AREA: Rapamycin, ambient temperature, and longevity

描述（由申请人提供）：机构威廉姆斯学院地址生物学系，马萨诸塞州威廉姆斯镇，01267首席研究员Steven J. swap标题-领域：雷帕霉素、环境温度和小鼠寿命直到最近，饮食中的添加剂还不能模仿热量限制的延长寿命效果。然而，最近的研究表明，在近亲繁殖的老鼠的饮食中添加雷帕霉素，一种免疫抑制药物，大大延长了它们的寿命。雷帕霉素的靶标TOR已经被很好地描述，并且与生长和能量平衡的调节密切相关——包括消耗和饥饿。受热量限制影响的信号通路聚集在调节mTOR（哺乳动物版本的TOR）并受其调节的相同通路上。热量限制延长小鼠寿命的大多数结果需要轻度冷应激（即典型的220℃的住房温度）。在这个提议中，我们将测试以下假设：1)口服雷帕霉素也需要相同的冷应激才能最大限度地延长寿命；2)雷帕霉素延长寿命的效果需要显著的代谢抑制、心动缓和体温过低；3)尽管体重正常，雷帕霉素治疗的小鼠将表现出与热量限制相似的生理变量。我们建议使用间接量热法和基于遥测的心率和体温检测系统来测量小鼠在不同环境温度下的这些生理变量，同时限制热量摄入或在饮食中添加雷帕霉素。威廉姆斯学院是一所小型文理学院，在教育和研究方面都取得了巨大的成功。这反映了学院对教师研究的真正支持性质。政府提供了非常有利的休假政策（每三年一次），五年前建造了一个5000万美元的科学设施，为实验室和动物收容所提供了充足的空间，并为资助项目（比如这个项目）提供了校内种子资金。威廉姆斯学院的科学使命之一是为本科生提供机会和成功的培训。学生经常承担研究项目的大量责任，实验室环境通常具有与研究生院研究环境相当的氛围，学生与教师并肩工作，设计和开展复杂的研究。我的研究项目继续让本科生参与主流研究，让他们接触到综合生物学方法中复杂和最新的技术，在这种方法中，测试特定的假设来推动研究。我提议的项目将为那些可能继续从事富有成效的科学事业的学生提供一个极好的研究经历。

DESCRIPTION (provided by applicant): Institution Williams College Address Department of Biology Williamstown, MA 01267 Principal Investigator Steven J. Swoap Title - AREA: Rapamycin, ambient temperature, and longevity in mice Until recently, additives to the diet have been unable to mimic the lifespan-extension effects of caloric restriction. However, it was very recently shown that the addition of rapamycin, an immunosuppressant drug, to the diet of outbred mice substantially extended their lifespan. The target of rapamycin, called TOR, has been well characterized and is intimately involved with regulation of growth and energy balance - both expenditure and hunger. Signaling pathways impacted by caloric restriction converge on the same pathways that regulate, and are regulated by, mTOR (the mammalian version of TOR). Most of the lifespan extension consequence of caloric restriction in mice requires a mild cold stress (i.e. a typical housing temperature of 220C). In this proposal, we will test the hypotheses that 1) orally administered rapamycin also requires the same cold stress for maximum lifespan extension, 2) significant metabolic depression, bradycardia, and hypothermia are required for rapamycin's effect on lifespan extension, and 3) despite a normal body weight, mice treated with rapamycin will exhibit similar physiological variables as seen with caloric restriction. We propose to use indirect calorimetry and a telemetry-based heart rate and body temperature detection system to measure these physiological variables in mice at different ambient temperatures while either being calorically restricted or with the addition of rapamycin to the diet. Williams College is a small liberal arts school that has had wonderful success excelling in both education and research endeavors. This reflects the truly supportive nature of the college towards faculty research. The administration offers an extremely beneficial sabbatical policy (every three years), built a $50 million science facility five years ago, provides ample space for labs and animal housing, and offers intramural seed money for grant initiatives (like this one). Part of our mission in the sciences at Williams College is the exposure and successful training of undergraduates. Students regularly assume a significant amount of responsibility with research projects and the laboratory environment often takes on an atmosphere comparable to a graduate school research environment where students are working side-by-side with the faculty to design and conduct sophisticated research. My research program continues to involve undergraduates in mainstream research, exposing them to sophisticated and current technology in an integrative biology approach where testing specific hypotheses drive the research. My proposed project would provide an excellent research experience for students who are likely to go on to productive scientific careers. PUBLIC HEALTH RELEVANCE: The restriction of caloric intake extends the lifespan of most organisms tested. In laboratory mice, caloric restriction has its greatest effect when the mice are housed at typical vivarium temperatures of 20-250C. When mice are housed within their thermal neutral zone and calorically restricted, lifespan extension is greatly diminished. Recently, rapamycin was shown to extend the lifespan of mice housed at ambient temperatures well below their thermal neutral zone. Whether rapamycin requires a cool ambient temperature, as does caloric restriction, to increase lifespan in mice remains to be tested and is one of the primary goals of this proposal. Rapamycin has been shown to have effects on the same biochemical pathways influenced by caloric restriction, but it is not known whether rapamycin can induce the same physiological changes induced by caloric restriction. Hence, understanding the physiological influences of rapamycin on mice is of significant importance if compounds like rapamycin are to be used for its life extension properties in other mammals. The overall goals of this proposal are to test the hypotheses that: 1) the extension of lifespan of mice by rapamycin requires a cool ambient temperature, and 2) the rapamycin-treatment mimics the physiological effects induced by caloric restriction.