The anticonvulsant ethosuximide disrupts sensory function to extend C. elegans lifespan

James J. Collins, Kimberley Evason, Christopher L. Pickett, Daniel L. Schneider, Kerry Kornfeld

Research output: Contribution to journalArticle

27 Citations (Scopus)

Abstract

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.

Original languageEnglish (US)
Article numbere1000230
JournalPLoS Genetics
Volume4
Issue number10
DOIs
StatePublished - Oct 2008

Fingerprint

Ethosuximide
anticonvulsants
Anticonvulsants
defect
mutation
drug
gene
animal
nematode
toxicity
mechanism of action
neurons
drugs
mutants
Neurons
Mutation
Caenorhabditis elegans
seizures
drug therapy
Pharmaceutical Preparations

ASJC Scopus subject areas

  • Genetics
  • Molecular Biology
  • Ecology, Evolution, Behavior and Systematics
  • Cancer Research
  • Genetics(clinical)

Cite this

The anticonvulsant ethosuximide disrupts sensory function to extend C. elegans lifespan. / Collins, James J.; Evason, Kimberley; Pickett, Christopher L.; Schneider, Daniel L.; Kornfeld, Kerry.

In: PLoS Genetics, Vol. 4, No. 10, e1000230, 10.2008.

Research output: Contribution to journalArticle

Collins, James J. ; Evason, Kimberley ; Pickett, Christopher L. ; Schneider, Daniel L. ; Kornfeld, Kerry. / The anticonvulsant ethosuximide disrupts sensory function to extend C. elegans lifespan. In: PLoS Genetics. 2008 ; Vol. 4, No. 10.
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