Kerry Kornfeld, M.D. Ph.D.
Project Overview:
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.
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.
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).
Final Report:
The identification of pharmacological compounds that delay human aging would be highly significant. Such compounds could be used to promote longevity and to treat age-related disorders such Alzheimer’s disease, cancer, and atherosclerosis. Screening for such drugs in humans is infeasible due to ethical and time constraints, so we chose the nematode worm C. elegans as an animal model. C. elegans is a complex animal that displays extensive conservation of fundamental biological processes with humans, including at least two pathways that regulate aging. We identified three drugs, ethosuximide, trimethadione, and 3,3-diethyl-2-pyrrolidinone (DEABL), that increase mean and maximum lifespan of Caenorhabditis elegans and delay age-related declines of physiological processes (Evason et al., 2005). Thus, these compounds retard the aging process. These compounds, two of which are approved for human use, are anticonvulsants that modulate neural activity. These compounds also regulated neuromuscular activity in nematodes. These findings suggest that the lifespan extending activity of these compounds is related to the anticonvulsant activity and implicate neural activity in the regulation of aging.
