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

项目总结/摘要 饮食限制（DR）延长寿命，延缓衰老相关的病理。雷帕霉素同样延伸 存活率和减少小鼠的衰老相关疾病，并延长果蝇的寿命。这些操纵 通过雷帕霉素复合物1（TORC 1）的激酶靶标共享共同的效应子。TORC 1影响 翻译和自噬，有可能控制衰老的过程。目前的重点工作是如何 这些TORC 1附属系统是雷帕霉素和DR延缓衰老所必需的。除了控制 蛋白质生产，TORC 1影响基因表达。雷帕霉素在哺乳动物中诱导数百个基因， 果蝇TORC 1如何直接影响转录在很大程度上是未知的，但最近在果蝇中的工作揭示了 一种新的机制：dTORC 1磷酸化转录辅因子REPTOR（“被TOR抑制”）。 REPTOR与REPTOR-BP相互作用，控制约300个雷帕霉素/dTORC 1介导的基因。此外，委员会认为， REPTOR和REPTOR-BP在果蝇中受饮食氨基酸的调节，我们发现它们的 哺乳动物同源物（CREBRF和CREBL 2）介导小鼠的葡萄糖代谢。作为 探索性/发展性研究补助金（R21）本提案旨在打破新的理解 DR和雷帕霉素如何与TORC 1一起通过REPTOR控制衰老。我们的初步结果是 阳性：REPTOR对DR延缓衰老至关重要，特别是DR需要神经元或肠道中的REPTOR 细胞来延长寿命。REPTOR --或许还包括DR、TORC 1和雷帕霉素--似乎减缓了 通过非自主TORC 1介导的机制衰老。在这里，我们的目标是确定是否激活 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 减缓衰老，以及哪些细胞需要REPTOR和REPTOR-BP来进行DR以减缓衰老。这些都是早期的步骤， 一个研究计划需要建立未来的工作，通过细胞机制，REPTOR控制 衰老

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.