Reactive oxygen species (ROS) is seemingly the major determinant of life-span. To understand the aging potential of specific cell types or tissue we need to understand the effect of intracellular ROS toxicity on specific tissue in vivo. The creation of an intrinsic oxidative stress environment in specific tissue without affecting others was not easy until the advent of molecular-genetic tools. It is now possible to ask this question in vivo in model systems like Drosophila. The enzyme manganese superoxide dismutase, which catalyzes the detoxification of superoxide radicals in the mitochondrial matrix, plays a central role in cellular aging, as evident from the fact that loss of MnSOD function severely reduces organismic life span, while its over-expression could extend it. Hypothesis: The specific hypothesis to be tested is that depletion of MnSOD activity from a specific tissue will trigger cellular damage through an intracellular rise in ROS concentration; however, the amount of damage to individual tissues will vary, as will their biological efficacies, which will be reflected at the organismal level. We will examine our hypothesis in four different tissues in Drosophila including fat body, muscle, brain and retinal cells of the eye, all of which are essential for the viability of the organism with the exception of retinal cells. By using a state-of-the-art technique, MnSOD function will be depleted in vivo from each of these tissues. We will address several important biological questions involving tissue specific ROS generation, tissue specific oxidative damage to DNA and protein, tissue specific apoptotic cell death potential. Depletion of MnSOD function from each of these tissues will provide important insight regarding the contribution of ROS towards cellular aging.

R15AG025754

2006-03-01

2010-02-28