Collins James J, Evason Kimberley, Pickett Christopher L, Schneider Daniel L, Kornfeld Kerry
Department of Developmental Biology, Washington University School of Medicine, St Louis, MO, USA.
PLoS Genet. 2008 Oct;4(10):e1000230. doi: 10.1371/journal.pgen.1000230. Epub 2008 Oct 24.
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.
乙琥胺是一种用于治疗人类癫痫疾病的药物，我们之前证明乙琥胺可以延缓与年龄相关的变化并延长线虫秀丽隐杆线虫的寿命。乙琥胺延长寿命的作用机制尚不清楚，阐明乙琥胺的作用方式对于确定影响寿命的内源性过程以及探索乙琥胺作为治疗与年龄相关疾病的潜力非常重要。为了鉴定介导乙琥胺活性的基因，我们进行了一项遗传筛选，并在两个基因che-3和osm-3中鉴定出突变，这些突变导致对乙琥胺介导的毒性产生抗性。che-3和osm-3中的突变导致重叠的化学感受神经元组出现缺陷，从而导致化学感觉缺陷和寿命延长。这些发现表明乙琥胺通过抑制特定化学感受神经元的功能来延长寿命。这一模型得到了以下观察结果的支持：经乙琥胺处理的动物表现出与具有化学感觉缺陷的突变体有许多表型相似性，这表明乙琥胺抑制化学感觉功能。此外，乙琥胺通过抑制化学感觉来延长寿命，因为长寿的osm-3突变体对乙琥胺引起的寿命延长具有抗性。这些研究证明了一种延长寿命药物的新作用机制，并表明感觉知觉在控制寿命中起关键作用。感觉知觉也影响果蝇的寿命，这表明感觉知觉在寿命控制中具有进化上保守的作用。这些研究突出了乙琥胺和相关药物调节感觉知觉以延长不同动物寿命的潜力。
