Thermosensation and longevity in C. elegans

描述(由申请人提供)：目前在感觉神经科学研究中的大部分努力都指向调查行为的感觉调节。这极大地提高了我们对行为的神经和遗传基础的理解。然而，应该注意的是，感觉环境不仅控制着行为。例如，环境因素对寿命有着深远的影响。然而，与行为不同的是，人们对长寿的感官调控知之甚少。温度是影响寿命的两个主要环境因素之一；然而，其根本机制在很大程度上仍然难以捉摸。据报道，近一个世纪前，变温(冷血)动物，如蠕虫、苍蝇和鱼，在较低的温度下活得更长。最近的研究表明，降低恒温(温血)动物(如小鼠)的体温也可以延长寿命，这突显了温度降低在延长寿命中的一般作用。一个著名的模型认为，寒冷的气温会降低化学反应的速度，从而导致生活节奏变慢。这个模型表明，在低温下观察到的延长寿命只是一个被动的热力学过程。然而，我们最近的工作挑战了这种百年来的观点。我们发现，遗传途径积极地促进线虫在低温下的寿命，线虫是研究衰老最常用的模式生物之一。我们发现，TRPA-1，一个保守的冷敏感Trp通道，作为一个热传感器来检测环境中的温度下降，从而启动一项延长寿命的遗传计划。有趣的是，人的TRPA-1可以在功能上替代蠕虫的TRPA-1在低温下延长寿命。这些结果证实了Trp家族通道在调节长寿方面的新功能。更重要的是，他们证明了冷诱导的寿命延长不是一个简单的被动热力学过程，而是一个受基因调控的主动过程。然而，仍有许多问题悬而未决。例如，动物如何检测环境中的温度下降并不是很好的理解。特别是，感觉寒冷温度的温度感觉神经元的身份仍然难以捉摸。目前也不清楚这些冷敏感神经元(如果存在的话)如何在低温下调节寿命延长。此外，尽管我们已经确定了一种在低温下调节寿命延长的遗传程序，但是否还有其他基因参与了这一途径？在这里，我们建议通过检验几个假设来解决这些问题。我们将采取遗传学和神经生理学相结合的方法。由于对寿命的温度调节知之甚少，我们的工作将填补感觉神经科学和衰老领域的一个关键空白。众所周知，从蠕虫到哺乳动物的衰老机制在进化上是保守的，这项拟议的工作也将为我们理解哺乳动物中的类似现象提供新的见解。

DESCRIPTION (provided by applicant): Much of the current effort in sensory neuroscience research has been directed to investigating sensory regulation of behavior. This has greatly advanced our understanding of the neural and genetic basis of behavior. Nevertheless, it should be noted that sensory environment not just regulates behavior. For instance, environmental cues have a profound impact on longevity. However, unlike behavior, relatively little is known about sensory regulation of longevity. Temperature is one of the two primary environmental factors that affect lifespan; however, the underlying mechanisms remain largely elusive. It was reported nearly a century ago that poikilothermic (cold-blooded) animals, such as worms, flies, and fish, live longer at lower temperatures. Recent work demonstrates that lowering the body temperature of homeothermic (warm-blooded) animals, such as mice, also extends lifespan, highlighting a general role of temperature reduction in lifespan extension. One prominent model argues that cold temperatures would reduce the rate of chemical reactions, thereby leading to a slower pace of living. This model suggests that the extended lifespan observed at low temperatures is simply a passive thermodynamic process. However, our recent work challenges this century-old view. We find that genetic pathways actively promote longevity at low temperatures in C. elegans, one of the most commonly used model organism for aging research. We show that TRPA-1, a conserved cold-sensitive TRP channel, acts as a thermal sensor to detect temperature drop in the environment to initiate a pro-longevity genetic program. Interestingly, human TRPA1 can functionally substitute for worm TRPA-1 in lifespan extension at cold temperatures. These results identify a novel function for TRP family channels in regulating longevity. More importantly, they demonstrate that cold-induced lifespan extension is not simply a passive thermodynamic process but rather an active process that is regulated by genes. Nevertheless, many unanswered questions remain. For example, how animals detect temperature drop in the environment is not very well understood. Particularly, the identity of the thermosensory neurons that sense cold temperatures remains elusive. It is also unclear how these cold-sensitive neurons, if present, mediate lifespan extension at low temperatures. In addition, though we have identified a genetic program that mediates lifespan extension at cold temperatures, are there other genes involved in the pathway? Here, we propose to address these questions by testing several hypotheses. We will take a combination of genetic and neurophysiological approaches. As very little is known about temperature modulation of lifespan, our work will fill in a critical gap in both the sensory neuroscience and aging fields. A aging mechanisms are known to be evolutionarily conserved from worms to mammals, the proposed work will also provide novel insights into our understanding of similar phenomena in mammals.