Role of the nutrient signaling integrator TOR in growth, cancer and ageing

Coupling the availability of nutrients with cellular growth is essential for all organisms. Indeed, growth is intimately linked to both the energy status of the cell and the presence of a sufficient amount of amino acids, the building blocks of proteins. A key signaling pathway that regulates growth and metabolism is the mammalian target of rapamycin complex 1 (mTORC1).

This protein complex consists of a sophisticated sensor and transduction system able to detect nutrient availability (1). Moreover, mTOR integrates other inputs such as growth factors, energy needs and stress and subsequently regulates cell growth through translational regulation (see our article “Effects of nutrients on the last step of genetic flow”). By modulating this last step of protein production, it can trigger rapid fine-tuned cellular responses to adjust cellular processes to meet the energetic needs of the cell. For instance, when food is scarce, the cell needs to concentrate its energy and work on a ‘spare’ modus. To this effect, the TOR pathway is repressed, thus lowering the general protein production rate (2).

mTOR has been quite intensively studied recently because dysfunctions of the TOR pathway have been associated with disease states where growth is deregulated and energy balance compromised, namely in metabolic disorders, cancer and ageing (1, 3). For instance over-stimulation of the TOR pathway by excess food intake might be a critical factor of the diabetes epidemics. Inversely, impairing TOR signaling through dietary restriction has been shown to extend lifespan in worms and mice (4), suggesting that inhibiting mTOR may represent a promising target to increase longevity in humans, too. Dietary restriction, defined as a decrease of caloric intake without any resulting deficiencies, is the only natural method to counter ageing so far. In rodents, dietary restriction is known to drastically increase lifespan and retard the onset of pathologies linked to age (5).

As a central sensor of nutrients and regulator of growth processes, highly active mTOR signaling promotes tumor development through continuous stimulation of protein synthesis (6). mTOR was first identified and named from studies of the growth inhibiting properties of the anti-fungal compound rapamycin (7). The existence of this naturally occurring strong inhibitor of mTOR first appeared very promising for anti-cancer therapies. Unfortunately, its use as an anti-cancer drug in clinical trials has been disappointing so far, partly because of its immunosuppressive effects (8, 9).

For a more detailed article on the mechanism of translational regulation and its importance for nutrigenomics research, consult our article on the subject.