We are addressing the quesfion of whether age-associated oncogenesis, and more specifically, tumor progression, is associated with mitochondrial (mt) ROS. We hypothesize that age-associated cancers are driven by increasing levels of mitochondrial-mediated ROS. Our preliminary data suggests that ROS is associated with tumor progression, and provides the rafionale for three specific aims to better understand the mechanisms whereby protection of mitochondria reduces oncogenesis. Aim 1 is designed to determine what cellular processes are involved in the mCAT suppression of metastatic tumor progression in the lungs of young and old mice, primary skin tumor progression in young and old mice. We will use primary skin tumor and pulmonary metastatic mammary tumor models in the presence and absence of mitochondrial-targeted catalase (mCAT) to analyze neoplastic progression and tumor metastasis. We will compare the host response and the protecfive effects of mCAT in young and old mice. Aim 2 is designed to determine the contribution of specific cell types in the mCAT suppression of tumor progression. There is increasing evidence that the microenvironment plays a crifical role in oncogeneis. Our preliminary results showing attenuation of tumor progression via expression of mCAT could be explained, in part, by mCAT expression within specific cell types within the microenvironment of the neoplastic cells. We will therefore assess the roles of mCAT expression in several different stromal cell types and compare their putative suppressive effects with epithelial cells (both neoplastic and non-neoplastic) that express mCAT. Specific mCAT expression will be driven by cell-specific Cre transgenesis. Aim 3 is designed to evaluate the efficacy of mitochondrial antioxidant and protective drugs for intervention in tumor progression and metastasis. We will correlate the differences in modes of acfion of the drugs with differences in effects on tumor progression, cell proliferafion and survival in order to better understand the mechanisms whereby protection of mitochondria reduces neoplasia and enhances an anti-aging phenotype. The experimental approach is designed to determine if specific mitochondrial targeted anfioxidant mimefics are effective in suppressing tumor progression in young and old animals with cancer or in aged wild type mice that develop multiple tumor types. RELEVANCE (See Instmctions): Project 3 is designed to determine if specific mitochondrial targeted antioxidants can provide a means of prevenfing tumor progression and metastasis associated with age-related increase in ROS. PROJECT/PERFORH/lANCE SITE(S) (if additional space is needed, use Project/Performance