Study of the role of oxidative stress in the etiology of aging has represented a multi-departmental and multidisciplinary area of research at UTHSCSA for over twenty years. This collaborative effort has resulted in significant research breakthroughs and successful applications for external funding by the participating investigators. Studies funded by this and other current and previous program project grants have led to the development of a number of transgenic/knockout mouse models animal models that coupled with new and novel optical imaging approaches developed in the last funding cycle, were used to test the hypothesis that oxidative stress contributes to aging by altering mitochondrial structure and function. Over the first five years of this program project, 38 publications (~8/year), 4 in press, 7 submitted and 13 in preparation manuscripts [unreadable] and abstracts have resulted from the collaborative work of this group. There were a number of major findings during the previous funding cycle including the establishment of a direct correlation between oxidant stress induced mitochondrial-dependent apoptosis and aging, a demonstration that loss of mitochondrial DMA is associated with a compensatory increase in mitochondrial mass and an increase in lysosomal mass putatively to remove damaged mitochondria, the discovery that while astrocytic neuronal protection decreases during aging, it is possible to enhance astrocytic neuronal protection in an aged animal through a mitochondrial dependent pathway, and most remarkably and unexpectedly of all, that genetically reducing various antioxidant enzymes in the mitochondria did not negatively impact the lifespan of these animals; in fact, a reduction in glutathione peroxidase 4 expression resulted in a significant increase in longevity. Collectively these findings have led us to reassess the importance of mitochondrial oxidative stress per se as the sole regulator of the aging process, and instead to focus on the contributions of age-dependent response to mitochondrial stress (i.e. mitochondrial function, autophagy and apoptosis) in aging. During the next funding period, our objectives are to identify novel mechanisms responsible for mitochondrial contributions to the aging phenotype including mechanisms responsible for caspase-2 medicated apoptosis in the development of age-related osteoporosis, how aging impacts the cellular response to the stress of mito DNA depletion, whether modulation of the mitochondrial dependent-apoptotic pathway can delay aging and extend lifespan, and whether upregulation of mitochondrial-dependent metabolism can be neuroprotective during aging. We believe that these studies should have practical consequences in the identification of molecular targets for rational new drug discovery in this field. [unreadable] [unreadable]