The metabolomic consequences of small size and long life

小尺寸和长寿命的代谢组学后果

• 批准号: 9902281
• 负责人: Jessica Marie Hoffman
• 金额: $ 12.14万
• 依托单位: UNIVERSITY OF ALABAMA AT BIRMINGHAM
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-04-01 至 2022-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9902281
• 关键词: Address; Affect; Age; Aging; Alabama; Animal Model; Animals; Biological Process; Biology of Aging; Body Size; Callithrix; Calories; Canis familiaris; Companions; Complex; Data Analyses; Diet; Dioxygenases; Down-Regulation; Drosophila genus; Energy Intake; Enzymes; Essential Amino Acids; Faculty; Female; Future; Genes; Genetic; Genetic Variation; Genotype; Goals; Health; Human; Individual; Insulin; Insulin-Like Growth Factor I; Intervention; Knowledge; Kynurenine; Lead; Life; Longevity; Measures; Melatonin; Mentors; Mentorship; Metabolic; Metabolic Pathway; Metabolism; Methionine; Molecular; Molecular Biology; Mus; Nerve Degeneration; Neurohormones; Nutrient; Pathway interactions; Pattern; Phase; Phenotype; Play; Positioning Attribute; Process; Production; Protein Biosynthesis; Research; Research Personnel; Research Project Summaries; Research Proposals; Role; Route; Serotonin; Shock; Signal Transduction; Sirolimus; Somatotropin; Techniques; The Sun; Training; Translating; Tryptophan; Tryptophan 2,3 Dioxygenase; Tryptophan Metabolism Pathway; Universities; Variant; Wild Type Mouse; Work; age effect; data acquisition; dietary manipulation; experience; experimental study; fly; genetic manipulation; healthspan; hormonal signals; improved; indoleamine; insulin signaling; member; metabolome; metabolomics; mouse model; novel; skills; tool

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.

项目概要 这项研究计划的制定是为了让候选人杰西卡·霍夫曼博士具备以下经验： 成功过渡到大型公立研究型大学的教职所需的技能和工具。这 拟议的研究将发现新的代谢机制，从而导致自然界中的小尺寸和长寿命 遗传变异和延长寿命的干预措施，特别关注色氨酸降解为 犬尿氨酸。霍夫曼博士将接受小鼠饲养技术、分子生物学和 在她的导师团队 Drs. 的指导下进行代谢组学数据采集和分析。史蒂文·奥斯塔德, Stephen Barnes 和 Liou Sun 均来自阿拉巴马大学伯明翰分校，也是阿拉巴马大学伯明翰分校的活跃成员 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，大小在解释体内代谢组谱的变化方面起着重要作用。 体型与寿命呈负相关的物种（伴侣犬）。并与博士一起工作。 Sun 表示，小而长寿命的生长激素 (GH) 破坏之间的代谢组谱有所不同 小鼠和野生型小鼠。两个物种之间发现的一种相似途径是分解 色氨酸转变为犬尿氨酸。在小型犬和 GH 破坏的小型小鼠中，犬尿氨酸水平较高，并且 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一个物种的小个体的寿命延长。总体目标为 这个项目是为了扩展我们对小尺寸和长寿命的认识，并进一步梳理分子 跨物种大小寿命权衡的机制。总体假设是 色氨酸代谢失调部分受 GH 和能量摄入调节，并提供 IGF- 跨物种的长寿命和小体型的独立机制。这个假设将是 由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研究者。 1) 确定色氨酸代谢动态对 GH 活性降低的长寿效应的影响。 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有何不同 显示出不同物种的体型更小、寿命更长。 3）确定遗传对寿命的影响 果蝇色氨酸代谢基因的操纵。总体而言，该提案将增加我们的知识 导致身体尺寸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寿命的潜在干预措施。