Short-Term Treatment With Rapamycin and Dietary Restriction Have Overlapping and Distinctive Effects in Young Mice

R ECENTLY, it has been shown that mTOR(definition)-inhibiting drug studied for extending healthspan and lifespan." style="text-decoration:underline dotted; text-underline-offset:2px; cursor:help;">rapamycin(definition) (Rapa) results in a signifi cant extension of both median and maximal life span in mice ( 1 , 2 ). Rapa is an antifungal drug that was fi rst discovered in the soil of Easter Island. Brown and coworkers ( 3 ) found that rapamycin inhibited mammalian cell cycle progression and interfered with the activation of S6K1. The signaling protein found to be directly inhibited by Rapa was thus named mammalian t arget of r apamycin (mTOR). mTOR forms two major complexes: mTORC1, which has been widely studied in regards to Rapa and is Rapa sensitive ( 4 ), and mTORC2, which has been shown to be Rapa insensitive in short-term Rapa treatment , but recent data suggest that it may be affected by long-term Rapa treatment ( 5 ). mTORC1, which consists of mTOR, Raptor, mLST8, FKBP38, PRAS40, and Deptor, is a downstream effector for many inputs, such as nutrients, growth factors, and cytokines ( 4 ). Activation of mTORC1 results in increased protein synthesis (through activation of S6 kinase [ S6K ] and eIF4-BP), a reduction in autophagy(definition), and an increase cell growth. Through specifi c binding of Rapa to the immunophilin, FKBP12, Rapa-FKBP12 complex inhibits the activity of mTOR by directly binding to the FKBP12-rapamycinbinding domain in mTOR, which is adjacent to the kinase domain of mTOR and disrupting the interaction of mTOR and Raptor ( 6 ). Inhibition of mTORC1 by Rapa in turn decreases protein synthesis, increases autophagy, and promotes inhibition of cell growth ( 7 ).