Sci. Aging Knowl. Environ., 9 April 2003
Spark of Life
Mutation in worm insulin-like gene kindles longevity pathway
R. John Davenporthttp://sageke.sciencemag.org/cgi/content/full/sageke;2003/14/nw55
Key Words: DAF-11 guanylyl cyclase pheromone furin
A newly identified nematode gene ignites a signaling pathway that spurs worms to age, researchers now report. Scientists knew that dousing the pathway retards aging, but the study is the first to pinpoint an alteration that smothers the initial spark.
In mammals, the insulin and insulin-like growth factor-1 (IGF-1) pathways influence longevity as well as metabolism and growth (see Bartke Viewpoint, "One for All," and "Lasting Without Fasting"). A similar pathway modulates life span in the nematode Caenorhabditis elegans. In this organism, a cell surface receptor protein called DAF-2 heads the pathway, which determines whether a young worm develops into an adult or enters a hibernation-like state known as dauer. Certain genetic changes that lower pathway activity double life span (see daf-2 and age-1). Although the wrigglers carry more than 30 genes that resemble our insulin gene, scientists hadn't homed in on any that fire the DAF-2 signal.
Li and colleagues have now uncovered one such gene. They focused on worms with a mutation called daf-28; the animals enter the dauer state unusually easily and live 10% longer than normal. Using genetic mapping, the researchers pinpointed the gene in which the mutation resides. They found a DNA base change in a previously undescribed gene that, based on its sequence, appears to produce an insulin-like protein.
Next, the team tested whether the altered insulin-like protein cripples the DAF-2 pathway. When the pathway is off, its main target protein, DAF-16, resides in the nucleus, where it turns on other genes. An activated pathway shuts down DAF-16 by booting it into the cytoplasm. In daf-28 worms, DAF-16 lurked in the cell nuclei at a developmental stage when normal worms held DAF-16 in the cytoplasm. The observation suggests that the mutation blocks other pathway members from ejecting the protein from the nucleus, and it also hints that the normal protein activates the pathway.
Additional studies reveal that DAF-28 accumulates in several sensory neurons that influence life span; impairing their function extends longevity, according to previous work. Conditions such as starvation or overpopulation that spur worms to inactivate the DAF-2 pathway and enter the dauer state decreased the amount of DAF-28 protein. When the researchers genetically crippled the worm's ability to sense crowding, DAF-28 production increased. Together, the results suggest that daf-28 produces an insulin-like molecule that kick-starts the DAF-2 pathway when external conditions turn favorable. DAF-28 probably isn't the only insulin-like molecule that prods DAF-2: Extra doses of two other related proteins compensated for mutant daf-28, suggesting that they also stimulate the receptor.
The work "closes the loop on the insulin signaling pathway" in worms by identifying a component that sets the chain of events in motion, says molecular biologist Adam Antebi of the Max Planck Institute for Molecular Genetics in Berlin, Germany. Deciphering how particular environmental signals modulate pathway activity is an important area for future work, he says. Knowing that DAF-28 resembles insulin and functions in the DAF-2 pathway might help scientists understand more about how blocking the signal extinguishes aging.
--R. John Davenport
April 9, 2003
Science of Aging Knowledge Environment. ISSN 1539-6150