The aging of the U.S. population represents an unprecedented challenge, which demands advances in basic and applied research- the proposed studies include both. Evidence continues to accumulate that mitochondria and reactive oxygen species are central to aging. Mitochondria are responsible for the bulk of ATP generation, oxygen consumption, and cellular oxygen radical generation, and are required for calcium homeostasis as well as essential biosynthetic pathways. They are involved in the control and execution of apoptosis, whose malfunction leads to degenerative disorders. The centrality of mitochondria, and their exposure to oxidative stress, have focused attention of their age-related decay, which includes: declines in respiratory and enzymatic activities, decreased membrane potential, increased oxidant generation, increased oxidative damage, alterations in membrane lipid profiles, and decreased transcriptional activity. What is not know, however, is whether mitochondrial decay itself is responsible for senescence at the physiological level, and whether it therefore principally determines the rate of aging and life span. On the applied front, the mitochondrial metabolite carnitine, administered as acetyl-L-carnitine (ALCAR), has been shown to antagonize mitochondrial dysfunction during pathological states and in aging, reversing some age-related changes. It has recently been administered in clinical trials as a treatment for Alzheimer's disease. The proposed studies will employ ALCAR and a second mitochondrial metabolite-the antioxidant lipoic acid-as pharmacological tools for basic and applied research. Preliminary studies have shown that short-term dietary supplementation of rats with ALCAR/lipoate reverses age-related mitochondrial decay in liver cells, and that both components of the mixture are required for optimal effects. The proposed experiments will 1) further characterize the ALCAR/lipoate mitochondrial intervention, in order to validate its effectiveness in other tissues and at lower doses; 2) use in vivo mitochondrial intervention with ALCAR/lipoate as a tool to ask the central outstanding question outlined above (""""""""does mitochondrial decay determine physiological decline?""""""""); and 3) assess the long-term effect of ALCAR/lipoate on senescence/vitality and life span, in order both to test the hypothesis that mitochondrial decay determines life-span, and as a model for intervention in human age-related disease.
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