Mechanisms of olfactory modulation of aging in Drosophila

描述（由申请人提供）：古代信号通路检测、解码并利用环境刺激来协调代谢、生长和成熟。野外生物学家早就认识到，环境线索能够引发生命史模式的改变，这种可塑性的好处是显而易见的。多变的环境条件要求个体利用外部信息做出经过计算的决定，比如是等待艰难时期过去，还是致力于繁殖，以最大限度地提高生殖适应性。事实上，对线虫秀丽隐杆线虫和果蝇黑腹果蝇的研究表明，衰老的感官控制在进化上是保守的。蛔虫特定感觉神经元的消融会影响寿命，感觉信号转导所需基因的突变也会影响寿命。我们实验室的研究表明，接触食物气味会缩短寿命，并在一定程度上弥补了饮食限制带来的好处。此外，单个气味受体的突变会使苍蝇失去嗅觉，从而导致惊人的长寿：与野生型动物相比，果蝇的平均寿命增加了60%（近30天）。虽然突变蝇具有正常的大小和代谢率，但它们对饥饿和高氧具有抵抗力，并且它们表现出增加的甘油三酯储存。我们试图阐明(i)调节寿命的特定嗅觉刺激；（ii）哪些细胞、分子和途径转导相关的感觉信息；（三）这些信息如何指导改变寿命的后续结果。我们将确定嗅觉突变果蝇的寿命增加是依赖于已知的长寿途径还是涉及新的途径；嗅觉信号是否在成年期起强烈作用；以及特定的气味受体是否调节果蝇的寿命。我们的研究将为后续分析果蝇衰老的特定分子和生物过程提供分子证据。这些研究也可能阐明哺乳动物控制发育、代谢和衰老的感觉信号网络。

DESCRIPTION (provided by applicant): Ancient signaling pathways detect, decode, and use environmental stimuli to coordinate metabolism, growth, and maturation. The power of environmental cues to trigger alterations in life history patterns has long been recognized by field biologists, and the benefit of such plasticity is clear. Variable environmental conditions demand that individuals use external information to make calculated decisions, such as whether to wait out the bad times or commit to reproduction, to maximize reproductive fitness. Indeed, evidence from work in the nematode worm, Caenorhabditis elegans, and from our work in the fruit fly, Drosophila melanogaster, has shown that sensory control of aging is evolutionarily conserved. Ablation of specific sensory neurons in the worm affects lifespan, as do mutations in genes required for sensory signal transduction. Work in our laboratory has shown that exposure to food-based odorants reduces lifespan and partially rescues the benefits of dietary restriction. Moreover, mutation of a single odorant receptor, which leaves flies broadly anosmic, results in striking longevity: up to 60% (nearly 30 days) increase in median lifespan compared to wild-type animals. While mutant flies have normal size and metabolic rate, they are resistant to starvation and hyperoxia, and they exhibit increased triglyceride storage. We seek to elucidate (i) specific olfactory stimuli that regulate longevity; (ii) which cells, molecules, and pathways transduce relevant sensory information; and (iii) how this information directs subsequent outcomes that alter lifespan. We will determine whether the increased lifespan of olfactory mutant flies relies on known longevity pathways or involves novel pathways; whether olfactory signaling acts acutely in the adult stage; and whether specific odorant receptors regulate longevity in Drosophila. Our studies will provide molecular evidence for subsequent analysis of specific molecules and biological processes that regulate aging in Drosophila. These studies may also illuminate sensory signaling networks in mammals that control development, metabolism, and aging.