Pharmacology of Lifespan Extension

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DESCRIPTION (provided by applicant): This proposal is in response to the American Recovery and Reinvestment Act 2009(ARRA) and to NOT-OD-09-058. Aging is the single largest risk factor for disease in developed countries. The ongoing demographic change in the American population is greatly increasing the proportion of the population at risk for socially and economically important age-related diseases including Parkinson's disease (PD), Alzheimer's disease and cancer. Age-related disease is arguably the single greatest challenge for biomedicine in the 21st Century. Age-related diseases increasingly represent a national emergency; one that may undermine the mid-term benefits of the American Recovery and Reinvestment Act (ARRA). This supplement application addresses the goals of the ARRA by creating two job opportunity and proposing to purchase supplies and equipment from American scientific suppliers. Prompted by our prior discovery of compounds which extend lifespan and protect against stress we proposed in the parent grant to find new compounds that slow aging rates of the nematode C. elegans and determine the mechanisms at play. We expected such work to open new avenues for development of therapeutics for age-related diseases. We have made the striking discovery that a group of compounds commonly used to stain aggregating proteins in neurological disease increase the normal lifespan of C. elegans. Moreover, we find evidence that the compounds, especially thioflavin T (ThT) are slowing in vivo protein aggregate formation. The compounds have been previously used in human clinical studies. We previously discovered that Lithium, commonly used as a drug for the treatment of bipolar disorder, extends C. elegans lifespan. We believe Lithium acts via a distinct mechanism involving epigenetic modifications. We now propose to extend the scope of the grant to investigate the mechanisms at play for both these interesting interventions. It is important to follow BOTH leads at this time because it appears they act by different mechanisms. By pursuing two potential mechanisms to slow aging, we are more likely to find an intervention with significance to human aging and age-related disease. Since Lithium is already a drug in widespread use and ThT has been used in clinical research the likelihood that this proposal will lead to translational research in aging appears high. PUBLIC HEALTH RELEVANCE: This request is directly relevant to American Recovery and Reinvestment Act (ARRA) as it calls for the creation of a new job opportunity and the purchase of scientific equipment and supplies from American companies. It also addresses the development of therapeutics for economically important age-related diseases and it directly addresses "healthspan", a strategic priority for the Division of Aging Biology.