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.

项目摘要/摘要 饮食限制（DR）延长了寿命并阻碍与衰老相关的病理学。雷帕霉素同样延伸 存活和减少小鼠衰老相关的疾病，并延长果蝇的寿命。这些操纵 通过雷帕霉素复合物1（TORC1）的激酶靶标共享一个共同的效应子。 TORC1影响 翻译和自噬，有可能控制衰老的过程。目前，密集型工作重点是 这些与TORC1相关的系统是雷帕霉素和DR需要减慢衰老所必需的。除了控制 蛋白质产生，TORC1影响基因表达。雷帕霉素在哺乳动物和 果蝇。 TORC1如何直接影响转录是未知的，但是果蝇的最新工作揭示了 一种新型的机制：DTORC1磷酸化转录辅因子过程（“被TOR抑制”）。 爬行动物与爬行动物-BP相互作用，以控制〜300个雷帕霉素/DTORC1介导的基因。此外， 爬行动物和珠宝​​BP受果蝇中饮食中的氨基酸调节，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 探索性/发展研究赠款（R21）该提案打算打破理解的新基础 DR和雷帕霉素如何通过TORC1发挥作用，可以通过Reptor控制衰老。我们的初步结果是 阳性：爬行动物对于DR降低衰老至关重要，尤其是DR需要神经元或肠道的爬行动物 细胞延长寿命。 Reptor - 也许是扩展博士，Torc1和雷帕霉素 - 似乎很慢 通过非自主TORC1介导的机制老化。在这里，我们旨在确定是否激活 爬行动物足以在果蝇中减慢衰老，无论雷帕霉素是否需要爬行动物和爬行动物BP 缓慢的衰老，哪些细胞需要Reptor和Reptor-BP才能减慢衰老。这些是早期步骤 需要一项研究计划，以在爬行者控制的细胞机制上设置未来的工作 老化。