Sci. Aging Knowl. Environ., 5 February 2003
New genome-wide search technique turns up genes that promote long life rather than curtail it
Key Words: transposable element conditional mutations phospholipid metabolism/signaling actin cytoskeleton overexpression Red herring
It's easy to cut life short: Walk in front of a moving truck. But studying such phenomena doesn't reveal much about aging. So when researchers want to know what genes control that process, they seek mutations that increase longevity. Usually, such alterations cripple genes that normally keep life-span in check. Less often do scientists find a gene that normally lengthens life. Using a relatively new technique, investigators now have identified several genes that augment fruit fly life-span when shifted into overdrive.
To study fruit flies, researchers exploit a family of short DNA sequences called P elements that reside in the animals' genome. These sequences can move, finding themselves new chromosomal homes. Two years ago, geneticist John Tower of the University of Southern California in Los Angeles and his colleagues engineered a custom P element to give flies an extra dose of randomly selected gene products on command. The doctored P element, called PdL, tends to insert itself near the start of a random gene, which PdL activates when the fly is fed the drug doxycycline. This approach, Tower says, eliminates the need to guess what genes influence life-span and might identify heretofore unsuspected participants in aging.
The members of Tower's team used PdL to turn on random genes in adult flies, then they waited to identify altered animals that lived longer than normal. From 10,000 flies, each carrying a different PdL insertion, the researchers isolated six such critters. Life-span gains ranged from 5% to 17%. Of the six genes, three had been identified previously but were not linked with aging; one encodes a protein that helps assemble the cell's internal scaffolding, and the other two produce enzymes that are necessary for the cells to regulate signaling processes and traffic through the cell membrane. Two others hadn't been characterized, but they appear to encode proteins that help transport molecules or ions across the cell membrane. The sixth mystified investigators because it resides within an intron of another gene and doesn't look like anything familiar, yet it produced the largest average life-span increase. The results surprised Tower, he says, because he expected to find at least one antioxidant, given that overproducing such proteins lengthens fly life-span (see Genes/Interventions Database entries: SOD1, SOD2, and CAT).
Future work will delve into how these genes fit into biochemical processes known to influence aging, or whether they define new aging pathways. For instance, disabling a protein that moves molecules across membranes extends life-span (see "Feed a Cell, Deprive an Organism?" and Genes/Interventions Database entry Indy), suggesting a precedent for aging-related activities of membrane-transport proteins, the authors point out. "The insight will come from trying to precisely determine why these gene products might influence life-span," says molecular geneticist Cynthia Kenyon of the University of California, San Francisco. Furthermore, she says, the technique takes aging research in a positive new direction: "It's really important for us to identify genes whose activity can extend life-span." The new approach puts researchers in the driver's seat to find genes that could stretch the road of life a little farther.
G. N. Landis, D. Bhole, J. Tower, A search for doxycycline-dependent mutations that increase Drosophila melanogaster life span identifies the VhaSFD, Sugar baby, filamin, fwd and Cct1 genes. Genome Biol. 4, R8 (2003). [Abstract/Full Text]
February 5, 2003
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Citation: C. Seydel, Think Positive. Science's SAGE KE (5 February 2003), http://sageke.sciencemag.org/cgi/content/full/sageke;2003/5/nw23
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