|Alzheimer > D. mTOR: The Ultimate Risk Factor|
mTOR refers to "mechanistic (or mammalian) target of rapamycin". It has been demonstrated to play pivotal roles in aging and diseases (Blagosklonny, 2008; Johnson et al., 2013; Kaeberlein, 2013). This article will present further evidence that mTOR could be the ultimate risk factor for most human diseases, including neurodegeneration, cardiac hypertrophy, diabetes, and cancer. Inhibition of mTOR may reduce the risk for these diseases, thereby extending lifespan. These lines of evidence support the "hyperfunction theory of aging" (Blagosklonny, 2012; Gems and de la Guardia, 2013), which postulates that aging is caused by hyperactive cellular processes. As discussed below, hyperactive mTOR may cause hyperexcitability (for neurons), hypertrophy (increase in cell size such as cardiac hypertrophy) and hyperplasia (increase in cell number as in cancer).
The principal function of mTOR is protein synthesis, in response to a wide range of signals: glucose, insulin, cytokines, hormones, protein misfolding, etc. mTOR is a protein kinase that catalyzes protein phosphorylation. Upon activation, it can phosphorylate two major targets, p70 ribosome S6 kinase (p70S6K) and eukaryotic initiation factor 4E-binding protein 1 (4EBP1), to initiate protein synthesis from mRNA to a globular protein. Since the normal function of a protein requires correct folding, mTOR and its regulatory proteins (together known as the mTORC1 complex) have the capability to sense a misfolded protein and trigger the synthesis of chaperones (e.g. heat shock proteins HSP70, HSP90, etc.) to ensure accurate folding from the amino acid chain to a three dimensional structure (Qian et al., 2010; Conn and Qian, 2011). However, mTOR activation by the misfolding of pathological proteins (e.g. mutated, oxidized or aberrantly phosphorylated) may cause diseases.
In addition to protein synthesis, mTOR activation also inhibits autophagy which is a degradation pathway for removing protein aggregates and dysfunctional organelles. This function is to promote cell survival because excessive autophagy may lead to cell death (Liu and Levine, 2015). On the other hand, prolonged inhibition of autophagy will result in accumulation of toxic materials in the cell.
Another important feature is that mTOR activation via the mTORC2 complex may inhibit FoxO3 (Johnson et al., 2013), which is a longevity protein involved in cell cycle progression and apoptosis (Nho and Hergert, 2014).
The free radical theory of aging (Harman,1956) posits that aging arises from accumulation of reactive oxygen species (ROS) which may damage cells. According to this theory, antioxidants should be able to extend lifespan. In the past several decades, numerous studies have attempted to test the theory. The results were disappointing. In some cases, antioxidants even have negative impact on lifespan (Ristow and Schmeisser, 2011). By contrast, mTOR inhibition consistently extends lifespan for all organisms investigated (Johnson et al., 2013; Kaeberlein, 2013).
Neuronal hyperexcitability plays a key role in neurodegeneration as discussed in Chapter 12 for Alzheimer's disease, Appendix A for Huntington's disease, Appendix B for amyotrophic lateral sclerosis (ALS) and Appendix C for Parkinson's disease. Over-production of Tau proteins has been demonstrated to cause hyperexcitability (Holth et al., 2013; DeVos et al., 2013; Li et al., 2014). The activation of mTOR promotes Tau production (Caccamo et al., 2013; Tang et al., 2013; Tang et al., 2015). Therefore, mTOR activation enhances excitability. This novel mechanism is now well-documented (see Epilepsy and mTOR).
mTOR can be activated by a wide range of signals, including brain-derived neurotrophic factor (BDNF) (Chapter 11, Figure 11-1). In neurons, BDNF elevation also up-regulates miR-132 to repress Tau synthesis, thereby reducing the toxicity of mTOR-induced hyperexcitability. The biosynthesis of miR-132 involves TDP-43 (Kawahara and Mieda-Sato, 2012; Freischmidt et al., 2013), which is associated with ALS (Scotter et al., 2015), Alzheimer's disease (Wilson et al., 2011), Huntington's disease (Schwab et al., 2008) and Parkinson's disease (Nakashima-Yasuda et al., 2007).
Cardiac hypertrophy is not always bad. The physiological cardiac hypertrophy, induced by physical exercise, is characterized by normal organization of cardiac structure and normal or enhanced cardiac function, whereas pathological hypertrophy is commonly associated with fibrosis and cardiac dysfunction, which may eventually lead to heart failure (McMullen and Jennings, 2007). Sustained activation of β-adrenergic receptors (βAR) plays a critical role in pathological hypertrophy by activating mTOR (Osadchii, 2007; Zhang et al., 2011). The chronic activation of βAR is, in turn, caused by hyperactive adrenergic nervous system (ANS), releasing epinephrine and norepinephrine to activate βAR (Lymperopoulos et al., 2013).
Whether or not the hyperactive ANS arises from Tau over-production remains to be investigated. In this regard, it is important to note that physical exercise increases BDNF level (Chapter 13) which, as mentioned above, can up-regulate miR-132 to repress Tau synthesis. If hyperactive ANS is due to Tau over-production, the exercise-induced hypertrophy may not associate with hyperactive ANS, and thus not pathological.
Diabetes is characterized by high level of glucose in the blood. Glucose may pass the blood-brain barrier (Simpson et al., 1999) and activate mTOR in neurons. This explains why type 2 diabetes is linked to Alzheimer disease by promoting Tau phosphorylation (Moran et al., 2015). Furthermore, the widely used anti-diabetic drug, metformin, inhibits mTOR activity (Gong et al., 2014).
The glucose circulating in the blood can also be absorbed by other types of cells in various organs, resulting in diabetic complications, such as cardiac hypertrophy (Srivastava et al., 2008), cancer (Giovannucci et al., 2010), renal hypertrophy and retinopathy which are associated with mTOR activation (Blagosklonny, 2013).
DNA damage is a hallmark of cancer (Lengauer et al., 1998). mTOR can be activated by DNA damage via the mTORC2 complex (Selvarajah et al., 2015) which results in the inhibition of the longevity protein, FoxO3a (Johnson et al., 2013). FoxO3a is a transcription factor, regulating the expression of proteins that suppress cell cycle progression and promote apoptosis (Nho and Hergert, 2014). Inhibition of FoxO3a allows abnormal cells to proliferate.
Chronic inflammation is a risk factor for cancer. Their link also converges to mTOR since inflammation produces cytokines which may activate mTOR (Lee et al., 2007). Furthermore, FoxO3a can be directly inhibited by IkB kinase (Hu et al., 2004) which is a major player in the immune response (Hinz and Scheidereit, 2013).
Stress is another risk factor for cancer. Stress increases the activity of ANS, releasing epinephrine and norepinephrine that may promote cancer progression (Moreno-Smith et al., 2010; Armaiz-Pena et al., 2013; Chen et al., 2014; Braadland et al., 2015; Chin et al., 2015).
Vitamin D is an mTOR inhibitor (Lisse and Hewison, 2011). This may explain why vitamin D deficiency is linked to cancer (Barreto and Neale, 2015), cardiac hypertrophy (Wu-Wong, 2011), Alzheimer's disease (Littlejohns et al., 2014), Parkinson's disease (Ng and Nguyen, 2012) and amyotrophic lateral sclerosis (Long and Nguyen, 2013).
The following is a list of mTOR inhibitors that do not need prescription.
Author: Frank Lee