Sci. Aging Knowl. Environ., 13 October 2004
Homing In on a Hormone
Fat-based molecules divert nematodes from survival mode
R. John Davenporthttp://sageke.sciencemag.org/cgi/content/full/2004/41/nf92
COLD SPRING HARBOR, NEW YORK--A phantom hormone hampers worm survival and promotes aging. Now, researchers have taken a step toward identifying the furtive molecule, according to work presented here on 7 October 2004 at the Molecular Genetics of Aging meeting. The advance should help scientists pad their knowledge about pathways that tweak longevity in nematodes.
When food is scarce, maturing nematodes enter a semidormant state known as dauer. Signals that encourage dauer formation also prolong life span in adults. For instance, mutations that short-circuit the worm's insulin-like signaling pathway double adult longevity. Glitches in the TGF- pathway also push worms into the dauer state but don't seem to prolong adult life span. The two pathways converge on a protein called DAF-12, whose sequence suggests that it binds to a cholesterol-derived hormone. Scientists haven't isolated the fatty molecule, but they've deduced that when DAF-12 grabs it, worms mature. Without the hormone, DAF-12 prompts dauer formation--and perhaps stretches adult longevity (see "Hard Times Teach Life-Extending Lessons" and "Hardy Helper").
To uncover the elusive hormone, endocrinologist Matthew Gill and colleagues at the Buck Institute for Age Research in Novato, California, isolated fatty components from ground-up worms. They fed the mixture to worms with mutations in the insulin-like signaling or the TGF- pathways; these animals enter dauer even when food is abundant. The compounds helped both mutants stop hibernating. The extracts also woke dauer worms with glitches in DAF-9, the enzyme that apparently manufactures the hormone to which DAF-12 binds. Worms with alterations in DAF-12 that perturb the protein's hormone-sticking capacity did not respond. Together, the results suggest that the mixture contains the hormone that DAF-9 generates and that adheres to DAF-12. Further supporting that idea, extracts from worms that carry faulty DAF-9--and cannot manufacture the hormone--couldn't rouse dauer worms. The hormone should accelerate aging, predicts Gill. The team is working to snare the molecule.
"It's exciting," says Adam Antebi, a geneticist at Baylor College of Medicine in Houston, Texas. Previous studies, including those from his lab, predicted that DAF-12 grabbed a hormone, but "this shows that it exists," he says. Teymuras Kurzchalia of the Max Planck Institute of Molecular Cell Biology and Genetics in Dresden, Germany, says, "All [dauer] pathways are in the end coming to this hormone. It's a key molecule." His team has also identified an ensemble of fatty molecules that liberate nematodes from the dauer state, they reported last month in PLoS Biology. The two studies' approaches differ, however. Kurzchalia's group forced worms to become dauers by depriving them of cholesterol rather than by tweaking genes, so the teams might be looking at different molecules, he conjectures. For instance, Kurzchalia might be tracking a precursor molecule to the hormone. Biochemist John Lenard of the University of Medicine and Dentistry of New Jersey in Piscataway says that although fat-soluble molecules control many processes in numerous species, researchers have ignored nematode lipids, focusing instead on their genes and proteins. The new approach might help researchers grasp the greasy problem of aging in worms--and other creatures.
October 13, 2004
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