Rapamycin and Its Effects on mTORC1 and mTORC2

The immunosuppressant compound rapamycin has been demonstrated to slow aging in mice, though with unpleasant side-effects, and some debate over whether this is in fact a slowing of aging or just a reduction in cancer incidence. The present consensus on its mode of operation is that it produces longevity-related effects by suppressing the generation of two protein complexes, mTORC1 and mTORC2, both of which include the mTOR protein that has long been associated with rapamcyin. Of these two complexes, the effects of lowered levels of mTORC1 are better understood and more clearly beneficial. Here researchers delve into mechanisms associated with mTORC2, which are much more of a mixed bag. For the research groups involved in this work, the goal is to design new drugs that only trigger the beneficial alterations from the full set of those induced by rapamycin:

The nematode worm Caenorhabditis elegans provides a powerful system for elucidating how genetic, metabolic, nutritional, and environmental factors influence aging. The mechanistic target of rapamycin (mTOR) kinase is important in growth, disease, and aging and is present in the mTORC1 and mTORC2 complexes. In diverse eukaryotes, lifespan can be increased by inhibition of mTORC1, which transduces anabolic signals to stimulate protein synthesis and inhibit autophagy. Less is understood about mTORC2, which affects C. elegans lifespan in a complex manner that is influenced by the bacterial food source. mTORC2 regulates C. elegans growth, reproduction, and lipid metabolism by activating the SGK-1 kinase, but current data on SGK-1 and lifespan seem to be conflicting.

Here, by analyzing the mTORC2 component Rictor (RICT-1), we show that mTORC2 modulates longevity by activating SGK-1 in two pathways that affect lifespan oppositely. RICT-1/mTORC2 limits longevity by directing SGK-1 to inhibit the stress-response transcription factor SKN-1/Nrf in the intestine. Signals produced by the bacterial food source determine how this pathway affects SKN-1 and lifespan. In addition, RICT-1/mTORC2 functions in neurons in an SGK-1-mediated pathway that increases lifespan at lower temperatures.

RICT-1/mTORC2 and SGK-1 therefore oppose or accelerate aging depending upon the context in which they are active. Our findings reconcile data on SGK-1 and aging, show that the bacterial microenvironment influences SKN-1/Nrf, mTORC2 functions, and aging, and identify two longevity-related mTORC2 functions that involve SGK-regulated responses to environmental cues.

Link: http://dx.doi.org/10.1111/acel.12248