Thermosensation and longevity in C. elegans

线虫的热感和寿命

• 批准号: 8742761
• 负责人: Shawn Xu
• 金额: $ 31.88万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-05-01 至 2019-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8742761
• 关键词: Address; Affect; Afferent Neurons; Aging; Animal Behavior; Animal Model; Animals; Behavior; Blood; Body Temperature; Caenorhabditis elegans; Calcium; Cues; Data; Drops; Environment; Environmental Risk Factor; Family; Fishes; Food; Genes; Genetic; Genetic Programming; Genome; Homologous Gene; Human; Investigation; Lead; Life; Longevity; Mammals; Mediating; Modeling; Mus; Neurodegenerative Disorders; Neurons; Neurosciences Research; Nutrient; Odors; Pathway interactions; Phosphoric Monoester Hydrolases; Phosphotransferases; Physiological Processes; Process; RNA Interference; Regulation; Reporting; Research; Role; Sensory; Sensory Physiology; TRP channel; Temperature; Testing; Thermodynamics; Work; age related; base; chemical reaction; cold temperature; fly; insight; nervous system disorder; neurophysiology; novel; programs; public health relevance; reaction rate (chemical); relating to nervous system; sensor; sensory neuroscience; transcription factor

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.

描述（由申请人提供）：目前感觉神经科学研究的大部分工作都致力于研究行为的感觉调节。这极大地增进了我们对行为的神经和遗传基础的理解。然而，应该指出的是，感官环境不仅仅调节行为。例如，环境因素对寿命有深远的影响。然而，与行为不同的是，人们对长寿的感觉调节知之甚少。温度是影响寿命的两个主要环境因素之一；然而，根本机制在很大程度上仍然难以捉摸。近一个世纪前就有报道称，蠕虫、苍蝇和鱼类等变温动物在较低温度下寿命更长。最近的研究表明，降低小鼠等恒温（温血）动物的体温也可以延长寿命，这凸显了温度降低在延长寿命中的普遍作用。一个著名的模型认为，寒冷的气温会降低化学反应的速度，从而导致生活节奏减慢。该模型表明，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个百年观点。我们发现，遗传途径积极促进线虫在低温下的寿命，线虫是衰老研究中最常用的模型生物之一。我们证明 TRPA-1 是一种保守的冷敏感 TRP 通道，可充当热传感器来检测环境中的温度下降，从而启动长寿基因程序。有趣的是，人类 TRPA1 可以在功能上替代线虫 TRPA-1，延长低温下的寿命。这些结果确定了 TRP 家族通道在调节寿命方面的新功能。更重要的是，他们证明寒冷引起的寿命延长不仅仅是一个被动的热力学过程，而是一个受基因调控的主动过程。尽管如此，仍有许多悬而未决的问题。例如，动物如何检测环境中的温度下降尚不十分清楚。特别是，感知低温的热感觉神经元的身份仍然难以捉摸。目前还不清楚这些冷敏感神经元（如果存在）如何在低温下介导寿命延长。此外，虽然我们已经确定了一种在低温下介导寿命延长的基因程序，但该途径中是否还有其他基因参与？在这里，我们建议通过测试几个假设来解决这些问题。我们将采取遗传和神经生理学方法相结合的方法。由于人们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，衰老机制在进化上是保守的，这项工作也将为我们对哺乳动物中类似现象的理解提供新的见解。