Genes that regulate dauer larva development and life span have been identified in the nematode C. elegans. This free-living soil nematode has a three day generation time, a two-week life span, and displays traits seen in other senescent animals. The age-1 gene, which when mutated increases life span, has been placed in the middle of the genetic pathway for life span determination in C. elegans. Recently, this gene has been cloned and shows homology to phosphatidylinositol-3- OH kinases and thus is likely to function as a regulator in this pathway. In addition, several enzyme activity levels have been measured in long-lived mutants and found to differ in comparison to those of wild-type animals. However, no mechanistic link has been established between the regulator and these candidate longevity effector genes which have been shown to increased or decreased enzyme activity levels. The goal of this proposal is to initiate identification of the regulation point which gives rise to increased activity. The steady-state mRNA and protein levels of candidate longevity effector genes will be ascertained in dauer larvae, wild-type adults and Age adults. The long-lived adult state and the dauer state are similar, yet different for genetic traits and a couple of enzyme activity levels. Therefore, the candidate longevity effector genes will be sorted with regard to which activities are necessary for the extended longevity. This analysis could reveal similarly controlled effector genes and from these consensus regulatory elements could be derived and a search for other in the genomic database conducted. Ultimately, the addition of verified components involved will result in a detailed mechanistic model of the control and execution of life span extension.
| Yu, H; Larsen, P L (2001) DAF-16-dependent and independent expression targets of DAF-2 insulin receptor-like pathway in Caenorhabditis elegans include FKBPs. J Mol Biol 314:1017-28 |
