We are using the nematode, C. elegans, as a model system for aging because it has a short lifespan, a powerful genetic toolkit and many mutants are already known to lengthen lifespan. Our goal is to identify genes that are differentially expressed in old versus young animals, and then to use these genes as molecular markers to dissect apart mechanisms of aging. We used DMA microarray to perform genome-wide screens for genes that change expression in old worms, in the dauer state and in two insulin-like signaling mutants with altered lifespans. By combining the expression results from these DNA microarray experiments, we identified a core set of 733 genes that show consistent changes in expression across different aging experiments. Interestingly, we discovered that the age-regulated genes are regulated by a GATA transcriptional circuit involving the elt-3 and egr-1 GATA transcription factors. Elt-3(+) and egr-1 (+) both promote longevity since RNAi treatment of either gene suppresses the longevity phenotype of daf-2 mutants Furthermore, expression of both genes decrease during normal aging, and causes changes in downstream aging target genes. From the large set of aging-regulated genes, we have generated a set of GFP aging reporter genes that will allow us to examine the process of aging at the molecular level.
In specific aim 1, we will use expression levels of the GFP aging markers as molecular clocks for aging, allowing us to study aging mechanisms such as whether there is a similar effect of aging in different tissues, and whether the GFP aging markers can predict the remaining life spans of worms while they are still alive.
In specific aim 2, we will analyze the functions of the elt-3 and egr-1 GATA genes that control expression of the downstream aging markers. In particular, we will test whether we can either speed up or slow down the rate of aging by decreasing or increasing expression of these two aging regulators.
In specific aim 3, we will examine upstream control of the elt-3/egr-1 GATA transcriptional network, such as regulation by the insulin-like signaling pathway. In addition, we will determine whether age-related changes in this transcriptional network are due to extrinsic factors such as cellular damage or to an intrinsic genetic pathway that first regulates elt-3 during development and that might continue to regulate elt-3 during aging.
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