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Understanding of mTOR pathway and lifespan refined in new study

Investigators have identified interventions that extend lifespan in model systems. For example, caloric restriction (CR) – a reduction in caloric intake while maintaining adequate nutrition – has been shown to increase insulin sensitivity, improve health, and extend lifespan in several organisms.  Although scientists do not fully understand the mechanisms through which CR may work, it is generally believed that it functions at least in part through inhibition of the protein complex mTORC1. Another intervention, the immunosuppressive drug rapamycin, extends the lifespans of yeast, flies, and mice, also by inhibiting mTORC1. However, unlike CR, long-term use of rapamycin causes insulin resistance in rodents; in humans, that could lead to diabetes and decreased lifespan.

NIH-supported investigators recently found that rapamycin disrupts a second protein complex, mTORC2, in mice, and that mTORC2 is required for efficient equilibrium between glucose production and consumption. When scientists decoupled protein complexes mTORC1 and mTORC2 in mice, they found that decreasing mTORC1 signaling alone extended lifespan without changes in glucose tolerance or insulin sensitivity. However, reduction in mTORC2 activity was associated with impaired insulin sensitivity in the liver and no increase in life span.  

These findings suggest  that rapamycin confers longevity through inhibition of mTORC1 and negatively effects glucose control through inhibition of mTORC2.The investigators note that a compound that would inhibit just mTORC1 might provide many of the same benefits of rapamycin on health and longevity, without the side effects that currently limit rapamycin’s utility.

Reference: Lamming DW, Le Y, Katajisto P, et al. Rapamycin-induced insulin resistance is mediated by mTORC2 loss and uncoupled from longevity. Science 335: 1638-1643, 2012. PubMed: