Aging ] Decreased TOR activity has been found to increase life span in
S. cerevisiae,
C. elegans, and
D. melanogaster. The mTOR inhibitor
rapamycin has been confirmed to increase lifespan in mice. It is hypothesized that some dietary regimes, like
caloric restriction and
methionine restriction, cause lifespan extension by decreasing mTOR activity. An alternative theory is mTOR signaling is an example of
antagonistic pleiotropy, and while high mTOR signaling is good during early life, it is maintained at an inappropriately high level in old age. Calorie restriction and methionine restriction may act in part by limiting levels of
essential amino acids including leucine and methionine, which are potent activators of mTOR. The administration of
leucine into the rat brain has been shown to decrease food intake and body weight via activation of the mTOR pathway in the
hypothalamus. According to the
free radical theory of aging,
reactive oxygen species cause damage to
mitochondrial proteins and decrease ATP production. Subsequently, via ATP sensitive
AMPK, the mTOR pathway is inhibited and ATP-consuming protein synthesis is downregulated, since mTORC1 initiates a phosphorylation cascade activating the
ribosome. These positive feedbacks on the aging process are counteracted by protective mechanisms: Decreased mTOR activity (among other factors) upregulates removal of dysfunctional cellular components via
autophagy.
Interleukin 1 alpha (IL1A) is found on the surface of
senescent cells where it contributes to the production of SASP factors due to a
positive feedback loop with NF-κB. Translation of
mRNA for IL1A is highly dependent upon mTOR activity. mTOR activity increases levels of IL1A, mediated by
MAPKAPK2.
Cancer Over-activation of mTOR signaling significantly contributes to the initiation and development of tumors and mTOR activity was found to be deregulated in many types of cancer including breast, prostate, lung, melanoma, bladder, brain, and renal carcinomas. Reasons for constitutive activation are several. Among the most common are mutations in tumor suppressor
PTEN gene. PTEN phosphatase negatively affects mTOR signalling through interfering with the effect of
PI3K, an upstream effector of mTOR. Additionally, mTOR activity is deregulated in many cancers as a result of increased activity of PI3K or
Akt. Similarly, overexpression of downstream mTOR effectors
4E-BP1,
S6K1,
S6K2 and
eIF4E leads to poor cancer prognosis. Also, mutations in
TSC proteins that inhibit the activity of mTOR may lead to a condition named
tuberous sclerosis complex, which exhibits as benign lesions and increases the risk of
renal cell carcinoma. Increasing mTOR activity was shown to drive cell cycle progression and increase cell proliferation mainly due to its effect on protein synthesis. Moreover, active mTOR supports tumor growth also indirectly by inhibiting
autophagy. Constitutively activated mTOR functions in supplying carcinoma cells with oxygen and nutrients by increasing the translation of
HIF1A and supporting
angiogenesis. mTOR also aids in another metabolic adaptation of cancerous cells to support their increased growth rate—activation of
glycolytic metabolism.
Akt2, a substrate of mTOR, specifically of
mTORC2, upregulates expression of the glycolytic enzyme
PKM2 thus contributing to the
Warburg effect.
Central nervous system disorders / Brain function Autism mTOR is implicated in the failure of a 'pruning' mechanism of the excitatory synapses in
autism spectrum disorders.
Alzheimer's disease mTOR signaling intersects with
Alzheimer's disease (AD) pathology in several aspects, suggesting its potential role as a contributor to disease progression. In general, findings demonstrate mTOR signaling hyperactivity in AD brains. For example, postmortem studies of human AD brain reveal dysregulation in PTEN, Akt, S6K, and mTOR. mTOR signaling appears to be closely related to the presence of soluble amyloid beta (Aβ) and tau proteins, which aggregate and form two hallmarks of the disease, Aβ plaques and neurofibrillary tangles, respectively. In vitro studies have shown Aβ to be an activator of the
PI3K/AKT pathway, which in turn activates mTOR. In addition, applying Aβ to N2K cells increases the expression of p70S6K, a downstream target of mTOR known to have higher expression in neurons that eventually develop neurofibrillary tangles. Chinese hamster ovary cells transfected with the 7PA2 familial AD mutation also exhibit increased mTOR activity compared to controls, and the hyperactivity is blocked using a gamma-secretase inhibitor. These in vitro studies suggest that increasing Aβ concentrations increases mTOR signaling; however, significantly large, cytotoxic Aβ concentrations are thought to decrease mTOR signaling. Consistent with data observed in vitro, mTOR activity and activated p70S6K have been shown to be significantly increased in the cortex and hippocampus of animal models of AD compared to controls. Pharmacologic or genetic removal of the Aβ in animal models of AD eliminates the disruption in normal mTOR activity, pointing to the direct involvement of Aβ in mTOR signaling. Given these findings, the mTOR signaling pathway appears to be one mechanism of Aβ-induced toxicity in AD. The hyperphosphorylation of tau proteins into neurofibrillary tangles is one hallmark of AD. p70S6K activation has been shown to promote tangle formation as well as mTOR hyperactivity through increased phosphorylation and reduced dephosphorylation. It has also been proposed that mTOR contributes to tau pathology by increasing the translation of tau and other proteins. Synaptic plasticity is a key contributor to learning and memory, two processes that are severely impaired in AD patients. Translational control, or the maintenance of protein homeostasis, has been shown to be essential for neural plasticity and is regulated by mTOR. Both protein over- and under-production via mTOR activity seem to contribute to impaired learning and memory. Furthermore, given that deficits resulting from mTOR overactivity can be alleviated through treatment with rapamycin, it is possible that mTOR plays an important role in affecting cognitive functioning through synaptic plasticity. Further evidence for mTOR activity in
neurodegeneration comes from recent findings demonstrating that eIF2α-P, an upstream target of the mTOR pathway, mediates cell death in prion diseases through sustained translational inhibition. Some evidence points to mTOR's role in reduced Aβ clearance as well. mTOR is a negative regulator of autophagy; therefore, hyperactivity in mTOR signaling should reduce Aβ clearance in the AD brain. Disruptions in autophagy may be a potential source of pathogenesis in protein misfolding diseases, including AD. Studies using mouse models of Huntington's disease demonstrate that treatment with rapamycin facilitates the clearance of huntingtin aggregates. Perhaps the same treatment may be useful in clearing Aβ deposits as well.
Lymphoproliferative diseases Hyperactive mTOR pathways have been identified in certain lymphoproliferative diseases such as
autoimmune lymphoproliferative syndrome (ALPS), multicentric
Castleman disease, and
post-transplant lymphoproliferative disorder (PTLD).
Protein synthesis and cell growth mTORC1 activation is required for myofibrillar muscle protein synthesis and skeletal
muscle hypertrophy in humans in response to both
physical exercise and ingestion of certain
amino acids or amino acid derivatives. Persistent inactivation of mTORC1 signaling in skeletal muscle facilitates the loss of muscle mass and strength during muscle wasting in old age,
cancer cachexia, and
muscle atrophy from
physical inactivity. mTORC2 activation appears to mediate
neurite outgrowth in differentiated mouse
neuro2a cells. Intermittent mTOR activation in
prefrontal neurons by
β-hydroxy β-methylbutyrate inhibits age-related cognitive decline associated with dendritic pruning in animals, which is a phenomenon also observed in humans.
Lysosomal damage inhibits mTOR and induces autophagy Active
mTORC1 is positioned on
lysosomes.
mTOR is inhibited when lysosomal membrane is damaged by various exogenous or endogenous agents, such as invading
bacteria, membrane-permeant chemicals yielding osmotically active products (this type of injury can be modeled using membrane-permeant dipeptide precursors that polymerize in lysosomes),
amyloid protein aggregates (see above section on
Alzheimer's disease) and cytoplasmic organic or inorganic
inclusions including
urate crystals and
crystalline silica. which is a metabolic response. During lysosomal damage however, mTOR inhibition activates
autophagy response in its quality control function, leading to the process termed lysophagy that removes damaged lysosomes. At this stage another
galectin,
galectin-3, interacts with
TRIM16 to guide selective autophagy of damaged lysosomes. many of them being under negative control of mTOR directly such as the ULK1-ATG13 complex, (ii)
ULK1-ATG13-
FIP200/RB1CC1 complex associates with the
Beclin 1-
VPS34-
ATG14 via direct interactions between
ATG13's
HORMA domain and
ATG14, (iii) ATG16L1 interacts with
WIPI2, which binds to
PI3P, the enzymatic product of the class III PI3K Beclin 1-VPS34-ATG14. Thus, mTOR inactivation, initiated through GALTOR
Beclin 1) of the autophagy systems listed above and further inactivates mTORC1, allows for strong autophagy induction and autophagic removal of damaged lysosomes. Additionally, several types of ubiquitination events parallel and complement the galectin-driven processes:
Ubiquitination of TRIM16-ULK1-Beclin-1 stabilizes these complexes to promote autophagy activation as described above. may contribute to the execution of lysophagy via autophagic receptors such as p62/
SQSTM1, which is recruited during lysophagy, mTOR plays a role in
fibrotic diseases and autoimmunity, and blockade of the mTORC pathway is under investigation as a treatment for scleroderma.
Smith-Kingsmore syndrome A rare gain-of-function mutation causes
Smith-Kingsmore syndrome. == mTOR inhibitors as therapies ==