The metabolomic consequences of small size and long life

项目摘要 这项研究计划的制定是为了使候选人杰西卡霍夫曼博士具备经验， 技能和工具，需要成功过渡到一个大型公立研究型大学的教师职位。的 拟议的研究将发现新的代谢机制，导致小尺寸和长寿命的自然 遗传变异和延长寿命的干预措施，特别关注色氨酸的降解， 犬尿氨酸霍夫曼博士将接受广泛的培训，在小鼠饲养技术，分子生物学， 在她的导师团队Steven Austad博士的指导下， 斯蒂芬巴恩斯和刘孙，都在伯明翰的亚拉巴马大学和UAB的积极成员， 内森·休克衰老生物学卓越中心。在指导下完成的初步研究 Steven Austad博士的研究表明，大小在解释代谢组学特征的变化方面起着很大的作用。 一些物种（伴侣犬）的体型与寿命呈负相关。与博士一起工作。 Sun认为，小的，长寿命的生长激素（GH）破坏之间的代谢组学特征是不同的。 小鼠和野生型小鼠。发现两个物种之间相似的一个途径是 色氨酸到犬尿氨酸。在小型犬和GH破坏的小型小鼠中，犬尿氨酸水平较高， 色氨酸水平低于其较大的对应物。这表明色氨酸降解为 犬尿氨酸可能会影响在一个物种的小个体中看到的寿命延长。的总目标 这个项目是为了扩大我们对小尺寸和长寿命的认识，并进一步梳理分子 这是一种跨物种的体型寿命权衡机制。首要假设是， 色氨酸代谢失调部分由GH和能量摄入调节，并提供IGF-1。 我独立的机制，长寿命和小的身体大小跨越物种。这一假设将是 通过三个具体目标来解决，每个目标都将有助于霍夫曼博士成为一名独立的研究者。 1)测定色氨酸代谢动力学对GH活性降低的长寿效应。2)确定 代谢组学特征，特别是色氨酸降解代谢在不同干预措施中如何变化 显示出不同物种的体型更小寿命更长。3)确定遗传因素对寿命的影响 操纵果蝇中的色氨酸代谢基因。总的来说，这项建议将增加我们对以下方面的了解： 导致身体大小和寿命变化的分子基础，并将提供新的假设 关于改善寿命和健康的潜在干预措施。

Project Summary This research proposal has been developed to equip the candidate, Dr. Jessica Hoffman, with the experience, skills, and tools needed to successfully transition into a faculty position at a large public research university. The proposed research will discover novel metabolic mechanisms that lead to small size and long life across natural genetic variation and lifespan extending interventions with a specific focus on the degradation of tryptophan to kynurenine. Dr. Hoffman will receive extensive training in mouse husbandry techniques, molecular biology, and metabolomics data acquisition and analysis under the guidance of her mentorship team, Drs. Steven Austad, Stephen Barnes, and Liou Sun, all at the University of Alabama at Birmingham and active members of UAB's Nathan Shock Center for Excellence in the Biology of Aging. Preliminary studies completed under the direction of Dr. Steven Austad indicate size plays a large role in explaining the variation in metabolomic profiles within a species (companion dogs) that show a negative correlation between body size and longevity. And work with Dr. Sun suggests that metabolomic profiles are different between small, long-lived growth hormone (GH) disrupted mice and wild type mice. One pathway found to be similar between the two species is the breakdown of tryptophan to kynurenine. In both small dogs and small GH disrupted mice kynurenine levels are higher and tryptophan levels are lower than their larger counterparts. This suggests that the degradation of tryptophan to kynurenine may be influencing the longevity extension seen in small individuals of a species. The overall goal of this project is to expand our knowledge of small size and long life and to further tease apart the molecular mechanisms that underlie the size longevity tradeoff seen across species. The overarching hypothesis is that tryptophan metabolic dysregulation is partially modulated by GH and energy intake and provides an IGF- I independent mechanisms of long-life and small body size across species. This hypothesis will be addressed by three specific aims, each of which will help develop Dr. Hoffman as an independent investigator. 1) Determine the dynamics of tryptophan metabolism to the longevity effect of reduced GH activity. 2) Determine how metabolomic profiles, specifically tryptophan degradation metabolism varies across different interventions that show smaller size and longer life across species. 3) Determine lifespan consequences of genetic manipulation of tryptophan metabolism genes in fruit flies. Overall, this proposal will increase our knowledge on the molecular underpinnings that lead to variation in body size and lifespan and will provide new hypotheses about potential interventions to improve lifespan and healthspan.