The anticonvulsant ethosuximide disrupts sensory function to extend C. elegans lifespan.
The anticonvulsant ethosuximide disrupts sensory function to extend C. elegans lifespan.
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DOI：
10.1371/journal.pgen.1000230
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发表时间：
2008-10
期刊：
影响因子：
4.5
通讯作者：
Kornfeld K
中科院分区：
文献类型：
--
作者：
Collins JJ;Evason K;Pickett CL;Schneider DL;Kornfeld K
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. Aging is a major factor that contributes to disease and disability in humans, but no medicines have been demonstrated to delay human aging. We previously conducted a screen for FDA-approved drugs that can extend the lifespan of the nematode worm C. elegans, resulting in the identification of ethosuximide, a medicine used to treat epilepsy. To elucidate the mechanism of action of ethosuximide in lifespan extension, we conducted a genetic screen for C. elegans mutations that cause resistance to ethosuximide. Here, we describe the identification of genes that are critical for ethosuximide sensitivity. These genes are necessary for the function of neurons that mediate sensory perception. Furthermore, ethosuximide treatment caused defects in sensory perception. These results indicate that ethosuximide affects lifespan by inhibiting neurons that function in the perception of sensory cues. These studies highlight the importance of sensory neurons in lifespan determination and demonstrate that a drug can act on specific cells within the nervous system to extend lifespan. Sensory perception also modulates Drosophila lifespan, suggesting this is an evolutionarily conserved relationship. Our results indicate that sensory perception may be a promising target for pharmacological extension of lifespan in a variety of animals.
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影响因子：
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作者：
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通讯作者：
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通讯作者：
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