Long-term treatment of mice and other organisms with the drug rapamycin extends life span. But, at the same time, the drug disrupts metabolic regulation and the action of the hormone insulin. Lamming et al. (see the Perspective by Hughes and Kennedy) dissected the action of rapamycin in genetically modified mice and found, encouragingly, that these two actions of rapamycin can be separated. Rapamycin inhibits a protein kinase complex known as mTORC1, and this appears to provide most of the life-lengthening effects of the drug. However, rapamycin also acts on a related complex known as mTORC2, and it is the disruption of mTORC2 action that produces the diabetic-like symptoms of decreased glucose tolerance and insensitivity to insulin.
D. W. Lamming, L. Ye, P. Katajisto, M. D. Goncalves, M. Saitoh, D. M. Stevens, J. G. Davis, A. B. Salmon, A. Richardson, R. S. Ahima, D. A. Guertin, D. M. Sabatini, J. A. Baur, Rapamycin-induced insulin resistance is mediated by mTORC2 loss and uncoupled from longevity. Science 335, 1638–1643 (2012). [Abstract] [Full Text]