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Aging is characterized by widespread degenerative changes in tissue morphology and function and an increase in the incidence of human diseases such as cancer, stroke, and Alzheimer disease. Findings from recent genetic studies suggest that molecular mechanisms that influence life span are evolutionarily conserved, and interventions that extend the life span of model organisms such as worms and flies are likely to have similar effects on vertebrates such as humans. However, little progress has been made in identifying drugs that delay aging. We identified 3 pharmacologic compounds, ethosuximide, trimethadione, and 3,3-diethyl-2-pyrrolidinone, that extend lifespan and delay age-related degenerative changes in the nematode worm Caenorhabditis elegans. All 3 compounds are anticonvulsants that modulate neural activity in vertebrates, and ethosuximide and trimethadione are used to treat absence seizures in humans. We discuss existing evidence that these drugs might also delay vertebrate aging and suggest experiments that could test this hypothesis. Genetic and cell ablation studies conducted with model organisms have demonstrated connections between the nervous system and aging. Our studies provide additional support for the hypothesis that neural activity plays a role in lifespan determination, since ethosuximide and trimethadione regulated neuromuscular activity in nematodes. Our findings suggest that the lifespan extending activity of these compounds is related to the anticonvulsant activity, implicating neural activity in the regulation of aging. We also discuss models that explain how the nervous system influences lifespan.

Absence seizure frequency was estimated in 20 patients (5 to 15 years old) before and after treatment with ethosuximide. Estimates were obtained from mothers' histories, observations by nurses, intensive observation by trained observers, physical and neurological examinations, routine EEG, and 12-hour telemetered EEG. Both before treatment (high seizure frequency) and after treatment (low frequency), telemetered EEG was the most reliable method of estimation, and intensive observation was the next best method. After treatment, the mothers' and nurses' estimates of seizure frequency were significantly less than the telemetered EEG estimates. The neurological examination and routine EEG were sufficient to diagnose absence attacks in all 20 patients and to determine if the attacks were completely controlled by therapy in all but two patients.

A 15-year-old girl was given two 250-mg doses of ethosuximide because of petit mal seizures. Within hours of taking the first pill she developed an acute reaction involving dyskinetic movements of the face, arms, and legs. These were abruptly and completely relieved by an intravenous injection of diphenhydramine hydrochloride.