CELLULAR LEVEL

Target of rapamycin (TOR)
 
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The protein with the name (m)TOR (mammalian/mechanistic Target of rapamycin) is an universally conserved kinase in eukaryotes and is a master regulator for several gene groups based on environmental cues. This kinase forms actively two distinct complexes with other proteins: mTORC1 (mechanistic target of rapamycin complex 1) and mTORC2 (mechanistic target of rapamycin complex 2), together these complexes are building the main sensing blocks of the mTOR signaling pathway. The mTOR signaling pathway is responding on nutritional levels and growth factors (e.g. insulin / IGF-1) and regulating many crucial processes (positive and negative regulation): protein synthesis, autophagy, inflammation, lipid synthesis, glycolysis, cytoskeleton and longevity (Hands et al, 2009; Johnson et al, 2013).

Inhibition via chemical inhibitors (e.g.: rapamycin a macrolide compound functioning as an immunosuppressant) of the mTORC1 pathway lead to an increase of lifespans in model organisms and some of these inhibitors are already clinically approved for diseases. Unfortunately these inhibitors show unwanted side effects, but chances are good that in the near future drugs with no or minor side effects could be used to get the beneficial effects on aging via the suppression of a partial mTOR signaling pathway (Johnson et al, 2013; McCormick et al, 2011).

Out of the two mTOR-complexes the mTORC1 is far better understood than mTORC2. mTORC1 is activated by the availability of nutrients or insulin and other hormones and is inactivated by the AMPK (AMP activated protein kinase). Altogether this complex regulates anabolic and catabolic processes which include longevity factors. Studies in all general model organisms (yeasts, nematodes, fruit flies, mice) showed that mutations or inhibition of mTOR and mTORC1 components lead to increased lifespans. The main correlation between lifespan and the mTOR signaling pathway is obviously that the mTORC complexes are downstream regulators of the only known effective method (caloric restriction, diet) of life extension besides genetic modification or drug treatment (Colman et al, 2010; Bjedov et al, 2010; Ehninger et al, 2014).

This lead to the conclusion over the last years that the mTOR pathway plays a very important role in aging and age-related diseases. A potential controlled drug treatment could lead to a healthy life span extension. At this stage we would need further and deeper understanding of the regulated pathways and the main signaling inputs of the mTOR pathway.


Bjedov I, Toivonen JM, Kerr F, Slack C, Jacobson J, Foley A & Partridge L (2010) Mechanisms of Life Span Extension by Rapamycin in the Fruit Fly Drosophila melanogaster. Cell Metab. 11: 35–46 Available at: http://dx.doi.org/10.1016/j.cmet.2009.11.010

Colman RJ, Anderson RM, Johnson SC, Kastman EK, Kosmatka KJ, Beasley TM, Allison DB, Cruzen C, Simmons a, Kemnitz JW & Weindruch R (2010) Monkeys. Animals 325: 201–204

Ehninger D, Neff F & Xie K (2014) Longevity, aging and rapamycin. : 4325–4346

Hands SL, Proud CG & Wyttenbach A (2009) mTOR’s role in ageing: protein synthesis or autophagy? Aging (Albany. NY). 1: 586–597

Johnson SC, Rabinovitch PS & Kaeberlein M (2013) mTOR is a key modulator of ageing and age-related disease. Nature 493: 338–45 Available at: http://www.nature.com.go.libproxy.wakehealth.edu/nature/journal/v493/n7432/full/nature11861.html

McCormick MA, Tsai SY & Kennedy BK (2011) TOR and ageing: a complex pathway for a complex process. Philos Trans R Soc L. B Biol Sci 366: 17–27 Available at: http://www.ncbi.nlm.nih.gov/pubmed/21115526%5Cnhttp://www.ncbi.nlm.nih.gov/pmc/articles/PMC3001303/pdf/rstb20100198.pdf