Chronic rapamycin disrupts mTORC2 as well, causing insulin resistance; lifespan extension can be uncoupled from this side effect.
| Evidence tier | D Mechanistic / in vitro / review |
| Study type | 5 - Mechanistic / In Vitro |
| Model system | Mouse |
| Journal | Science |
| Year | 2012 |
| Peer reviewed | Yes |
| Source | DOI 10.1126/science.1215135 · PMID 22461615 · Free full text (PMC3324089) |
Rapamycin, an inhibitor of mechanistic target of rapamycin complex 1 (mTORC1), extends the life spans of yeast, flies, and mice. Calorie restriction, which increases life span and insulin sensitivity, is proposed to function by inhibition of mTORC1, yet paradoxically, chronic administration of rapamycin substantially impairs glucose tolerance and insulin action. We demonstrate that rapamycin disrupted a second mTOR complex, mTORC2, in vivo and that mTORC2 was required for the insulin-mediated suppression of hepatic gluconeogenesis. Further, decreased mTORC1 signaling was sufficient to extend life span independently from changes in glucose homeostasis, as female mice heterozygous for both mTOR and mLST8 exhibited decreased mTORC1 activity and extended life span but had normal glucose tolerance and insulin sensitivity. Thus, mTORC2 disruption is an important mediator of the effects of rapamycin in vivo.
| Intervention | Rapamycin (chronic) |
| Target | mTORC1 vs mTORC2 |
| Model | Mouse |
| Effect | Chronic rapamycin causes insulin resistance via disruption of mTORC2, uncoupled from its longevity effect |