The kinase mTOR exists as part of two different complexes, mTORC1 and mTORC2, each with distinct roles. mTORC1 regulates cell growth and differentiation, whereas mTORC2 modulates insulin signalling. Inhibition of mTORC1 is well known to promote longevity; indeed, rapamycin, a drug thought to specifically inhibit mTORC1, increases lifespan in many species. However, rapamycin treatment can also induce glucose intolerance and insulin resistance. Sabatini, Baur and colleagues resolve this paradox by showing that rapamycin also inhibits mTORC2 function (Science 335, 1638–1643; 2012).

Rapamycin treatment in mice promoted expression of gluconeogenic genes and altered glucose homeostasis. These mice eventually developed insulin resistance. Intriguingly, genetic ablation of mTORC2, but not mTORC1, also led to defects in glucose homeostasis and insulin resistance. Rapamycin treatment inhibited phosphorylation of mTORC2 substrates, indicating that rapamycin blocks the activity of both mTORC1 and mTORC2. The authors went on to show that mice heterozygous for certain mTORC1 components had an increased lifespan but normal glucose tolerance and insulin sensitivity.

These findings support the hypothesis that enhanced longevity can be achieved without defects in glucose homeostasis by specifically targeting the mTORC1 complex. The presumption that rapamycin is a specific mTORC1 inhibitor will also have to be reconsidered in light of these data.