mTOR is a key modulator of ageing and age-related disease

Abstract

Many experts in the biology of ageing believe that pharmacological interventions to slow ageing are a matter of 'when' rather than 'if'. A leading target for such interventions is the nutrient response pathway defined by the mechanistic target of rapamycin (mTOR). Inhibition of this pathway extends lifespan in model organisms and confers protection against a growing list of age-related pathologies. Characterized inhibitors of this pathway are already clinically approved, and others are under development. Although adverse side effects currently preclude use in otherwise healthy individuals, drugs that target the mTOR pathway could one day become widely used to slow ageing and reduce age-related pathologies in humans.

Figure 1. The two mTOR complexes have distinct constituent proteins and regulate different downstream processes

Here (figure represents data from studies in mice) mTORC1 comprises deptor, PRAS40, raptor, mLST8, mTOR and TTI1–TEL2. mTORC2 is comprised of deptor, mLST8, protor, rictor, mSIN1, mTOR and TTI1–TEL2. Rapamycin binds to FKBP12 and inhibits mTORC1 by disrupting the interaction between mTOR and raptor. Regulation of lipid synthesis by mTORC1 is thought to occur mainly through sterol-regulatory-element-binding protein transcription factors (shown here as SREBP1) by a mechanism that is not completely understood. mTORC1 negatively regulates autophagy through multiple inputs, including inhibitory phosphorylation of ULK1, preventing formation of the ULK1–ATG13–FIP200 complex (which is required for initiation of autophagy). mTORC1 promotes protein synthesis through activation of the translation initiation promoter S6K and through inhibition of the inhibitory mRNA cap binding 4E-BP1, and regulates glycolysis through HIF-1α. mTORC2 inhibits FOXO3a through S6K1 and AKT, which can lead to increased longevity. The complex also regulates actin cytoskeleton assembly through protein kinase C α (PKCα), Rho GTPases and Ras proteins.

Figure 2. Interactions between mTOR and other longevity pathways

mTORC1 responds to a variety of environmental cues and communicates with several known longevity factors in a complex network of interactions. mTORC1 activity limits longevity, and several pathways related to mTORC1 can result in the extension of lifespan. Rapamycins inhibit mTORC1 and decrease its activity. mTORC1 can be activated by environmental nutrients such as amino acids. Hormonal cues can stimulate IIS, which can increase longevity through PI(3)K and AKT mediation of the FOXO family of transcription factors. mTORC1 can also negatively regulate IIS through inhibition of IRS-1. Sensing of low oxygen levels stimulates mTORC1 to activate the hypoxic response by enhancing translation of HIF-1, which inhibits FOXO family members and increases longevity. HIF-1 is also thought to extend longevity at high and low temperatures, or inhibit it at low temperatures. Inhibition of mTORC1 signalling has been linked to stress resistance, and inhibition of the stress response transcription factor SKN-1 (an orthologue of Nrf2) by mTORC1 has been implicated in lifespan extension. Glucose and metabolite sensing as a result of dietary restriction can lower mTORC1 signalling partly through activation of AMPK, which can inhibit mTORC1 and promote longevity. The complex actively promotes mitochondrial biogenesis and metabolism through PGC-1α and YY-1. Inhibition of this results in greater mitochondrial respiration, leading to increased longevity. Dietary restriction and IIS can also influence each other and their related pathways. The relationship between mTORC2 and mTORC1 is still unclear. The interactions shown have been described in studies of yeast, nematodes, fruitflies and mice.

Figure 3. The impact of mTORC1 on diseases of ageing

Ageing drives the onset and progression of multiple disorders that are modulated by mTORC1 signalling. Data from animal and human studies indicate that some disorders (red arrows) are improved by rapamycins. However, for others (blue arrows), although influenced by rapamycins, evidence suggests there are both beneficial and detrimental consequences of mTORC1 inhibition.