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. ? ? ? ?

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Research Project (R01)
Project #
5R01AG026561-03
Application #
7415140
Study Section
Cellular Mechanisms in Aging and Development Study Section (CMAD)
Program Officer
Mccormick, Anna M
Project Start
2006-08-15
Project End
2011-04-30
Budget Start
2008-05-01
Budget End
2009-04-30
Support Year
3
Fiscal Year
2008
Total Cost
$266,862
Indirect Cost
Name
Washington University
Department
Other Basic Sciences
Type
Schools of Medicine
DUNS #
068552207
City
Saint Louis
State
MO
Country
United States
Zip Code
63130
Kumar, Sandeep; Dietrich, Nicholas; Kornfeld, Kerry (2016) Angiotensin Converting Enzyme (ACE) Inhibitor Extends Caenorhabditis elegans Life Span. PLoS Genet 12:e1005866
Warnhoff, Kurt; Kornfeld, Kerry (2015) New links between protein N-terminal acetylation, dauer diapause, and the insulin/IGF-1 signaling pathway in Caenorhabditis elegans. Worm 4:e1023498
Kumar, Sandeep; Kocsisova, Zuzana; Kornfeld, Kerry (2014) Keep on laying eggs Mama, RNAi my reproductive aging blues away. PLoS Genet 10:e1004808
Warnhoff, Kurt; Murphy, John T; Kumar, Sandeep et al. (2014) The DAF-16 FOXO transcription factor regulates natc-1 to modulate stress resistance in Caenorhabditis elegans, linking insulin/IGF-1 signaling to protein N-terminal acetylation. PLoS Genet 10:e1004703
Pickett, Christopher L; Dietrich, Nicholas; Chen, Junfang et al. (2013) Mated progeny production is a biomarker of aging in Caenorhabditis elegans. G3 (Bethesda) 3:2219-32
Pickett, Christopher L; Kornfeld, Kerry (2013) Age-related degeneration of the egg-laying system promotes matricidal hatching in Caenorhabditis elegans. Aging Cell 12:544-53
Roh, Hyun Cheol; Collier, Sara; Guthrie, James et al. (2012) Lysosome-related organelles in intestinal cells are a zinc storage site in C. elegans. Cell Metab 15:88-99
Murphy, John T; Bruinsma, Janelle J; Schneider, Daniel L et al. (2011) Histidine protects against zinc and nickel toxicity in Caenorhabditis elegans. PLoS Genet 7:e1002013
Davis, Diana E; Roh, Hyun Cheol; Deshmukh, Krupa et al. (2009) The cation diffusion facilitator gene cdf-2 mediates zinc metabolism in Caenorhabditis elegans. Genetics 182:1015-33
Collins, James J; Evason, Kimberley; Pickett, Christopher L et al. (2008) The anticonvulsant ethosuximide disrupts sensory function to extend C. elegans lifespan. PLoS Genet 4:e1000230

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