Today’s post is likely to be of interest to those dealing with allergy and mast cell activation, but it may have broader implications for those with excess brain mTOR activity.
In the jargon, we are told that:
“enhanced mammalian target of rapamycin (mTOR) signaling in the brain has been implicated in the pathogenesis of autism spectrum disorder”.I have discussed mTOR and mTOR inhibitors previously on this blog.
Amino acids, not just for body builders?
mTOR plays a key role in aging and many human diseases ranging from cancer, diabetes and obesity to autism and Alzheimer’s.
The greatest interest in mTOR seems to be in cancer care. Many cancer genes and pathways are also involved in autism, so we can benefit from the cancer research. Another autism gene that is also a cancer gene is PTEN. PTEN is a tumor suppressor and in the most common male cancer, prostate cancer (PCa), what happens is that PTEN gets turned off and so the cancer continues to grow. If you upregulate PTEN you slow the cancer growth and if you upregulated this gene in those people at risk of Pca perhaps they would never develop this cancer in the first place? PTEN is upregulated by statin-type drugs and people already on this type of drug have better PCa prognoses. The beneficial of effect of statins on PCa is known, but the mechanism being PTEN upregulation does not seem to have been noticed. No surprise there.
Inhibiting mTOR using cancer drugs is very expensive.
Other substances affecting mTOR include amino acids, growth factors, insulin, and oxidative stress.
The amino acid Leucine is an mTOR activator, we don’t need that. We actually want the opposite effect and, at least in mice, we can get it from some of the other amino acids.
· Amino acids, his, lys and thr, inhibited mTOR pathway in antigen-activated mast cells
· Amino acids, his, lys and thr inhibited degranulation and cytokine production of mast cells
· Amino acid diet reversed mTOR activity in the brain and behavioral deficits in allergic and BTBR mice.
Neuroprotective and anti-inflammatory diet reduced behavioral deficits only in allergic mice.
Enhanced mammalian target of rapamycin (mTOR) signaling in the brain has been implicated in the pathogenesis of autism spectrum disorder (ASD). Inhibition of the mTOR pathway improves behavior and neuropathology in mouse models of ASD containing mTOR-associated single gene mutations. The current study demonstrated that the amino acids histidine, lysine, threonine inhibited mTOR signaling and IgE-mediated mast cell activation, while the amino acids leucine, isoleucine, valine had no effect on mTOR signaling in BMMCs. Based on these results, we designed an mTOR-targeting amino acid diet (Active 1 diet) and assessed the effects of dietary interventions with the amino acid diet or a multi-nutrient supplementation diet (Active 2 diet) on autistic-like behavior and mTOR signaling in food allergic mice and in inbred BTBR T + Itpr3tf/J mice. Cow’s milk allergic (CMA) or BTBR male mice were fed a Control, Active 1, or Active 2 diet for 7 consecutive weeks. CMA mice showed reduced social interaction and increased self-grooming behavior. Both diets reversed behavioral impairments and inhibited the mTOR activity in the prefrontal cortex and amygdala of CMA mice. In BTBR mice, only Active 1 diet reduced repetitive self-grooming behavior and attenuated the mTOR activity in the prefrontal and somatosensory cortices. The current results suggest that activated mTOR signaling pathway in the brain may be a convergent pathway in the pathogenesis of ASD bridging genetic background and environmental triggers (food allergy) and that mTOR over-activation could serve as a potential therapeutic target for the treatment of ASD.
So in mice a combination of the three amino acids Histidine, Lysine and Threonine reduced brain mTOR activity and improved autism.
I did look at all three of these amino acids and their other effects and I choose Histidine.
Histidine can be produced in adult humans in very small amounts, but in young children they need to obtain some from other sources, usually dietary.
Histidine is the precursor of histamine. Histamine has both good and bad effects.
Histidine decarboxylase (HDC) is the enzyme that catalyzes the reaction that produces histamine from histidine with the help of vitamin B6 as follows:
You can treat allergy by inhibiting HDC.
Tritoqualine, is an inhibitor of the enzyme histidine decarboxylase and therefore an atypical antihistamine,
You might think that having extra histidine would result in extra histamine, but this appears not to be the case. There is a paradoxical reaction where increasing histadine actually seems to reduce the release of histamine from the mast cells that store it. This may indeed be a case of feedback loops working in our favour.
So it seems that histidine may give two different benefits, it reduces IgE-mediated mast cell activation and it reduces mTOR signalling in the brain.
If the effect on mTOR is sufficient we would then benefit from an increase in autophagy, the cellular garbage disposal service that does not work well in autism. We might eventually see a benefit from increased synaptic pruning which might be seen in improved cognition.
Recap on mTOR and Synaptic Pruning
This has been covered in earlier posts.
In autism loss of mTOR-dependent macro-autophagy causes synaptic pruning deficits; this results in too many dendritic spines.
A dendritic spine (or spine) is a small membranous protrusion from a neuron's dendrite that typically receives input from a single axon at the synapse. Dendritic spines serve as a storage site for synaptic strength and help transmit electrical signals to the neuron's cell body. The dendrites of a single neuron can contain hundreds to thousands of spines. In addition to spines providing an anatomical substrate for memory storage and synaptic transmission, they may also serve to increase the number of possible contacts between neurons.
A feature of autism is usually too many, but can be too few, dendritic spines. In an earlier post we saw how the shape of individual spines affects their function. The shape is constantly changing and can be influenced by external therapy. Wnt signaling affects dendritic spine morphology and so using this pathway you could fine-tune dendritic spine shape. We did look at PAK1 inhibitors in connection with this.
Synaptic pruning is an ongoing process well into adolescence.
So it may be possible to improve synapse density and structure well after the onset of autism.
It should be noted that using Rapalogs, the usual mTOR inhibiting drugs, would have a negative effect in the minority of autism that feature hypo-active growth signalling. That would be people born with small heads and small bodies. So a child affected by the zika virus, might very likely exhibit autism and ID, but likely has too few dendritic spines and would then need more mTOR, rather than less.
Rapalog drugs like Everolimus are very expensive, but as in this recent paper do show effect in some autism.
Everolimus improves neuropsychiatric symptoms in a patient with tuberous sclerosis carrying a novel TSC2 mutation
The mTOR pathway is a central regulator of mammalian metabolism and physiology, with important roles in the function of tissues including liver, muscle, white and brown adipose tissue, and the brain, and is dysregulated in human diseases, such as diabetes, obesity, depression, and certain cancers.
mTOR Complex 1 (mTORC1) is composed of MTOR, regulatory-associated protein of MTOR (Raptor), mammalian lethal with SEC13 protein 8 (MLST8) and the non-core components PRAS40 and DEPTOR. This complex functions as a nutrient/energy/redox sensor and controls protein synthesis. The activity of mTORC1 is regulated by rapamycin, insulin, growth factors, phosphatidic acid, certain amino acids and their derivatives (e.g., L-leucine and β-hydroxy β-methylbutyric acid), mechanical stimuli, and oxidative stress
Rapamycin inhibits mTORC1, and this appears to provide most of the beneficial effects of the drug (including life-span extension in animal studies). Rapamycin has a more complex effect on mTORC2.
How do amino acids affect mTOR?
This is not fully understood by anyone, but here is a relevant paper, for those interested.
The role of amino acid-induced mammalian target of rapamycin complex 1(mTORC1) signaling ininsulin resistance
Mammalian target of rapamycin (mTOR) controls cell growth and metabolism in response to nutrients, energy, and growth factors. Recent findings have placed the lysosome at the core of mTOR complex 1 (mTORC1) regulation by amino acids. Two parallel pathways, Rag GTPase-Ragulator and Vps34-phospholipase D1 (PLD1), regulate mTOR activation on the lysosome. This review describes the recent advances in understanding amino acid-induced mTOR signaling with a particular focus on the role of mTOR in insulin resistance.
We then discuss how mTORC1 activation by amino acids controls insulin signaling, a key aspect of body metabolism, and how deregulation of mTOR signaling can promote metabolic disease.
Recent findings of new mediators and their regulatory mechanisms have broadened our understanding of amino acid-induced mTOR signaling. In addition to the role of the TSC1-TSC2-Rheb hub in transducing upstream signals from growth factors, stressors and energy to mTOR, the lysosomal regulation of mTOR functions as a platform to connect nutrient signals to the Rheb axis. Furthermore, two parallel pathways of amino acid signaling explain the diverse regulation of mTOR signaling. It is yet to be determined which regulators sense amino acids directly and whether the two pathways require separate amino acid sensing mechanisms. The identification of a direct amino acid sensor will shed light on these uncertainties.
A more integrated understanding of mTOR regulation in amino acid signaling will open the door for new therapeutic approaches for metabolic diseases, especially type 2 diabetes. Already, metformin, an antidiabetic drug, inhibits mTOR in an AMP-activated kinase (AMPK)-independent and Rag-dependent manner,64 providing further support for the idea that the regulation of amino acid sensing could be a therapeutic target for diabetes.
How typical is the level of amino acids in autism?
As regards essential amino acid levels, autistic children had significant lower plasma levels of leucine, isoleucine, phenylalanine, methionine and cystine than controls ( no statistical difference in the level of tryptophan, valine, threonine, arginine, lysine and histidine ( > 0.05). In non-essential amino acid levels, phosphoserine was significantly raised in autistic children than in controls ( < 0.05). Autistic children had lower level of hydroxyproline, serine and tyrosine than controls ( < 0.05). On the other hand there was no significant difference in levels of taurin, asparagine, alanine, citrulline, GABA, glycine, glutamic acid, and ornithine ( > 0.05). < 0.05),while there was
There was no significant difference between cases and controls as regards the levels of urea, ammonia, total proteins, albumin and globulins (alpha 1, alpha 2, beta and gamma) ( > 0.05).
For the more common hyperactive pro growth signaling pathway types of autism, histidine should be a good amino acid, whereas for the hypoactive type, that might feature microcephaly, leucine should be a good choice.
Histidine is already used by some people to treat allergy.
Histidine does have numerous other functions and one relates to zinc, so it is suggested that people who supplement histidine add a little zinc. For this reason German histidine supplements thoughtfully all seem to include zinc.
Histidine also has some direct antioxidant effects and has an effect on Superoxide dismutase (SOD).
It is not clear how much histidine would be needed in humans to achieve the mTOR inhibiting effect found in mice.
The RDA for younger teenagers is histidine 850 mg and leucine 2450 mg. What the therapeutic dose to affect mTOR in humans remains to be seen.
Histidine is also claimed to help ulcers, which is plausible.
For allergy some people are taking 1,500mg of histidine a day.