Ethosuximide is a medication used to treat
seizure disorders in humans, and we previously demonstrated that
ethosuximide can delay age-related changes and extend the lifespan of the nematode Caenorhabditis elegans. The mechanism of action of
ethosuximide in lifespan extension is unknown, and elucidating how
ethosuximide functions is important for defining endogenous processes that influence lifespan and for exploring the potential of
ethosuximide as a therapeutic for age-related diseases. To identify genes that mediate the activity of
ethosuximide, we conducted a genetic screen and identified mutations in two genes, che-3 and osm-3, that cause resistance to
ethosuximide-mediated toxicity. Mutations in che-3 and osm-3 cause defects in overlapping sets of chemosensory neurons, resulting in defective chemosensation and an extended lifespan. These findings suggest that
ethosuximide extends lifespan by inhibiting the function of specific chemosensory neurons. This model is supported by the observation that
ethosuximide-treated animals displayed numerous phenotypic similarities with mutants that have chemosensory defects, indicating that
ethosuximide inhibits chemosensory function. Furthermore,
ethosuximide extends lifespan by inhibiting chemosensation, since the long-lived osm-3 mutants were resistant to the lifespan extension caused by
ethosuximide. These studies demonstrate a novel mechanism of action for a lifespan-extending
drug and indicate that sensory perception has a critical role in controlling lifespan. Sensory perception also influences the lifespan of Drosophila, suggesting that sensory perception has an evolutionarily conserved role in lifespan control. These studies highlight the potential of
ethosuximide and related drugs that modulate sensory perception to extend lifespan in diverse animals.