Pharmacologic Compounds that Extend C. elegan Life Span
Principal Investigator: Kerry Kornfeld MD, PhD

Summary:

The identification of drugs that delay human aging would be highly significant. Such drugs could be used to promote human longevity and to treat diseases that accompany aging such as Alzheimer's Disease, cancer, and heart disease. However, using people to screen drugs for possible life-extending effects is infeasible due to ethical concerns and practical constraints due to the long lifespan of humans. Therefore, we chose a simple, short-lived animal, the nematode worm C. elegans, as a model system to screen for drugs that extend lifespan. This animal is an appropriate substitute because very similar pathways regulate lifespan in C. elegans and humans. Furthermore, this animal has a short lifespan of about 2.5 weeks. After testing a wide variety of drugs, we identified three drugs that extend the lifespan of these animals: ethosuximide, valproic acid, and trimethadione. These drugs have been used for many years to treat epilepsy in humans. Epilepsy is a seizure disorder, and these drugs alter electrical activity in the brain. The goal of this proposal is to investigate how these drugs extend lifespan. Characterizing the mechanism of action of these drugs is an important step in establishing the feasibility of using the compounds to promote human longevity.

Specific Aims:

I. We have identified three pharmacological compounds that are approved for human use and extend the lifespan of C. elegans: ethosuximide, valproic acid, and trimethadione. We will test the hypothesis that these compounds function by regulating one of the well established pathways that regulates longevity of C. elegans, the insulin pathway, mitochondrial function, and caloric intake.

II. We will test the hypothesis that the life-extending compounds function by affecting the activity of specific neurotransmitter systems such as calcium channels and g-aminobutyric acid (GABA).