AREA: Rapamycin, ambient temperature, and longevity

描述(由申请人提供)：研究所威廉姆斯学院地址生物学系威廉斯敦，马萨诸塞州01267首席研究员史蒂文J·斯沃普标题-领域：雷帕霉素，环境温度和小鼠寿命直到最近，饮食中的添加剂一直无法模拟卡路里限制的延长寿命的效果。然而，最近的研究表明，在杂交小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，称为TOR，已经被很好地描述出来，并与增长和能量平衡--包括支出和饥饿--的调节密切相关。受热量限制影响的信号通路汇聚在调节mTOR(哺乳动物版本的TOR)并受其调节的相同通路上。卡路里限制延长小鼠寿命的大部分结果需要温和的冷应激(即典型的住房温度为220摄氏度)。在这项提案中，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)雷帕霉素对延长寿命的效果需要显著的代谢抑制、心动过缓和低温，以及3)尽管体重正常，但服用雷帕霉素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不同环境温度下小鼠的这些生理变量，同时限制卡路里或在饮食中添加雷帕霉素。威廉姆斯学院是一所小型文科学校，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。政府提供了一项极其有利的休假政策(每三年一次)，五年前建造了一座耗资5000万美元的科学设施，为实验室和动物住所提供了充足的空间，并为资助计划提供了校内种子资金(如这一项)。我们在威廉姆斯学院的科学使命的一部分是曝光和成功地培养本科生。学生经常对研究项目承担相当大的责任，实验室环境通常呈现出一种可与研究生院研究环境相媲美的氛围，在这种环境中，学生与教师并肩工作，设计和开展复杂的研究。我的研究计划继续让本科生参与主流研究，让他们以一种综合的生物学方法接触尖端和当前的技术，在这种方法中，测试特定的假设推动研究。我提议的项目将为那些可能继续从事富有成效的科学职业的学生提供极好的研究体验。 与公共健康相关：限制卡路里摄入量延长了大多数被测试生物的寿命。在实验室小鼠中，当小鼠被安置在20-250摄氏度的典型间隔室温度下时，热量限制的效果最好。当小鼠被安置在它们的热中立区并受到卡路里限制时，寿命的延长就会大大减少。最近，雷帕霉素被证明可以延长被安置在远低于热中性区域的环境温度下的小鼠的寿命。雷帕霉素是否需要凉爽的环境温度，就像限制卡路里一样，来延长小鼠的寿命仍有待测试，这也是这项提议的主要目标之一。雷帕霉素已被证明对热量限制影响的生化途径具有相同的作用，但尚不清楚雷帕霉素是否能引起热量限制所引起的相同的生理变化。因此，如果像雷帕霉素这样的化合物被用于其他哺乳动物的延寿特性，了解雷帕霉素对小鼠的生理影响是非常重要的。这项提议的总体目标是检验以下假设：1)雷帕霉素延长小鼠的寿命需要凉爽的环境温度，2)雷帕霉素治疗模拟热量限制引起的生理效应。

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.