Rapamycin extends life in mice through mechanisms similar to those of calorie restriction, but has serious side-effects - though researchers are working to separate the positive mechanisms from the undesirable negative mechanisms. Metformin is also thought to be a calorie restriction mimetic drug, but the evidence for it to extend life in mice is mixed. Here, researchers suggest trying both drugs at the same time in the hopes that metformin blunts some of the side-effects of rapamycin: "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, [might] be expected to block the glucose dysmetabolism mediated by rapamycin."