Aging is characterized by progressive, degenerative changes in many organ systems. These changes result in significant functional declines in elderly people and often contribute to death. Treatments that delay age- related degeneration would be desirable, but few are available. The long-term objective of this proposal is to identify drugs that can delay age-related degeneration. This proposal exploits nematode worms and mice as model systems to analyze aging. Nematodes are a powerful experimental system that is convenient for genetic, molecular, and pharmacologic studies, whereas mice are highly relevant to humans. The preliminary studies describe the identification of FDA-approved drugs that can extend the adult lifespan of worms including ethosuximide, trimethadione and valproic acid.
Specific aim 1 proposes to characterize the mechanism of action of valproic acid by testing the hypothesis that valproic acid functions as an inhibitor of histone deacetylases. In addition, the hypothesis that ethosuximide and trimethadione function by modulating neural activity will be tested by analyzing mutants that are resistant to these drugs. A detailed, mechanistic understanding of the action of these drugs is important because it will elucidate endogenous pathways that influence aging, and establish a foundation for considering the therapeutic use of these drugs.
Specific aim 2 proposes to identify FDA-approved drugs that can extend worm lifespan and characterize the mechanism of action of these drugs. The identification of drugs that delay aging is significant for two reasons. First, it might lead to the identification of new mechanisms that influence aging. Second, because these drugs are approved for human use, these studies might lead to therapies that can delay age-related degenerative changes in humans.
Specific aim 3 proposes to determine if trimethadione and valproic acid can extend the lifespan of mice or delay age-related changes. The demonstration that these FDA-approved drugs delay aging in a vertebrate would be significant. ? ? ? ?
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