The recent identification of novel regulators and their mode of action further strengthen the idea that the basic layout of the mTOR pathway is that of a signal integrator. The TSC node computes signals from growth factors, stressors and energy to regulate Rheb. A second node is mTORC1 itself, where raptor and PRAS40 directly relay energy and growth factors. Finally, the lysosomal membrane acts as a platform for integration of nutrient inputs with the Rheb axis. It remains to be determined whether signal integration also occurs at the level of mTORC2, and whether mTORC1 and mTORC2 are coordinated to a greater extent than is currently known. The identification of upstream regulators of mTORC2 will likely shed light on these questions.
Given its many cellular actions, it is puzzling that only few substrates of mTOR have been identified so far. This is partly due to the weak and transient nature of the mTOR-substrate interaction; the continuous improvement of mass spectrometry techniques, combined with the use of the novel mTOR catalytic inhibitors will likely bring important advances in this area. Moreover, the emerging concept that whole classes of genes may be co-regulated by mTORC1-mediated translational control further extends the range of its downstream effectors.
A more integrated understanding of the mTOR pathway will pave the way for novel approaches to old diseases; mTOR has evolved to accelerate growth, but it also speeds up cancer, metabolic derangement and ageing in adulthood. For these reasons, a chronic but well tolerated inhibition of mTOR starting in mid-life could bring significant improvements to human health.
This lifestyle improvement may come at a cost. For instance, it has been observed that lifespan extension by various manipulations comes at the expense of fertility and reproductive success, but recent findings indicate that there may be a way around it: in D. melanogaster
, supply of a single amino acid, methionine, allows maintenance of reproductive potency in the context of CR-induced lifespan extension176
. Another potential risk is that over-stimulation of autophagy by chronic mTOR inhibition may actually speed up ageing. Furthermore, the many feedback loops in which mTOR participates may actually result in harmful outcomes. Thus, the particular regimen of mTOR inhibition may have to be carefully chosen while considering the advantages of rapamycin versus catalytic inhibitors and chronic versus intermittent administration.
Finally, it remains to be seen whether limiting mTOR activity in adult humans would really enable a longer lifespan, or it would only bring an increase in the quality of life and the way we age, without necessarily affecting how long we live.