Dopamine, Tryosine, and their Metabolites in Aging in Neurodegenerative Disease

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DESCRIPTION (provided by applicant): This application describes a 4 year training program for the development of an academic career in Geriatrics with a research focus on the basic Biology of Aging. The principal investigator has completed clinical training in Geriatrics and is now pursuing research using the free-living nematode, C. elegans, to study the genetic regulation of aging and lifespan determination. The training program consists of structured didactic work and mentored research experiences designed to build upon the principal investigator's prior research experience in the areas of molecular biology and fruit fly, Drosophila, genetics. Specifically the program will develop new research abilities in the areas of Biology of Aging, C. elegans genetics, Biology of Dopamine, and Molecular Toxicology. The application also includes a research program which seeks to advance the understanding of aging through studies using the worm. Specifically, study will focus on the 4-hydroxyphenylpyruvate dioxygenase gene which is a target gene of the orphan nuclear hormone receptor daf-12. This gene is down-regulated in both long-lived daf-12 mutants and in long-lived daf-2 insulin/IGF-1 receptor mutants suggesting a role in the regulation of aging. Consistent with this, down-regulation of this single gene by RNAi extends worm lifespan by up to 30%. The mechanisms involved in the increase in longevity will be investigated in worms using a combination of RNA interference studies and genetics. It appears that tyrosine metabolites may be toxic to tissues and reduction of these metabolite levels may explain some or all of the extension of lifespan. A parallel investigation during the project will be to investigate whether the tyrosine-derived neurotransmitter dopamine may share common toxic effects on worms. The ultimate goal of the training program is to allow the principal investigator to develop a program in the basic Biology of Aging within a Geriatrics Division. An improved understanding of the biochemical events involved in aging and the responses of an organism to these events will greatly enhance our understanding of the aging process and the link between aging and disease. This understanding holds the potential for the development of treatments to address the negative consequences of aging or to prevent diseases associated with aging. Additionally, an improved understanding of the aging process will provide insight into the differences between geriatric patients and younger patients especially with regards to differences in disease symptoms and response to treatments.