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

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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.