keep on looking."

Olsen says he is eager to do just that--but from the comfort of his desk, leaving the heavy lifting to his trusty new worm sorter.

Eli Kintisch is a science reporter at the St. Louis Post-Dispatch, where he's developing a high-throughput method to write newspaper articles.