Regulation of survival, growth, and metabolism by neuronal mTOR

Reducing activity of the mechanistic/mammalian target of rapamycin (mTOR) with rapamycin extends lifespan and healthspan in many species. The mechanisms by which mTOR regulates lifespan and healthspan, however, are still unknown. Understanding how mTOR signaling in different cell types regulates lifespan and aspects of healthspan is urgently needed if we are to harness the potential individual and societal benefits of healthspan extension by mTOR attenuation. mTOR kinase can form two complexes, mTOR complex 1 (mTORC1) and mTOR complex 2 (mTORC2). The regulatory associated protein of mTOR (Raptor) is required for the assembly of mTORC1, the primary target of rapamycin. To define the role of mTORC1 and mTORC2 signaling during development in the regulation of healthspan we either ablated or reduced expression of Rptor (Raptor) or Mtor (mTOR) in neurons of mice. Developmental knock-down of Mtor (mTOR^KD) exclusively in neurons, had no significant impact on embryonic survival, but significantly increased adult mortality. In contrast, neuronal knockdown of Rptor (Raptor^KD) during development reduced embryonic viability, but did not appear to impact adult survival, suggesting that reducing mTORC1 may confer a survival advantage after birth. Reduction of either Rptor or Mtor (mTOR^KD, Raptor^KD) during development, however, significantly decreased growth rates, body weight, fat mass, resting and fasting blood glucose, and exercise capacity. Taken together, our studies indicate that neuronal mTORC1 plays a critical role in the determination of body size during development, as well as fat mass, metabolic states and exercise capacity during adulthood.