Research into the molecular, genetic, and cellular aspects of aging has greatly expanded our understanding of the basic processes that contribute to both longevity and age-related diseases. The primary focus of this Program since its inception is the assertion that age-dependent increases in oxidative stress and alterations in cellular Ca2+-handling converge to produce several of the well-known manifestations of aging, such as progressive muscle weakness and compromised cognitive performance. Our past efforts have led to the identification of protein markers of oxidative stress and the characterization of the effects of oxidation and aging on critical Ca -regulating proteins, using both in vivo and in vitro models of aging. We also made a number of important observations supporting the occurrence of oxidative modifications on proteins involved in Ca2+signaling in aging tissues. Over the past few years, enormous shifts have occurred in the overall research enterprise, primarily due to the sequencing of the human genome and development of new technologies for the analysis of transcriptional, translational, and signaling events occurring in cells and tissues. As a result, the strategies that Program participants are using to study the aging process have evolved to take advantage of the latest research advances. The major theme for the overall research effort, though, continues to be oxidative stress and Ca2+ regulation in aging. New approaches involving sub-proteomic studies of protein complexes, genomics, and transgenic mouse models of metabolic stress and recovery of structure and function, are now integral components of the research in this Program. The application is a resubmission for renewal of the Program Project and consists of 3 Projects: Project 1, Sarcopenia and Apoptosis: Role of SERCA and Bcl-2; Project 2, Age-Dependent Changes in Synaptic Raft Domains and Plasma Membrane Ca2+-ATPase; Project 3, Glutamate Neurotransmission, Aging, Longevity and Neurite Remodeling. The activities of the 2 scientific Cores have been expanded to provide new services and essential expertise needed to accomplish the aims of the projects. Core B was expanded to include detailed lipid analyses of neuronal membranes from aging tissues and protein isotopic labeling methods for quantification of protein changes. Electron microscopy and quantitative imaging were added to Core C. Core A, B and C were all expanded to include enhanced data sharing, relational databases, and bioinformatics analytical tools for systematic integration of the information from the Projects. The short term objectives for the Program are to define the molecular changes in neurons and muscle cells during aging that bring about altered control of intracellular Ca2+, metabolic stress, oxidative stress, initiation of apoptotic events, and cell recovery processes. The long-term objectives are to characterize the molecular events involved in the induction of two debilitating conditions of the aged, sarcopenia (muscle cell loss/ loss of muscle strength) and selective neurodegeneration. It is hoped that defining the molecular and cellular processes that produce these conditions of aging may lead to the discovery of new targets for future therapeutic interventions. ? ? ?
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