The rationale for this grant application grew out of our studies with two knockout mouse models, one deficient in Mn-superoxide reductase (Sod2+A), where we showed that increased generation of reactive oxygen species (ROS) and increased oxidative damage to DNA did not lead to a reduction in life span, while the other model, lacking methionine sulfoxide reductase A (MsrA-/-) and sensitive to hyperoxia, showed increased protein oxidation and a 40% decrease in life span. We believe that these contradictory results are most likely explained by the different type(s) of oxidative damage altered by the two genetic manipulations. The basic underlying premise of this grant application is that not all types of oxidative damage are important in the aging process, but that oxidative damage to protein (most likely specific proteins) is the type of oxidative damage that plays a role in the mechanism underlying aging. Because the effective concentration ? of methionine is high in proteins and because methionine is easily oxidized, methionine residues in proteins function as a """"""""last chance"""""""" antioxidant defense system for proteins. The cyclic oxidation and the reduction of methionine residues by the methionine sulfoxide reductases inactivate ROS before they oxidize other amino acid residues that are critical to protein function. We hypothesize that oxidative damage to protein is a key mechanism responsible for the reduced life span of the MsrA-/- mice. We propose to test this hypothesis by the following specific aims: 1. To determine if MsrA-/- mice show accelerated aging. 2. To determine if MsrA-/- mice show an increase in oxidative damage to protein in the cytosol and mitochondria, and determine if the increase in oxidative damage has an effect on mitochondrial function. 3. To identify the specific proteins in the cytosol and mitochondria that show increased oxidative damage in tissues of the MsrA-/- mice using novel technologies developed in our laboratory. 4. To rescue the short life span of the MsrA-/- mice and determine if this rescue is associated with reduced oxidative damage to protein. ? ? ? ?
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