S. Kerry Kornfeld, M.D.
Project Overview:
There are currently no well-documented pharmacological treatments that delay normal human aging and extend human lifespan. To identify drugs that can delay aging, we chose to screen drugs used to treat a variety of human diseases, reasoning that these compounds might have effects on aging that had not been previously identified. After screening about 20 compounds, we identified one drug that significantly extended C. elegans life span, the anticonvulsant medication ethosuximide. Screening drugs with a related structure or function identified two additional compounds that extend lifespan, trimethadione and 3,3-diethyl-2-pyrrolidinone. Ethosuximide and trimethadione are approved for human use; these compounds are used to treat absence seizures, a form of epilepsy. These drugs increase mean and maximum life span of C. elegans and delay age-related declines of physiological processes, indicating that these compounds retard the aging process. We conducted a dose-response analysis and showed that the effective dose of ethosuximide in worms overlaps the therapeutic range in humans, suggesting that the anti-aging effect and the anti-seizure effect have a similar mechanism. These compounds are likely to act on the C. elegans nervous system since they cause several behavioral phenotypes. Our findings suggest that the life-span-extending activity of these compounds is related to the anticonvulsant activity and implicate neural activity in the regulation of aging. These findings were published in the January 14, 2005 issue of Science (Evason, K., C. Huang, I. Yamben, D.F. Covey and K. Kornfeld. 2005. Anticonvulsant medications extend worm life span. Science 307: 258-262).
I propose to test whether trimethadione or ethosuximide can delay aging and extend the lifespan of mice. This is the next critical question in determining if these drugs might have benefits for treating human aging. We will use mice of the inbred strain, C57Bl/6J. We will first determine the oral dosage that achieves an effective serum concentration. To measure life span, we will include 80 mice in each treatment group and the control group. The drugs will be obtained comercially and delivered in the food. Dosage will be monitored by testing serum concentration. Because these drugs are used to treat human epilepsy, this is a standard test performed by the clinical lab at Mayo Hospital. If these drugs cause a statistically significant extension of lifespan, it will demonstrate that the drugs also have anti-aging effects in a mammal. These results would provide a compelling rational for testing these drugs in humans. The fact that ethosuximide and trimethadione are approved for human use will significantly facilitate conducting such future studies.
Final Report:
There are currently no well-documented pharmacological treatments that delay normal human aging and extend human lifespan. To identify drugs that can delay aging, we chose to screen drugs used to treat a variety of human diseases, reasoning that these compounds might have effects on aging that had not been previously identified. After screening about 20 compounds, we identified two drugs that significantly extended C. elegans life span, the anticonvulsant medication ethosuximide and the neuroactive medication valproic acid. Ethosuximide and valproic acid are approved for human use. These drugs increase mean and maximum life span of C. elegans and delay age-related declines of physiological processes, indicating that these compounds retard the aging process. Our major accomplishments during the grant period included characterizing the mechanism of action of these drugs in extending lifespan. We demonstrated that valproic acid acts differently from ethosuximide, and these two drugs can be combined to produce additive lifespan extensions. Valproic acid may influence the insulin/IGF signaling pathway. We demonstrated that ethosuximide extends lifespan by inhibiting the activity of specific ciliated neurons in the head of the animal. These studies contribute to understanding how the nervous system influences lifespan, and demonstrate the possibility of using drugs that affect the nervous system to affect longevity.
