Mechanisms of olfactory modulation of aging in Drosophila

描述（由申请人提供）：古老的信号通路检测、解码和使用环境刺激来协调新陈代谢、生长和成熟。野外生物学家早已认识到环境线索触发生活史模式改变的力量，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精心计算的决定，比如是等待逆境结束还是致力于繁殖，以最大限度地提高生殖适应度。事实上，从线虫（秀丽隐杆线虫）和果蝇（黑腹果蝇）的研究中得到的证据表明，衰老的感觉控制在进化上是保守的。蠕虫中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。我们实验室的工作表明，暴露于基于食物的气味会缩短寿命，并部分挽救饮食限制的好处。此外，一个单一的气味受体的突变，使苍蝇广泛的嗅觉丧失，导致惊人的寿命：高达60%（近30天）的中位数寿命增加相比，野生型动物。虽然突变果蝇具有正常的大小和代谢率，但它们对饥饿和高氧有抵抗力，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，分子和途径与相关的感觉信息有关;以及（iii）这些信息如何指导随后改变寿命的结果。我们将确定嗅觉突变果蝇的寿命增加是否依赖于已知的长寿途径或涉及新的途径;嗅觉信号传导是否在成年阶段急性作用;以及特定的气味受体是否调节果蝇的寿命。我们的研究将为随后分析调节果蝇衰老的特定分子和生物学过程提供分子证据。这些研究也可能阐明哺乳动物中控制发育、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.