Aging in mammals is associated with progressive loss of muscle mass, bone demineralization, vascular calcification and progressive hypertension, sensory perception deficits, hypo functioning immune systems, and loss of tissue elasticity. The original program project proposal five years ago was based on the two hypotheses of cell aging, the free radical theory and the Ca2+ hypothesis of aging, that we believe explain many of the cell and molecular changes that occur with aging. Chronic imbalances between oxidant and anti-oxidant processes in cells cause oxidative stress during aging and progressive deterioration of macromolecular structures such as proteins, DNA, and lipids. Progressive deterioration of processes that control [Ca2+]i leads down a path of cellular deterioration and organ malfunction. One of the operating mechanisms for the loss of the capacity of cells to handle the rise in [Ca2}]i may be oxidant-induced protein and membrane damage, especially of proteins that regulate Ca2+ entry into cells, transport out of cells, transport into intracellular organelles, or release from such organelles. The research performed in our laboratories under the auspices of the program project has contributed substantial and detailed new information to support the two major hypotheses of aging. We have provided chemical evidence for the presence of post-translational modification of proteins brought about by ROS. These modifications occur in proteins that regulate intracellular Ca2+ and the function of Ca2+ as an intracellular messenger. The current program project renewal application expands upon the work already accomplished and attempts to define not only the chemical and biochemical modifications due to increasing oxidative stress during aging, but also the cellular and physiological consequences of such modifications. An additional focus of the proposed work is that of cellular mechanisms for protein repair or degradation following insults produced by oxidation. The areas of focus in the continuation of this program project are: a) characterization of the pathways of repair or degradation of calmodulin and the Ca-ATPases b) mechanisms of protein repair by methionine sulfoxide reductase c) age-dependent changes in NMDA receptor function, intracellular calcium channels, protein phosphatases and kinases, and the multi- catalytic proteases d) chemical sensitivity of tyrosine nitration, sulfhydryl group oxidation, and the chemical nature of protein carbonyl groups. To accomplish these goals we will continue to use the expertise of the protein and peptide analysis core. We have also established a new core in cell culture and molecular biology that will assist us in our investigations of changes in cell biology, cell physiology and molecular biology. It is our hope and expectation that the studied proposed in this program will provide us with new insights into basic biological and chemical processes associated with aging. And, that this program will also provide us with targets for potential therapeutic intervention to ameliorate the gradual deterioration in cell and organ functions that occur with aging.
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