REPTOR as a mechanism for aging control by dietary restriction and rapamycin

REPTOR作为通过饮食限制和雷帕霉素控制衰老的机制

• 批准号: 9299810
• 负责人: MARC TATAR
• 金额: $ 20.31万
• 依托单位: BROWN UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-03-01 至 2019-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9299810
• 关键词: Affect; Aging; Amino Acids; Animals; Autophagocytosis; Cells; Complex; Development; Diet; Disease; Drosophila genus; Future; Gene Expression; Genes; Genetic Transcription; Human; Longevity; Mammals; Mediating; Modeling; Mus; Neurons; Nutrient; Pathology; Phosphotransferases; Process; Production; Proteins; Regulator Genes; Research; Research Project Grants; Sirolimus; System; Translations; Work; blood pressure regulation; cofactor; dietary control; dietary restriction; gene discovery; glucose metabolism; novel; programs

Project Summary/Abstract Dietary restriction (DR) extends life span and retards aging-associated pathology. Rapamycin likewise extends survival and reduces aging-related disease in mice, and extends lifespan in Drosophila. These manipulations share a common effector through the kinase Target of Rapamycin complex 1 (TORC1). TORC1 impacts translation and autophagy, processes with potential to control aging. Intensive work currently focuses on how these TORC1-affiliated systems are required for rapamycin and DR to slow aging. Aside from its control of protein production, TORC1 impacts gene expression. Rapamycin induces hundreds of genes in mammals and Drosophila. How TORC1 directly affects transcription is largely unknown, but recent work in Drosophila reveals a novel mechanism: dTORC1 phosphorylates the transcriptional cofactor REPTOR (“Repressed by TOR”). REPTOR interacts with REPTOR-BP to control ~300 rapamycin/dTORC1-mediated genes. Furthermore, REPTOR and REPTOR-BP are regulated by dietary amino acids in Drosophila, and we find that their mammalian homologs (CREBRF and CREBL2) mediate glucose metabolism in mice. As an Exploratory/Developmental Research Grant (R21) this proposal intends to break new ground in understanding how DR and rapamycin function with TORC1 to control aging via REPTOR. Our preliminary results are positive: REPTOR is essential for DR to slow aging and in particular, DR requires REPTOR in neurons or gut cells to extend lifespan. REPTOR -- and perhaps by extension DR, TORC1 and rapamycin -- appears to slow aging through non-autonomous TORC1 mediated mechanisms. Here we aim to determine whether activated REPTOR is sufficient to slow aging in Drosophila, whether rapamycin requires REPTOR and REPTOR-BP to slow aging, and which cells require REPTOR and REPTOR-BP for DR to slow aging. These are early steps in a research program needed to set-up future work on the cellular mechanisms through which REPTOR controls aging.

项目概要/摘要 饮食限制（DR）可延长寿命并延缓与衰老相关的病理变化。雷帕霉素同样延长 小鼠的生存并减少与衰老相关的疾病，并延长果蝇的寿命。这些操纵 通过雷帕霉素靶标复合物 1 (TORC1) 的激酶靶点共享一个共同的效应子。 TORC1 影响 翻译和自噬是具有控制衰老潜力的过程。目前的密集工作重点是如何 这些 TORC1 附属系统是雷帕霉素和 DR 延缓衰老所必需的。除了它的控制 蛋白质生产，TORC1 影响基因表达。雷帕霉素在哺乳动物体内诱导数百个基因 果蝇。 TORC1 如何直接影响转录尚不清楚，但最近在果蝇中的研究表明 一种新机制：dTORC1 磷酸化转录辅助因子 REPTOR（“被 TOR 抑制”）。 REPTOR 与 REPTOR-BP 相互作用来控制约 300 个雷帕霉素/dTORC1 介导的基因。此外， REPTOR 和 REPTOR-BP 在果蝇中受到膳食氨基酸的调节，我们发现它们 哺乳动物同源物（CREBRF 和 CREBL2）介导小鼠的葡萄糖代谢。作为一个 探索性/发展性研究补助金（R21）该提案旨在在理解方面开辟新天地 DR 和雷帕霉素如何与 TORC1 一起发挥作用，通过 REPTOR 控制衰老。我们的初步结果是 阳性：REPTOR 对于 DR 延缓衰老至关重要，特别是 DR 需要神经元或肠道中的 REPTOR 细胞以延长寿命。 REPTOR——或许还有 DR、TORC1 和雷帕霉素——似乎速度缓慢 通过非自主 TORC1 介导的机制衰老。这里我们的目的是判断是否激活 REPTOR足以减缓果蝇的衰老，无论雷帕霉素是否需要REPTOR和REPTOR-BP来延缓果蝇的衰老 延缓衰老，以及哪些细胞需要 REPTOR 和 REPTOR-BP 来进行 DR 延缓衰老。这些是早期的步骤 需要开展一项研究计划，以建立有关 REPTOR 控制的细胞机制的未来工作 老化。