mTOR mediates Wnt-induced epidermal stem cell exhaustion and aging

Cell Stem Cell. 2009 Sep 4;5(3):279-89.

mTOR mediates Wnt-induced epidermal stem cell exhaustion and aging.
Castilho RM, Squarize CH, Chodosh LA, Williams BO, Gutkind JS.

Oral and Pharyngeal Cancer Branch, National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, MD 20892, USA.

Epidermal integrity is a complex process established during embryogenesis and maintained throughout the organism lifespan by epithelial stem cells. Although Wnt regulates normal epithelial stem cell renewal, aberrant Wnt signaling can contribute to cancerous growth. Here, we explored the consequences of persistent expressing Wnt1 in an epidermal compartment that includes the epithelial stem cells. Surprisingly, Wnt caused the rapid growth of the hair follicles, but this was followed by epithelial cell senescence, disappearance of the epidermal stem cell compartment, and progressive hair loss. Although Wnt1 induced the activation of beta-catenin and the mTOR pathway, both hair follicle hyperproliferation and stem cell exhaustion were strictly dependent on mTOR function. These findings suggest that whereas activation of beta-catenin contributes to tumor growth, epithelial stem cells may be endowed with a protective mechanism that results in cell senescence upon the persistent stimulation of proliferative pathways that activate mTOR, ultimately suppressing tumor formation.

This essentially supports the reason why pharmaceutical Wnt and Hedgehog agonists were failures due to cancer growths.

Any thoughts on how to enhance mTOR expression?

thelibrarian - Based on what little research is available, there is the amino acid Leucine
in the activation of mTOR. This is a potentially effective aid in insulin resistance.

I should also point about that leucine inactivates glycogen synthase kinase-3 (GSK-3). It may improve beta-catenin apparently without regard to wnt signaling. I haven't explored this before and I wonder if anyone has. A poster already asked about Leucine, so from the looks of it, might have something to offer.