Sci. Aging Knowl. Environ., 17 October 2001
Genetic Ducklings: Putting aging genes in a row
R. John Davenporthttp://sageke.sciencemag.org/cgi/content/abstract/sageke;2001/3/nw12
Key Words: IGF-1 insulin daf-16 daf-2 age-1 old-1 transcription forkhead transcription factor
Abstract: No gene is an island; they collaborate with each other to execute biological processes such as aging. To understand such phenomena, scientists must sort out exactly how they work together. New results shed light on how one longevity gene fits into a cellular pathway already linked to aging. Although many components in the pathway are well known, its presumptive downstream targets have remained elusive.
Previous work has indicated that a number of Caenorhabditis elegans genes--including daf-2, age-1, and daf-16--team up as part of an insulin-like signaling pathway that governs life-span in worms and other animals (see "Growing Old Together"). The daf-2 gene activates age-1, which triggers a cascade of events that thwarts daf-16. That gene encodes a protein that is thought to regulate the transcription of other genes based on its similarity to the forkhead family of mammalian transcription factors. But no one has identified the genes that DAF-16 presumably controls. The new work indicates that daf-16 activates transcription of old-1, a gene that can lengthen the life-span of worms when it is overproduced.
Murakami and Johnson first looked within the old-1 gene for sequences that forkhead-binding proteins grab when they regulate genes; they found six such sequences. To determine whether daf-16 activates old-1 production, the researchers linked the gene for green fluorescent protein (GFP) to the tail end of old-1 using standard genetic engineering techniques and assessed quantities of the fusion protein by measuring GFP fluorescence. They also used a polymerase chain reaction technique to assess the amount of old-1 messenger RNA (mRNA). As normal worms age or face stresses such as ultraviolet (UV) light, heat, or starvation, the production of old-1 mRNA and protein increases, the researchers found. Perhaps old-1 provides extra resistance against these environmental insults, the researchers suggest. For comparison, they studied worms carrying a life-shortening mutation that cripples daf-16. After exposure to UV light, heat, or starvation, these worms produce old-1 mRNA in lower quantities than do worms with normal daf-16. Together, these results suggest that daf-16 normally increases the amount of old-1.
The group also probed whether old-1 follows the age-1 and daf-2 genes in the insulin-like signaling pathway, as expected if old-1 is controlled by daf-16. Mutations in either age-1 or daf-2 that extend longevity ramp up production of old-1 mRNA. Furthermore, destruction of old-1 mRNA by means of a technique called RNA interference in worms with defective age-1 and daf-2 counteracts the life-span extension normally afforded by these mutations. These observations are consistent with a scenario in which old-1 lies downstream of the other genes in the pathway.
The old-1 gene is the first potential target of daf-16 to be identified, but the exact relation between them isn't yet clear. Worms with a life-shortening mutation in daf-16 do not live longer when they also carry multiple chromosomal copies of old-1, which normally results in overactivation of the gene. In a simple genetic scheme, the observation that the daf-16 mutation trumps overproduction of old-1 indicates that old-1 precedes daf-16 in the pathway. But because daf-16 normally spurs old-1 output, old-1 might not be abundant in the mutant, where daf-16 is defective. Nailing down this issue requires further work, but the potential extension of the pathway will undoubtedly lure researchers deeper into it.
--R. John Davenport; suggested by Matt Kaeberlein
S. Murakami, T. E. Johnson, The OLD-1 positive regulator of longevity and stress resistance is under DAF-16 regulation in Caenorhabditis elegans. Curr. Biol. 11, 1517-1523 (2001). [Abstract] [Full Text]
Citation: R. J. Davenport, Genetic Ducklings: Putting aging genes in a row. Science's SAGE KE (17 October 2001), http://sageke.sciencemag.org/cgi/content/abstract/sageke;2001/3/nw12
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