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    Frederick George Mann, Jr.
    Aging is a fundamental biological process seen in nearly all organisms. While research has discovered hundreds of genes whose dosage can modify lifespan, it is unclear how many of these genes play a role in the normal transition from the young state to the old state. To better understand aging, it is critical to identify which processes are driving aging in wildtype organisms. Our approach is to search for direct regulators of molecular changes that appear over time in the nematode worm Caenorhabditis elegans. This is a quantitative, global, and relatively unbiased way to find potential drivers of aging. We begin with a set of over 1,000 gene expression changes between young and old worms. In this work, we used a computational screen to identify transcription factors that directly bind to our list of age-regulated genes. The top hit from our screen is a conserved GATA transcription factor called ELT-2 that functions during development to effect the terminal differentiation of the intestine. The expression of ELT-2 and its direct transcriptional targets decline during aging. Lifespan can be either extended or shortened by increasing or decreasing the dosage of ELT-2. Together, these findings provide strong evidence to support the idea that changes in the expression of ELT-2 drive transcriptional changes during aging and limit lifespan.
    Digital Access   2016