Understanding the genetic mechanisms affecting variation in lifespan in natural populations is crucial for understanding the genetic basis of age-related diseases. Lifespan is known to vary in natural populations due to the segregation of multiple genetic factors as well as to exposure to different environmental conditions with a heritability of approximately 10-30%. Further, many pathways associated with lifespan, such as the insulin or insulin-like signaling pathway, are evolutionarily conserved between humans and model organisms. Drosophila melanogaster is a powerful model for assessing naturally occurring genetic variation in lifespan because of the ability to perform genomic analyses on a large scale while effectively monitoring genetic backgrounds and controlling environmental conditions. The D. melanogaster Genetic Reference Panel (DGRP), which consists of 205 sequenced inbred lines, allows for the investigation of natural genetic variation on phenotypically variable traits. To identify polymorphisms associated with variation in aging, a genome wide association (GWA) study utilizing the DGRP was conducted. This resulted in the identification of 28 genes significantly associated with lifespan. To validate their effects on lifespan, we knocked down the expression of these genes using RNA interference (RNAi) and a ubiquitous driver. This revealed several significant results associated with lifespan in the RNAi knockdown genotypes relative to their controls. Specifically, 13 genes (48%) had an effect in at least one sex, demonstrating sex-specific genetic architecture of lifespan. Additionally, 8 of the most significant genes (p-value < 0.01) increased lifespan when knocked down, providing evidence that lifespan is regulated at the transcriptional level. In the future, we plan to further functionally validate the role of these genes in the genetic control of lifespan using an overexpression assay. These experiments will contribute to our overall goal in establishing novel genetic networks associated with variation in aging. Since basic biological processes, such as aging, are evolutionarily conserved, these studies will also provide candidate genes for investigation in other species, including humans.