Dissecting mammalian target of rapamycin to promote longevity

Treatment with rapamycin, an inhibitor of mammalian target of rapamycin complex 1 (mTORC1) can increase mammalian life span. However, extended treatment with rapamycin results in increased hepatic gluconeogenesis concomitant with glucose and insulin insensitivity through inhibition of mTOR complex 2 (C2). Genetic studies show that increased life span associated with mTORC1 inhibition can be at least partially decoupled from increased gluconeogenesis associated with mTORC2 inhibition. Adenosine monophosphate kinase (AMPK) agonists such as metformin, which inhibits gluconeogenesis by downregulating expression of glucose-6-phosphatase and phosphoenolpyruvate carboxykinase, might be expected to block the glucose dysmetabolism mediated by rapamycin. The search for inhibitors of the mTORC1 component Raptor may prove a productive approach to create a better mTOR inhibitor.