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Thursday, 11 June 2015

mTOR – Indirect inhibition, the Holy Grail for Life Extension and Perhaps Some Autism




 Not cheap at about $1,000 for just 140mg


Life extension may come as a surprise, but it is interesting because it is well studied and, in mice at least, easy to measure.  Most research into mTOR relates to cancer, but this is a very complex condition. With various feedback loops it means that sometimes the actual effect is the opposite of what was predicted.  For example, a substance that can help prevent cancer can actually become harmful later and promote its growth.

Direct inhibition of mTOR with Everolimus and similar drugs (variants/analogs of Rapamycin, all called Rapalogs) has not been as successful as hoped in cancer research.  Trials of direct inhibition of mTOR will shortly start in one rare single gene type of autism (TSC).  The drugs are so expensive that many providers do not want to pay for them.

As you will see mTOR is just one process in a cloud of interrelated processes.  Almost everything has a role/effect:- growth factors, cytokines, amino acids, mitochondria, dendritic spines, PPAR gamma, hormones, oxidative stress, autophagy ….

While it would be nice to think that a single protein complex like mTORC1 or mTORC2 is the root of all evil in autism, I rather doubt it can be so simple.

The knowledge that one factor controlling mTORC1 and mTORC2 is oxidative stress, does raise the possibility that, yet again, the root problem could be oxidative stress.  
Nonetheless, we will see in today’s post that too much mTOR activity is clearly not good and that it is associated with lots of bad things:-

·        Epilepsy
·        Autistic behaviours
·        Food allergies
·        Mitochondrial dysfunction
·        Cognitive impairment

as well as aging, cancer ….


Indirect reduction in mTOR activity

Rather than the very expensive first and second generation mTOR inhibiting drugs developed for cancer,  I think the safe way forward for autism (and aging) may be indirect reduction in mTOR activity, and there is already a wide choice of methods.

Ketogenic Diet, (or just reduction in carbohydrate intake)

This diet has been used for a hundred years to control epilepsy, which it now seems can be triggered by elevated mTOR.  Research has shown that the ketogenic diet reduces mTOR. 

Low glycemic index diet

This is a low carbohydrate, no sugar diet, typical of someone with diabetes.  It avoids rapid change in blood sugar.  This will lower mTOR and has recently been shown in a mouse model to improve autistic behaviors.

Growth factors

The blood levels of growth factors such as insulin and IGF-1 reflect the fed status of the organism. When food is plentiful, levels of these growth factors are sustained and promote anabolic cell processes such as translation, lipid biosynthesis, and nutrient storage via mTORC1.  So, dietary restriction, which lowers IGF-1, will reduce mTOR; but it will also reduce growth.
Note that one autism therapy under trial does just the opposite, it is to increase IGF-1 levels via injections of IGF-1.

Increase amino acids, particularly leucine

Ask any body builder about BCAA (Branch Chained Amino Acids)

  
Reduce oxidative stress

We know how to do that

NMDA agonists

NMDA receptor activation decreases mTOR signaling activity. 


Note that D-Cycloserine is used in autism and D-Serine is used in schizophrenia


Increase PTEN, for example with a Statin drug


Reduce RAS signaling, for example with a Statin drug


I am not the first person to realize this.  Here is a very highly cited paper:-


  
Since the body is controlled via feedback loops, there might exist a clever way to “trick” the body into lowing mTOR.  For example PPAR gamma, which we have come across in earlier posts, is controlled via mTOR.  If you stimulate PPAR gamma externally this might well have an effect back stream on mTOR activity, via these feedback loops.  Just like if you supplement Melatonin, you will likely affect the behaviour back stream of the pineal gland.


mTOR and Aging

A surprising number of emerging autism therapies are actually also put forward by the life extension people.  In case you did not know, there is a small industry of pills and potions dedicated to making you live longer.  Some serious institutions like MIT and Harvard are involved, as in the paper below.



We earlier saw that PAK-1 is probably there to make sure you do eventually die, reducing mTOR signaling can probably extend your lifetime and, more importantly, your healthy lifetime.


Ketogenic Diet

We did see a case report a while back from Martha Herbert, from Harvard, who has a good result with the ketogenic diet



  
  
The Science of mTOR

In the following section there are numerous scientific papers explaining mTOR, so you can choose just how deep you want to go into the details.

You may notice on the complex diagram below various substances that we have already encountered in this blog as relevant to autism.

·        PTEN ( increased by Statins) reduced in some autism
·        Growth factors (disturbed in autism and therapeutic to some)
·        Ras / Rasopathy (increased by statins, linked to some autism and MR/ID )
·        Wnt (affects morphology of those dendritic spines, malformed in autism)
·        Lipid metabolism/synthesis (disturbed in autism)
·        TSC1  (tuberous sclerosis autism variant)
·        PPAR alpha and gamma affecting inflammation
·        Mitochondrial metabolism, dysfunctional in autism
·        Autophagy was explained in recent post and, if impaired, will degrade cellular health and function, particularly in mitochondria
·        Note Stress/Hypoxia, we have mentioned Hypoxia before.  REDD1 inhibits mTOR.  REDD1 was first identified as a gene induced by hypoxia and DNA damage, other environmental stresses such as energy stress, glucocorticoid treatment and reactive oxygen species have also been reported to induce REDD1 transcription  





Pathway Description: The mechanistic target of Rapamycin (mTOR) is an atypical serine/threonine kinase that is present in two distinct complexes.
The first, mTOR complex 1 (mTORC1), is composed of mTOR, Raptor, GβL, and DEPTOR and is inhibited by Rapamycin. It is a master growth regulator that senses and integrates diverse nutritional and environmental cues, including growth factors, energy levels, cellular stress, and amino acids. It couples these signals to the promotion of cellular growth by phosphorylating substrates that potentiate anabolic processes such as mRNA translation and lipid synthesis, or limit catabolic processes such as autophagy. The small GTPase Rheb, in its GTP-bound state, is a necessary and potent stimulator of mTORC1 kinase activity, which is negatively regulated by its GAP, the tuberous sclerosis heterodimer TSC1/2. Most upstream inputs are funneled through Akt and TSC1/2 to regulate the nucleotide-loading state of Rheb. In contrast, amino acids signal to mTORC1 independently of the PI3K/Akt axis to promote the translocation of mTORC1 to the lysosomal surface where it can become activated upon contact with Rheb. This process is mediated by the coordinated actions of multiple complexes, notably the v-ATPase, Ragulator, the Rag GTPases, and GATOR1/2.

The second complex, mTOR complex 2 (mTORC2), is composed of mTOR, Rictor, GβL, Sin1, PRR5/Protor-1, and DEPTOR. mTORC2 promotes cellular survival by activating Akt, regulates cytoskeletal dynamics by activating PKCα, and controls ion transport and growth via SGK1 phosphorylation.
Aberrant mTOR signaling is involved in many disease states including cancer, cardiovascular disease, and diabetes.






Growth factors regulate mTORC1
Energy and stress regulate mTORC1
mTOR regulates metabolism in mammals
mTOR in fasting and starvation
mTOR, over-feeding, and insulin sensitivity
One of the most efficient forms of energy storage are triglycerides, because they provide a high energetic yield per unit of mass. mTORC1 mediates lipid accumulation in fat cells
mTORC1 may impact on PPAR-γ activity by increasing its translation118 and by activating the transcription factor SREBP-1c . Active SREBP-1c enhances PPAR-γ activity and transactivates a set of genes directly involved in lipid synthesis. At present, the molecular links between mTORC1, SREBP-1c and PPAR-γ activity remain to be clarified.

Thus, mTORC1 coordinates food intake with energy storage at multiple levels, from central control of food seeking to energy storage and expenditure in peripheral tissues. This multi-level regulation explains the profound consequences that dysregulated mTOR signaling exerts on human metabolism.

Aging

Due to its role at the interface of growth and starvation, mTOR is a prime target in the genetic control of ageing, and evidence from genetic studies supports the view that mTOR may be a master determinant of lifespan and ageing in yeast, C. elegans, flies and mice.
The only ‘natural’ method available to counter ageing is dietary restriction (DR), where the caloric intake is decreased anywhere from 10% to 50%. DR appears to act mainly through the inhibition of mTORC1, and genetic inactivation of mTORC1 pathway components provides no additional benefit over DR. In mice, DR causes lifespan extension and changes in gene expression profile similar to those resulting from loss of S6K1 further supporting the view that DR acts through inhibition of mTORC1
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.


mTOR in food allergy


Highlights
mTOR pathway is implicated in gut–brain axis of food allergy-induced ASD-like behavior.
Food allergy is associated with enhanced mTOR signaling in the brain and gut.
mTORC1 inhibitor Rapamycin improved the behavioral deficits of allergic mice.
Rapamycin reduced mTORC1 activity in the brain and gut of allergic mice.
Rapamycin inhibited food allergy and increased the number of Treg cells in the ileum.


5. Conclusions

In conclusion, the current studies provide strong and first evidence
that the enhanced mTOR signaling pathway in the brain as well as in the intestines plays a pivotal role in the behavioral and immunological changes in CMA mice. mTOR might be the linking pin involved in gut-immune-brain axis in ASD and the intestinal tract could be a potential target in the treatment of patients with ASD and comorbid intestinal symptoms. It is a compelling hypothesis that an enhanced mTOR activity throughout the body may account for both the behavioral as well as the gastrointestinal dysfunctions in patients with ASD. Whether inhibition of mTOR is able to treat both allergic and behavioral deficits of ASD patients remains to be further investigated. Importantly, increased gastrointestinal deficits and in particular behavioral abnormalities are commonly reported in other neurodevelopmental diseases such as attention deficit hyperactivity disorder (ADHD), multiple sclerosis , schizophrenia, Parkinson's disease , however the role of mTOR needs to be investigated. Our findings on the gut-immune-brain connection in a murine model of CMA indicate that targeting mTOR signaling pathway might be applicable to various neurological disorders. Future studies focusing on the mTOR signaling pathway should shed more light on the effective treatment of ASD and other neurodevelopmental disorders.


  
mTOR and Autism



Hyperconnectivity of neuronal circuits due to increased synaptic protein synthesis is thought to cause autism spectrum disorders (ASDs). The mammalian target of Rapamycin (mTOR) is strongly implicated in ASDs by means of upstream signaling; however, downstream regulatory mechanisms are ill-defined. Here we show that knockout of the eukaryotic translation initiation factor 4E-binding protein 2 (4E-BP2)—an eIF4E repressor downstream of mTOR—or eIF4E overexpression leads to increased translation of neuroligins, which are postsynaptic proteins that are causally linked to ASDs. Mice that have the gene encoding 4E-BP2 (Eif4ebp2) knocked out exhibit an increased ratio of excitatory to inhibitory synaptic inputs and autistic-like behaviours (that is, social interaction deficits, altered communication and repetitive/stereotyped behaviours). Pharmacological inhibition of eIF4E activity or normalization of neuroligin 1, but not neuroligin 2, protein levels restores the normal excitation/inhibition ratio and rectifies the social behaviour deficits. Thus, translational control by eIF4E regulates the synthesis of neuroligins, maintaining the excitation-to-inhibition balance, and its dysregulation engenders ASD-like phenotypes.



 Reversing autism by targeting downstream mTOR signaling
 Autism spectrum disorders (ASDs) are a group of clinically and genetically heterogeneous neurodevelopmental disorders characterized by impaired social interactions, repetitive behaviors and restricted interests. The genetic defects in ASDs may interfere with synaptic protein synthesis. Synaptic dysfunction caused by aberrant protein synthesis is a key pathogenic mechanism for ASDs Understanding the details about aberrant synaptic protein synthesis is important to formulate potential treatment for ASDs. The mammalian target of the Rapamycin (mTOR) pathway plays central roles in synaptic protein. Recently, Gkogkas and colleagues published exciting data on the role of downstream mTOR pathway in autism





Previous studies have indicated that upstream mTOR signaling is linked to ASDs. Mutations in tuberous sclerosis complex (TSC) 1/TSC2, neurofibromatosis 1 (NF1), and Phosphatase and tensin homolog (PTEN) lead to syndromic ASD with tuberous sclerosis, neurofibromatosis, or macrocephaly, respectively. TSC1/TSC2, NF1, and PTEN act as negative regulators of mTOR complex 1 (mTORC1), which is activated by phosphoinositide-3 kinase (PI3K) pathway. Activation of cap-dependent translation is a principal downstream mechanism of mTORC1. The eIF4E recognizes the 5′ mRNA cap, recruits eIF4G and the small ribosomal subunit. The eIF4E-binding proteins (4E-BPs) bind to eIF4E and inhibit translation initiation. Phosphorylation of 4E-BPs by mTORC1 promotes eIF4E release and initiates cap-dependent translation. A hyperactivated mTORC1–eIF4E pathway is linked to impaired synaptic plasticity in fragile X syndrome, an autistic disorder caused by lack of fragile X mental retardation protein (FMRP) due to mutation of the FMR1 gene, suggesting that downstream mTOR signaling might be causally linked to ASDs. Notably, one pioneering study has identified a mutation in the EIF4E promoter in autism families, implying that deregulation of downstream mTOR signaling (eIF4E) could be a novel mechanism for ASDs.As an eIF4E repressor downstream of mTOR, 4E-BP2 has important roles in synaptic plasticity, learning and memory. Writing in their Nature article, Gkogkas and colleagues reported that deletion of the gene encoding 4E-BP2 (Eif4ebp2) leads to autistic-like behaviors in mice. Pharmacological inhibition of eIF4E rectifies social behavior deficits in Eif4ebp2 knockout mice. Their study in mouse models has provided direct evidence for the causal link between dysregulated eIF4E and the development of ASDs.Are these ASD-like phenotypes of the Eif4ebp2 knockout mice caused by altered translation of a subset mRNAs due to the release of eIF4E? To test this, Gkogkas et al. measured translation initiation rates and protein levels of candidate genes known to be associated with ASDs in hippocampi from Eif4ebp2 knockout and eIF4E-overexpressing mice. They found that the translation of neuroligin (NLGN) mRNAs is enhanced in both lines of transgenic mice. Removal of 4E-BP2 or overexpression of eIF4E increases protein amounts of NLGNs in the hippocampus, whereas mRNA levels are not affected, thus excluding transcriptional effect. In contrast, the authors did not observe any changes in the translation of mRNAs coding for other synaptic scaffolding proteins. Interestingly, treatment of Eif4ebp2 knockout mice with selective eIF4E inhibitor reduces NLGN protein levels to wild-type levels. These data thus indicate that relief of translational suppression by loss of 4E-BP2 or by the overexpression of eIF4E selectively enhances the NLGN synthesis. However, it cannot be ruled out that other proteins (synaptic or non-synaptic) may be affected and contribute to animal autistic phenotypes.Aberrant information processing due to altered ratio of synaptic excitation to inhibition (E/I) may contribute to ASDs. The increased or decreased E/I ratio has been observed in ASD animal models  In relation to these E/I shifts, Gkogkas et al then examined the synaptic transmission in hippocampal slices of Eif4ebp2 knockout mice. They found that 4E-BP2 de-repression results in an increased E/I ratio, which can be explained by the increase of vesicular glutamate transporter and spine density in hippocampal pyramidal neurons. As expected, application of eIF4E inhibitor restores the E/I balanceFinally, in view of the facts that genetic manipulation of NLGNs results in ASD-like phenotypes with altered E/I balance in mouse models  and NLGN mRNA translation is enhanced concomitant with increased E/I ratio in Eif4ebp2 knockout mice, Gkogkas et al. tested the effect of NLGN knockdown on synaptic plasticity and behaviour in these mice . NLGN1 is predominantly postsynaptic at excitatory synapses and promotes excitatory synaptic transmission. The authors found that NLGN1 knockdown reverses changes at excitatory synapses and partially rescues the social interaction deficits in Eif4ebp2 knockout mice. These findings thus established a strong link between eIF4E-dependent translational control of NLGNs, E/I balance and the development of ASD-like animal behaviors (Figure 1).
In summary, Gkogkas et al. have provided a model for mTORC1/eIF4E-dependent autism-like phenotypes due to dysregulated translational control (Gkogkas et al., 2013). This novel regulatory mechanism will prompt investigation of downstream mTOR signaling in ASDs, as well as expand our knowledge of how mTOR functions in human learning and cognition. It may narrow down therapeutic targets for autism since targeting downstream mTOR signaling reverses autism. Pharmacological manipulation of downstream effectors of mTOR (eIF4E, 4E-BP2, and NLGNs) may eventually provide therapeutic benefits for patients with ASDs.

  



3.3. Autism
As with epilepsy, the link between aberrant mTOR activation and autism is strongest in tuberous sclerosis complex; between 20 and 60% of tuberous sclerosis patients are diagnosed with autism [219, 237], which may account for 1–4% of all autism cases [238]. In addition to tuberous sclerosis, however, there is growing evidence that dysregulated mTOR activity may contribute to a wider variety of autism spectrum disorders. As with epilepsy, mutations in PTEN that lead to aberrant activation of mTOR are associated with autism [239]. In addition, mutations in the downstream mTOR target eukaryotic translation initiation factor 4E (eIF4E) have also been associated with autism [240]. There is also evidence for a strong association between macrocephaly (large head size) early in life and autism spectrum disorders, as well as genetic diseases linked to autism and mTOR hyperactivation, including tuberous sclerosis complex, neurofibromatosis type I, Lhermitte-Duclos syndrome, and Fragile X syndrome [241]. Taken together these data suggest that disinhibited mTOR may cause, or at least contribute to, many cases of autism spectrum disorder. Clinical trials are ongoing to assess whether Everolimus can reduce autistic symptoms in tuberous sclerosis patients.

5. Conclusion
Given the breadth of pathological conditions where mTOR has already been implicated, it seems likely that additional therapeutic uses for mTOR inhibitors will be discovered in the near future. While potential negative effects of mTOR inhibition need to be addressed, they appear generally manageable and, as new mTOR inhibitors continue to be developed, it may be possible to maximize the beneficial effects of targeted mTOR inhibition while reducing adverse effects.






This paper is very comprehensive and this graphic has everything you could ever need to know.  You can use it to figure out your own therapy.












mTOR and seizures




Epilepsy, a common neurological disorder and cause of significant morbidity and mortality, places an enormous burden on the individual and society. Presently, most drugs for epilepsy primarily suppress seizures as symptomatic therapies but do not possess actual antiepileptogenic or disease-modifying properties. The mTOR (mammalian target of Rapamycin) signaling pathway is involved in major multiple cellular functions, including protein synthesis, cell growth and proliferation and synaptic plasticity, which may influence neuronal excitability and be responsible for epileptogenesis. Intriguing findings of the frequent hyperactivation of mTOR signaling in epilepsy make it a potential mechanism in the pathogenesis as well as an attractive target for the therapeutic intervention, and have driven the significant ongoing efforts to pharmacologically target this pathway. This review explores the relevance of the mTOR pathway to epileptogenesis and its potential as a therapeutic target in epilepsy treatment by presenting the current results on mTOR inhibitors, in particular, Rapamycin, in animal models of diverse types of epilepsy. Limited clinical studies in human epilepsy, some paradoxical experimental data and outstanding questions have also been discussed.



  
The ketogenic diet (KD) is an effective treatment for epilepsy, but its mechanisms of action are poorly understood. We investigated the hypothesis that KD inhibits mammalian target of Rapamycin (mTOR) pathway signaling. The expression of pS6 and pAkt, markers of mTOR pathway activation, was reduced in hippocampus and liver of rats fed KD. In the kainate model of epilepsy, KD blocked the hippocampal pS6 elevation that occurs after status epilepticus. As mTOR signaling has been implicated in epileptogenesis, these results suggest that the KD may have anticonvulsant or antiepileptogenic actions via mTOR pathway inhibition.







Highlights

Tsc1 deletion in neurons causes epilepsy and autism-like behaviors in mice.
Epileptiform activity spreads to the brainstem.
mTOR becomes hyperactivated in 5-HT neurons following seizure onset.
mTOR hyperactivity in 5-HT neurons causes autism behaviors.
Autism-like behaviors can be reversed following treatment with Rapamycin.

Abstract
Epilepsy and autism spectrum disorder (ASD) are common comorbidities of one another. Despite the prevalent correlation between the two disorders, few studies have been able to elucidate a mechanistic link. We demonstrate that forebrain specific Tsc1 deletion in mice causes epilepsy and autism-like behaviors, concomitant with disruption of 5-HT neurotransmission. We find that epileptiform activity propagates to the raphe nuclei, resulting in seizure-dependent hyperactivation of mTOR in 5-HT neurons. To dissect whether mTOR hyperactivity in 5-HT neurons alone was sufficient to recapitulate an autism-like phenotype we utilized Tsc1flox/flox;Slc6a4-cre mice, in which mTOR is restrictively hyperactivated in 5-HT neurons. Tsc1flox/flox;Slc6a4-cre mice displayed alterations of the 5-HT system and autism-like behaviors, without causing epilepsy. Rapamycin treatment in these mice was sufficient to rescue the phenotype. We conclude that the spread of seizure activity to the brainstem is capable of promoting hyperactivation of mTOR in the raphe nuclei, which in turn promotes autism-like behaviors. Thus our study provides a novel mechanism describing how epilepsy can contribute to the development of autism-like behaviors, suggesting new therapeutic strategies for autism.




mTOR inhibition via carbohydrate restriction







  


  



Amino acids and mTOR




The activity of mammalian target of Rapamycin (mTOR) complexes regulates essential cellular processes, such as growth, proliferation or survival. Nutrients such as amino acids are important regulators of mTOR Complex 1 (mTORC1) activation, thus affecting cell growth, protein synthesis and autophagy.
Here, we show that amino acids may also activate mTOR Complex 2 (mTORC2). This activation is mediated by the activity of class I PI3K and of Akt. Amino acids induced a rapid phosphorylation of Akt at Thr308 and Ser473. Whereas both phosphorylations were dependent on the presence of mTOR, only Akt phosphorylation at Ser473 was dependent on the presence of rictor, a specific component of mTORC2. Kinase assays confirmed mTORC2 activation by amino acids. This signaling was functional, as demonstrated by the phosphorylation of Akt substrate FOXO3a. Interestingly, using different starvation conditions, amino acids can selectively activate mTORC1 or mTORC2. These findings identify a new signaling pathway used by amino acids underscoring the crucial importance of these nutrients in cell metabolism and offering new mechanistic insights.

Finally, this report shows the crucial importance of dietary restriction/starvation conditions for understanding the amino acid signaling. Several studies show the effects of amino acid intake in obesity [23,27,28], and of dietary restriction in human cancers [79,80]. Although more physiological studies are needed to link these effects to mTOR complex regulation, it is noteworthy that a study in human muscle shows activation of both mTORC1 and mTORC2 by ingestion of
a leucine-enriched amino acid-carbohydrate mixture [86]. It has been recently described that branched-chain amino acid dietary supplementation increased the average life span in mice and cardiac and skeletal muscle improvement [87] validating the physiological relevance of amino acid supplementation. In this context, we now report that cell supplementation with amino acids can activate both mTOR complexes (Figures 10 and 11). In summary, this manuscript shows for the first time that amino acids can activate mTORC1 and mTORC2 complexes, thus underscoring the crucial importance of these nutrients in cell metabolism and offering new mechanistic insights with potential therapeutic applications in cancer, obesity and aging.

  

Recent evidence points to a strong relationship between increased mitochondrial biogenesis and increased survival in eukaryotes. Branched-chain amino acids (BCAAs) have been shown to extend chronological life span in yeast. However, the role of these amino acids in mitochondrial biogenesis and longevity in mammals is unknown. Here, we show that a BCAA-enriched mixture (BCAAem) increased the average life span of mice. BCAAem supplementation increased mitochondrial biogenesis and sirtuin 1 expression in primary cardiac and skeletal myocytes and in cardiac and skeletal muscle, but not in adipose tissue and liver of middle-aged mice, and this was accompanied by enhanced physical endurance. Moreover, the reactive oxygen species (ROS) defense system genes were upregulated, and ROS production was reduced by BCAAem supplementation. All of the BCAAem-mediated effects were strongly attenuated in endothelial nitric oxide synthase null mutant mice. These data reveal an important antiaging role of BCAAs mediated by mitochondrial biogenesis in mammals.

  

Amino acid deficiency causing Autism



A rare, hereditary form of autism has been found — and it may be treatable with protein supplements.

Genome sequencing of six children with autism has revealed mutations in a gene that stops several essential amino acids being depleted. Mice lacking this gene developed neurological problems related to autism that were reversed by dietary changes, a paper published today in Science shows1.
Some children with autism have low blood levels of amino acids that can't be made in the body.
“This might represent the first treatable form of autism,” says Joseph Gleeson, a child neurologist at the University of California, San Diego, who led the study. “That is both heartening to families with autism, and also I think revealing of the underlying mechanisms of autism.”

He emphasizes, however, that the mutations are likely to account for only a very small proportion of autism cases. “We don’t anticipate this is going to have implications for patients in general with autism,” says Gleeson. And there is as yet no proof that dietary supplements will help the six children, whose mutations the researchers identified by sequencing the exome — the part of the genome that codes for proteins.

In mice, at least, the chemical imbalance can be treated. The mutant mice had neurological problems typical of mouse versions of autism, including tremors and epileptic seizures. But those symptoms disappeared in less than a week after the mice were put on diets enriched in branched-chain amino acids.

Gleeson’s team has tried supplementing the diets of the children with this form autism, using muscle-building supplements that contain branched-chain amino acids. The researchers found that the supplements restore the children's blood levels of amino acids to normal. As for their autism symptoms, Gleeson says, the “patients did not get any worse and their parents say they got better, but it’s anecdotal”.

  

  
This paper is very recent and suggests, at least in one mouse model, that oxygen consumption in the brain is dysfunction and that this was rescued using the mTOR inhibitor Rapamycin.

  
Tuberous sclerosis (TSC) is associated with autism spectrum disorders and has been linked to metabolic dysfunction and unrestrained signaling of the mammalian target of Rapamycin (mTOR). Inhibition of mTOR by Rapamycin can mitigate some of the phenotypic abnormalities associated with TSC and autism, but whether this is due to the mTOR-related function in energy metabolism remains to be elucidated. In young Eker rats, an animal model of TSC and autism, which harbors a germ line heterozygous Tsc2 mutation, we previously reported that cerebral oxygen consumption was pronouncedly elevated. Young (4 weeks) male control Long–Evans and Eker rats were divided into control and Rapamycin-treated (20 mg/kg once daily for 2 days) animals. Cerebral regional blood flow (14C-iodoantipyrine) and O2 consumption (cryomicrospectrophotometry) were determined in isoflurane-anesthetized rats. We found significantly increased basal O2 consumption in the cortex (8.7 ± 1.5 ml O2/min/100 g Eker vs. 2.7 ± 0.2 control), hippocampus, pons and cerebellum. Regional cerebral blood flow and cerebral O2 extractions were also elevated in all brain regions. Rapamycin had no significant effect on O2 consumption in any brain region of the control rats, but significantly reduced consumption in the cortex (4.1 ± 0.3) and all other examined regions of the Eker rats. Phosphorylation of mTOR and S6K1 was similar in the two groups and equally reduced by Rapamycin. Thus, a Rapamycin-sensitive, mTOR-dependent but S6K1-independent, signal led to enhanced oxidative metabolism in the Eker brain. We found decreased Akt phosphorylation in Eker but not Long–Evans rat brains, suggesting that this may be related to the increased cerebral O2 consumption in the Eker rat. Our findings suggest that Rapamycin targeting of Akt to restore normal cerebral metabolism could have therapeutic potential in tuberous sclerosis and autism.



Mitochondrial Dysfunction  and mTOR
  
  
Mitochondria are organelles that play a central role in processes related to cellular viability, such as energy production, cell growth, cell death via apoptosis, and metabolism of reactive oxygen species (ROS). We can observe behavioral abnormalities relevant to autism spectrum disorders (ASDs) and their recovery mediated by the mTOR inhibitor Rapamycin in mouse models. In Tsc2+/- mice, the transcription of multiple genes involved in mTOR signaling is enhanced, suggesting a crucial role of dysregulated mTOR signaling in the ASD model. This review proposes that the mTOR inhibitor may be useful for the pharmacological treatment of ASD. This review offers novel insights into mitochondrial dysfunction and the related impaired glutathione synthesis and lower detoxification capacity. Firstly, children with ASD and concomitant mitochondrial dysfunction have been reported to manifest clinical symptoms similar to those of mitochondrial disorders, and it therefore shows that the clinical manifestations of ASD with a concomitant diagnosis of mitochondrial dysfunction are likely due to these mitochondrial disorders. Secondly, the adenosine triphosphate (ATP) production/oxygen consumption pathway may be a potential candidate for preventing mitochondrial dysfunction due to oxidative stress, and disruption of ATP synthesis alone may be related to impaired glutathione synthesis. Finally, a decrease in total antioxidant capacity may account for ASD children who show core social and behavioral impairments without neurological and somatic symptoms.



PTEN-type Autism and mTOR



Germline mutations in PTEN, which encodes a widely expressed phosphatase, was mapped to 10q23 and identified as the susceptibility gene for Cowden syndrome, characterized by macrocephaly and high risks of breast, thyroid, and other cancers. The phenotypic spectrum of PTEN mutations expanded to include autism with macrocephaly only 10 years ago. Neurological studies of patients with PTEN-associated autism spectrum disorder (ASD) show increases in cortical white matter and a distinctive cognitive profile, including delayed language development with poor working memory and processing speed. Once a germline PTEN mutation is found, and a diagnosis of phosphatase and tensin homolog (PTEN) hamartoma tumor syndrome made, the clinical outlook broadens to include higher lifetime risks for multiple cancers, beginning in childhood with thyroid cancer. First described as a tumor suppressor, PTEN is a major negative regulator of the phosphatidylinositol 3-kinase/protein kinase B/mammalian target of Rapamycin (mTOR) signaling pathway—controlling growth, protein synthesis, and proliferation. This canonical function combines with less well-understood mechanisms to influence synaptic plasticity and neuronal cytoarchitecture. Several excellent mouse models of Pten loss or dysfunction link these neural functions to autism-like behavioral abnormalities, such as altered sociability, repetitive behaviors, and phenotypes like anxiety that are often associated with ASD in humans. These models also show the promise of mTOR inhibitors as therapeutic agents capable of reversing phenotypes ranging from overgrowth to low social behavior. Based on these findings, therapeutic options for patients with PTEN hamartoma tumor syndrome and ASD are coming into view, even as new discoveries in PTEN biology add complexity to our understanding of this master regulator


Intellectual Disability (MR) and mTOR




Protein synthesis regulation via mammalian target of Rapamycin complex 1 (mTORC1) signaling pathway has key roles in neural development and function, and its dysregulation is involved in neurodevelopmental disorders associated with autism and intellectual disability. mTOR regulates assembly of the translation initiation machinery by interacting with the eukaryotic initiation factor eIF3 complex and by controlling phosphorylation of key translational regulators. Collybistin (CB), a neuron-specific Rho-GEF responsible for X-linked intellectual disability with epilepsy, also interacts with eIF3, and its binding partner gephyrin associates with mTOR. Therefore, we hypothesized that CB also binds mTOR and affects mTORC1 signaling activity in neuronal cells. Here, by using induced pluripotent stem cell-derived neural progenitor cells from a male patient with a deletion of entire CB gene and from control individuals, as well as a heterologous expression system, we describe that CB physically interacts with mTOR and inhibits mTORC1 signaling pathway and protein synthesis. These findings suggest that disinhibited mTORC1 signaling may also contribute to the pathological process in patients with loss-of-function variants in CB.



mTORC2 as opposed to mTORC1 as a target in Autism Research



The goal of my DOD-supported research is determine the role of the new mTOR complex (mTORC2) in Autism Spectrum Disorder (ASD). ASD individuals exhibit impaired social interactions, seizures and abnormal repetitive behavior. In addition, 70-80% of autistic individuals suffer from mental retardation. Autism is a heritable genetically heterogeneous disorder and mutations in negative regulators of the mammalian target of Rapamycin complex 1 (mTORC1) signaling pathway, such as PTEN were associated with ASD. Here, we show that in the hippocampus of Pten fb-KO mice – where Pten is conditionally deleted in the murine forebrain – the activity of both mTORC1 and mTORC2 is increased. In addition, Pten fb-KO mice exhibit seizures, learning and memory and social deficits. Our remarkable preliminary data show that genetic inhibition of mTORC2 activity in Pten-deficient mice significantly promotes survival. In addition, Pten-rictor fb- double KO (DKO) mice, in which mTORC2 activity is restored to normal levels, EEG seizures, learning and memory as well as social phenotypes, are all rescued. In the second year, we will study the molecular mechanism underlying this process. These insights hold the promise for new treatment of ASD.



1. Introduction:

Autism represents a heterogeneous group of disorders, which are defined as “autism spectrum disorders” (ASDs). ASD individuals exhibit common features such as impaired social interactions, language and communication, and abnormal repetitive behavior. In addition, 70-80% of autistic individuals suffer from mental retardation1-3. The major goal of this award is to determine the role of mTORC2 in two mouse models of ASD.

Recently, we have shown that mTORC2 plays a crucial role in long-term memory formation. Briefly, mice lacking mTORC2 showed impaired long-lasting changes in synaptic strength (L-LTP) as well as impaired long-term memory (LTM). In addition, we have found that by promoting mTORC2 activity, with a new agent A-443654, it facilitates L-LTP and enhances long-term memory formation in WT mice. Interestingly, mTORC2 activity is altered in both ASD patients and ASD mouse models harboring mutation in Tsc and Pten5,6. Hence, in this proposal we will test the hypothesis that the neurological dysfunction in several ASD mouse models is caused by dysregulation of mTORC2 rather than mTORC1 activity.


4. Key Research Accomplishment

- We developed a way to specifically block mTORC2 activity in Pten-deficient mice.
- Genetic deletion of mTORC2 prolongs the survival of Pten-deficient mice.
- Genetic deletion of mTORC2 dramatically attenuates seizures in Pten-deficient mice.
- Genetic deletion of mTORC2 improves cognitive and social phenotypes in Pten-deficient mice.

5. Conclusion

It has been proposed that the increased mTORC1 in Pten-deficient or Tsc-deficient mice causes the cellular and behavioral phenotypes associated with ASD. Our new data challenge this view and posit that the neurological dysfunction in ASD, at least in the Pten-ASD mouse model, is caused by dysregulation of mTORC2. Hence, these preliminary data are very important since they identified a new signaling pathway involved in ASD and seizure disorders that could be targeted and lead to the development of new treatments for ASD and seizure disorders.


E/I Imbalance in Schizophrenia and Autism




This paper looks really useful and does refer to mTOR, but is not open access

Autism Spectrum Disorders (ASD) and Schizophrenia (SCZ) are cognitive disorders with complex genetic architectures but overlapping behavioral phenotypes, which suggests common pathway perturbations. Multiple lines of evidence implicate imbalances in excitatory and inhibitory activity (E/I imbalance) as a shared pathophysiological mechanism. Thus, understanding the molecular underpinnings of E/I imbalance may provide essential insight into the etiology of these disorders and may uncover novel targets for future drug discovery. Here, we review key genetic, physiological, neuropathological, functional, and pathway studies that suggest alterations to excitatory/inhibitory circuits are keys to ASD and SCZ pathogenesis.


NMDA activation, Sociability and mTOR



Highlights
Several syndromic forms of ASD are associated with disinhibited activity of mTORC1.
Rapamycin, an inhibitor of mTORC1, improved sociability in mouse models of TSC.
NMDA receptor-mediated neurotransmission regulates sociability in mice.
NMDA receptor activation decreases mTOR signaling activity.
D-Cycloserine improved sociability in the Balb/c and BTBR mouse models of ASD.
  
Abstract

Tuberous Sclerosis Complex is one example of a syndromic form of autism spectrum disorder associated with disinhibited activity of mTORC1 in neurons (e.g., cerebellar Purkinje cells). mTORC1 is a complex protein possessing serine/threonine kinase activity and a key downstream molecule in a signaling cascade beginning at the cell surface with the transduction of neurotransmitters (e.g., glutamate and acetylcholine) and nerve growth factors (e.g., Brain-Derived Neurotrophic Factor). Interestingly, the severity of the intellectual disability in Tuberous Sclerosis Complex may relate more to this metabolic disturbance (i.e., overactivity of mTOR signaling) than the density of cortical tubers. Several recent reports showed that Rapamycin, an inhibitor of mTORC1, improved sociability and other symptoms in mouse models of Tuberous Sclerosis Complex and autism spectrum disorder, consistent with mTORC1 overactivity playing an important pathogenic role. NMDA receptor activation may also dampen mTORC1 activity by at least two possible mechanisms: regulating intraneuronal accumulation of arginine and the phosphorylation status of a specific extracellular signal regulating kinase (i.e., ERK1/2), both of which are “drivers” of mTORC1 activity. Conceivably, the prosocial effects of targeting the NMDA receptor with agonists in mouse models of autism spectrum disorders result from their ability to dampen mTORC1 activity in neurons. Strategies for dampening mTORC1 overactivity by NMDA receptor activation may be preferred to its direct inhibition in chronic neurodevelopmental disorders, such as autism spectrum disorders.


Dendritic Spine Dysgenesis in Autism and mTOR




The activity-dependent structural and functional plasticity of dendritic spines has led to the long-standing belief that these neuronal compartments are the subcellular sites of learning and memory. Of relevance to human health, central neurons in several neuropsychiatric illnesses, including autism related disorders, have atypical numbers and morphologies of dendritic spines. These so-called dendritic spine dysgeneses found in individuals with autism related disorders are consistently replicated in experimental mouse models. Dendritic spine dysgenesis reflects the underlying synaptopathology that drives clinically relevant behavioral deficits in experimental mouse models, providing a platform for testing new therapeutic approaches. By examining molecular signaling pathways, synaptic deficits, and spine dysgenesis in experimental mouse models of autism related disorders we find strong evidence for mTOR to be a critical point of convergence and promising therapeutic target.






3. Spine dysgenesis in autism related disorders Spine dysgenesis has been described in autopsy brains of several ARDs, their genetic causes ranging from hundreds of affected genes to one, with their pervasiveness relating to both severity and number of clinical symptoms. By examining common clinical phenotypes correlated to spine and synaptic abnormalities between the disorders, we can work to recognize causalities in dysgenesis and identify potential targets for therapeutic intervention.

4. mTOR: a convergence point of spine dysgenesis and synaptopathologies in ASD Dysgenesis of dendritic spines occurs in the majority of individuals afflicted with ARDs, as well as in most experimental mouse models of these syndromes. It would, therefore, follow that there must be a converging deregulated molecular pathway downstream of the affected genes and upstream of dendritic spine formation and maturation. Identifying this pathway will not only define a causal common denominator in autism-spectrum disorders, but also open new therapeutic opportunities for these devastating conditions. The Ras/ERK and PI3K/mTOR pathways, which regulate protein translation in dendrites near excitatory synapses, have received the most attention as such candidate convergence points


5. Conclusion Cajal once postulated, “the future will prove the great physiological role played by the dendritic spines” [229]. And indeed, it is now widely accepted that dendritic spines are the site of neuronal plasticity of excitatory synapses and the focal point for synaptopathophysiologies of ARDs. Individuals and mouse models of ARDs all display spine dysgenesis, with mTOR-regulated protein translation being a critical point of convergence. Deviations from optimal levels of protein synthesis correlate with the magnitude of dendritic spine pruning and LTD in ARDs. Alleviation of heightened mTOR activity rescues both synaptic and behavioral phenotypes in FXS and TS animals. Correcting mTOR signaling levels also reversed ARD phenotypes in adult fully symptomatic mice, challenging the traditional view that genetic defects caused irreversible developmental defects [230]. More excitingly, these observations demonstrate the potential of pharmacological therapies for neurodevelopmental disorders. The list of ARDs that have been reversed in adult symptomatic mice continues to grow, and also includes RTT [231], DS [232,233], and AS [92]. Together, these findings demonstrate the remarkable plastic nature of the brain and imply that if the causal denominator of ARDs could be found and therapeutically targeted, we may be able to allow the ARD brain to rewire itself and relieve clinical symptoms once believed to be irreversible. The analysis of correlative physiological and behavioral phenotypes and identification of the common mTOR pathway will hopefully provide such potential targets.

  

Clinical Trials


It will be interesting to see the results of the current trials on children with Tuberous Sclerosis Complex, a rare type of autism, that is the most likely to respond to mTOR inhibition.


The purpose of this study is to assess the feasibility and safety of administering rapalogs sirolimus or everolimus, in participants with Tuberous Sclerosis Complex (TSC) and self-injury and to measure cognitive and behavioral changes, including reduction in autistic symptoms, self-injurious and aggressive behaviors, as well as improvements in cognition across multiple domains of cognitive function.



Tuberous sclerosis complex (TSC) is a genetic disease that leads to mental retardation in over 50% of patients, and to learning problems, behavioral problems, autism and epilepsy in up to 90% of patients. The underlying deficit of TSC, loss of inhibition of the mammalian target of Rapamycin (mTOR) protein due to dysfunction of the tuberin/hamartin protein complex, can be rescued by everolimus. Everolimus has been registered as treatment for renal cell carcinoma and giant cell astrocytoma (SEGA). Evidence in human and animal studies suggests that mTOR inhibitors improve learning and development in patients with TSC.







24 comments:

  1. Hi this is the guy posting about Candesartan before.

    I have spent well over two years studying mTOR and more specifically autophagy inducing agents for attenuating autism symptoms and a study not long ago suggested that dendritic overgrowth was a consequence of upregulated mTOR. If you want a forum of people who spend all their free time studying this stuff and the fringe science associated with it, you can go to http://www.longecity.org. It is a community dedicated to stuff like life extension and transhumanism which I don't necessarily agree with for multiple reasons when it comes to topics like immortality, but it is a great resource to farm for ideas since aging, cancer, and autism all seem to have so many similarities once you read enough research papers covering those topics.

    As to what I have learned, intermittent fasting is the most practical way to lower mTOR, but in children this can be a difficult intervention because low blood sugar from fasting generally leads to irritability due to the prefrontal cortex needing lots of glucose, as well as the fact children are literally growing. Fasting seems to work due to methionine and cysteine restriction which has a side effect of producing hydrogen sulfide in the body that kicks off a bunch of genes that promote stress resistance and autophagy (at least in lab mice).

    Also, with BCAA's I have used those for over a year now for a totally different reason than you might think in that my goal with them is to attenuate the entry of L-Kynurenine from the periphery into the brain since BCAA's use the same transporter as tryptophan and L-Kynurenine (this creates side effects with the lack of L-Tryptophan into the brain that are dealt with other ways but that is a long discussion I won't go into unless you want me to). The thing about Leucine though is that its effects are complex and paradoxical in that it stimulates mTOR (which is why bodybuilders use BCAA's with a very high ratio of Leucine to kickstart mTOR in the muscles), while at the same time somehow promoting autophagy (generally reducing mTOR expression promotes autophagy).

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    1. Thanks for your comments.

      Intermittent fasting is interesting and I wonder in the people that reverse type 2 diabetes via near starvation, whether the diabetes comes back when they start eating "normally". You would think it should come back.

      I think that mTOR is just a part of the story. In people with impaired calcium homeostasis (Alzheimer's and autism) it looks like you may be able to increase autophagy with a calcium channel blocker.



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  2. As far as supplements go with mTOR, you are looking at agents that regulate the sirtuin genes, most specifically sirt1 while avoiding supplements that downregulate sirtuin genes.

    For autophagy in general you are looking at:

    (1) Stilbenes - Resveratrol and Pterostilbene (found in blueberry skins)

    (2) NAD+ promoting agents - The best agent for this is Nicotanimide Riboside (marketed as an anti-aging drug but in clinical trials has been useful for diseases such as mitochondrial myopathy). Pretty much every NR supplement buys their stuff from Chromadex who has their own NR product called Niagen. NR is a form of Vitamin B3 only found in small amounts in milk products, but Chromadex bought the patents for manufacturing it efficiently, hence why everyone buys from them and hence why it is not a cheap supplement (yet it is very potent IMHO and is generally more effective the older you happen to be). You would think plain old Niacin or Nicotinimide would work just as well, but why NR works to promote intracellular NAD levels is complex and Nicotinimide will actually downregulate SIRT1. Also, Resveratrol helps with NAD+ by upregulating an enzyme called NAMPT which salvages NADH and converts it back to NAD+ (this is the primary method of keeping NAD+ levels high enough in the body beside direct producting of NAD along the kynurenine pathway via quinolinic acid).

    (3) Spermidine - Found in high concentrations in wheat germ and natto. Spermidine is a polyamine that declines with age and helps maintain the stability of chromatin. Some small rodent studies have shown dietary interventions with spermidine to increase lifespan and promote autophagy. Note, most cancers love high levels of polyamines and even leech polyamines from neighboring cells to help themselves grow so this is an area that some people are concerned about, though I am more in the camp that spermidine is more good than bad.

    (4) Trehalose - This is a sugar that insects use instead of glucose and is thought to be one of the main factors in the amazing cryopreservation abilities of waterbears. Trehalose unlike all other sugars also does not seem to produce advanced glycation endproducts with proteins. It also has been shown to produce autophagy and promote life extension in some animals. Human beings though have an enzyme in the lower intestine called trehalase that breaks trehalose down into glucose (trehalose has two glucose molecules) but it is thought a small amount of it makes its way into the blood stream and acts on cells directly. Also, trehalose does not promote mTOR while fructose does.

    (5) Curcumin - Promotes autophagy though it is a weak inducer. It is a common supplement used for autism due to its anti-inflammatory properties.

    There are some posts on a popular anti-aging blog that you can farm for ideas as I have done:

    http://www.anti-agingfirewalls.com/

    which might help save you some time on some of this stuff with mTOR and autophagy.

    http://selfhacked.com also is another blog with some useful, yet kind of out there and controversial ideas that parallel some of the stuff I have been looking at with respect to autism myself. Again I don't agree with all or even half of the stuff I have cited, but they are great resources from people who have put the time into doing their best to connect the dots on topics that I feel intersect strongly with autism etiologies.

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  3. David Robertson14 June 2015 at 03:17

    As a newcomer to the maze of autism, I find myself adrift in an ocean of information and misinformation. That said, I am finding your line of reasoning to be coherent and well researched. The concept that ASD is in some way related to glandular malfunction helps bring together many diverse opinions and observations. Does it offer any explanation as to why the condition should be so much more prevalent in boys than girls. (please forgive me if this has been tackled in one of your earlier blogs as I have not yet been able to search through them all)

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    1. The female hormone progesterone (also found in males) is found to be highly neuro-protective. It has been successfully trialed to increase survival after traumatic brain injury (TBI) in the ER. So it looks like when things start going wrong inside the developing brain, the cascade of events that leads to autism in the male brain, may be halted in the female brain. Research has shown that the female brain is somehow protected and it is my suggestion that progesterone may be the key. Less girls do have autism, but those that do have it, tend to have severe autism. If anyone collected serious statistics (which they do not) this would become evident, so it is just anecdotal that the girls with ASD tend to have classic autism/ Kanners autism/autistic disorder, whichever name you prefer.

      On the simplistic level some people look at autism as the extreme male brain, so logically it would affect females less. I think this kind of argument is unscientific nonsense, which is all to common in the field of autism.

      There are some vaguely related conditions that affect females more than males, and I did suggest that this is what happened to all the females that "would have had" autism. One such condition is fibromyalgia.

      Autism appears to be caused by multiple "hits", so girls just have capacity to absorb one or two more "hits" than the boys.

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    2. I read similar observation in Yasko book. She also believes that progesterone protects girls from autism, that's why it is a lot less girls with autism.
      According to Yasko, besides male gender, some other factors that increase your chances to get autism Include:
      - higher than average intelligence, because some enzymes responsible for intellect make it more difficult to detox.
      - emotional stress
      - heavy metals
      - excessive vaccination, especially the MMR vaccine
      - certain blood types (type O and A, I think)


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    3. Re progesterone being neuroprotective, estrogen actually has been found to reduce microglial activation following endotoxin exposure and other immune stressor, here a taster:

      https://www.researchgate.net/profile/Angelo_Sala/publication/12086013_Estrogen_prevents_the_lipopolysaccharide-induced_inflammatory_response_in_microglia/links/53d0e5470cf25dc05cfe6fc1.pdf

      and before you say 'autism happens too early in life' for estrogen to make a difference, it is actually present in the brain in early childhood in high enough levels to make a difference

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  4. I stumbled upon your blog last night after countless hours spent trying to wade through the peer reviewed literature on the causes and potential treatments for my daughter's autism. I am a professor of Sociology and a believer in the value of empirical evidence, but I haven't taken a biology or chemistry class since I was in high school and therefore haven't been able to make sense of many of the technical reports. Your blog has been a revelation! I stayed up until 5:00AM last night reading, and I can't wait until my kids go to bed tonight to read more. I've started at the beginning and am still reading posts from 2013, so your research process has likely changed significantly since then. However, I wanted to make you an offer. I noticed that you have had to purchase some full-text articles that aren't available through open access channels, and you have skipped others because you didn’t think they were worth the cost. As a University faculty member, I am able to access the full-text of virtually any journal article through our library, including interlibrary loan services that deliver PDFs of articles not owned by our library completely free of charge usually within 24 hours. I would be happy to obtain and forward any article you need. It is the least I can do to further the wealth of information you are providing to parents like me who are trying desperately to help their autistic children.

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    1. Anna, thanks for the offer. I only ever bought one paper and have reviewed thousands. Unfortunately the peer reviewed literature does not tell you what to do. Lots of clever ideas are raised, but almost none are followed through. The current version of my therapy (the Polypill for autism) can be found on the horizontal tabs at the top of the page, under the Banner heading. There are very many types of autism, but there are clusters where many children respond to the same therapy. You need to start by classify the severity of the autism and the onset, i.e. was it always there, or is it regressive. My blog is more about early onset classic autism, which some people might call autistic disorder, or severe autism. I do not call it severe autism, because I have met much more severely affected children than my son. Many children today are diagnosed with ASD, who are really very mildly affected.

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  5. I am a big fan of Arnold Erhet and his Mucusless Diet System (http://www.amazon.com/Mucusless-Healing-System-Arnold-Ehret/dp/0879040041).
    He successfully treated schizophrenia patients in his clinic over a hundred years ago, using just his diet.
    I had some autoimmune problems that were triggered by the flu vaccine given me at 7 month pregnancy with my son, and those problems resolved by switching to this diet. It is basically all fruit and vegetable diet, with a regular mini-fasting each morning, which allows the body to detox naturally.
    When it became apparent that my son also had problems, around 18 month old, I put him on a similar diet, but with lots of meat and fish, because he likes them and there are not a lot of foods that he likes. For the last two years he eats exact same menu each day - orange juice for breakfast, 1-2 bananas for lunch, one avocado for second lunch, and meat plus veggies for dinner. It's basically the same diet as proposed by Erhet, except his diet doesn't have meat. But for kids I think meat is important.
    By not eating in the morning the body is able to detox itself. This diet has helped me with my arthritis, but I do not see a lot of improvement in my son. Perhaps, without this diet he would have been even more severe. I am thinking of trying some form of keto diet on him. Even though keto diet is not as well balanced as Erhet diet. But it seems to be helping in autism and with seizures.
    I am a big believer in diets, ever since no doctors could help me with my inflammation in my wrists and it got cured by switching to Erhet's diet. He believed that all of the illnesses can be cured with his diet, and he had success curing his patients with schizophrenia with this diet alone. Autism is a form of schizophrenia, that's why I thought this diet would work on my son, but aparantley it does not. Perhaps it's because I modified it for him, including lots of meats. But I'd be too scared to try all vegetarian diet on a child. Especially, since he loves meat.
    Anybody tried vegetarian diet on their kids?

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    1. Polly, in your quest to understand your son's autism, it may be helpful to consider both his other health issues and those of his parents. If you have arthritis at an early age, you might want to follow that through and look at what therapies are effective in treating the MIA (Maternal Immune Activation) model of autism. Just google it.

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    2. Thanks! I will check it out.

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    3. Hi Polly,

      I do not know whether a reply to your question regarding vegetarian diet is still relevant but I am a big fan of vegetarian diet as well as role of suppressed psychological issues behind many biological problems.

      I am a vegetarian by choice (compassion issues) and kept my son on a vegeyarian, not a vegan, diet with lots of whole grain, legumes, green vegetables, and broccoli was a part of his daily diet in the early years. Yogurt and eggs are the only non veg food that he consumes. He did not touch table salt and sugar or candies or crispies till almost 3 years of age and I too believe that his case would have been much more severe had I compromised on his diet. Well, we will never know.

      But, my father, a non veg enthusiast, suffered an auto immune disorder following a family tragedy. His kind, idiopathic thrombocytopenia, where immune cells destroyed his own platelets, leading to bruises and bleeding was largely controlled for months by blood transfusions as standard immune suppressants did not help much. Then we made an observation. Dramatic falls in platelet count, terrible oral lesions and bruises almost always followed his gorging on animal protein, which he continued to do, even when hospitalised. Although no clinician believed us or pretended not to do so, multiple biopsies, tragic loss to his eyes and muscles (he is a retd Prof of sociology) due to long steroid use, and mental trauma later, forfeiting the animal protien, cured him of ITP.

      Probably you can remove the mutton and fish from your son's diet and observe although most people would recommend high quality protien for a growing child, especially autistic children, as they are already nutritionally deficient.

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  6. The article you refered to earlier called "Common Mechanisms of Excitatory and Inhibitory Imbalance in Schizophrenia and Autism Spectrum Disorders" can be acessed on this link for free.

    http://www.researchgate.net/publication/273153801_Common_Mechanisms_of_Excitatory_and_Inhibitory_Imbalance_in_Schizophrenia_and_Autism_Spectrum_Disorders

    If it does not work for you somehow I can email you a pdf copy of it.

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    1. Thanks.

      It is a very interesting paper, worthy of its own post.

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    2. Peter-

      I'm interested in hearing any thoughts you have on the Maternal Immune Activation model of autism as it pertains to some of your treatment protocols.

      My wife was diagnosed with early-onset Rheumatoid Arthritis and very likely had it while she was carrying our youngest son. He is quite mildly affected--a true American-style "borderline case," but we want to do all we can to help him with his behavioral and attentional challenges.

      Does the MIA phenotype typically respond well to your Polypill? Are there certain aspects of it we should prioritize?

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    3. Andrew, it is a good question. If you know your autism is similar to a common mouse model you could then look for what therapies rescue that mouse model. This data is all on the Simons Foundation website. Bumetanide was trialled in at least two mouse models.

      To what extent humans match the mouse phenotypes I am not sure. I would do quick trials of several therapies and then see what it tells you.

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  7. I recently learned of this article.

    http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0149041

    It seems PTEN has not been the only cancer gene associated with autism.My MR11 mutations are not mentioned here,perhaps because they are so rare,but they are cancer genes all the same.I am more medically complex than the cases described here,but this is the closest I have found to my own case so far.

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  8. Perhaps I am interpreting it wrong, but doesn't the study on amino acids and leucine indicate that increased amounts activate mTOR? Thus wouldn't it be that restricting BCAAs and leucine in particular be the way to reduce mTOR as opposed to increasing leucine/BCAAs? Am I misreading this?

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  9. Laura, you are correct, the text above has got it the wrong way round. Leucine is definitely an activator of mTOR. Note that it turns out that while some people have too much mTOR, some have too little.

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  10. I realize that many of the readers of this blog are from outside of the US, but for those living in the states I wanted to make you aware of genetic testing that is being done free of charge. I found out about it from my son's doctor by chance as he works for a research hospital that is participating. It is through the Simons foundation and it is called SPARK. If you go to sparkforautism.org you can sign up to be a participant. At least one parent, the affected child and any siblings are asked to provide a saliva sample which will go through a genetic analysis. Getting specific genetic information can help you better tailor treatments and also you are then first priority for any research being done for your child's specific type. Since we are all trying to get as much information about our child's autism, I thought this might be of interest.
    --Christine

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  11. Found this article very interesting. Isolated amino acids can be purchased separately, so it should be possible to concoct your own blend and try it out.

    Joel

    http://dspace.library.uu.nl/handle/1874/330735

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  12. For the record, more and more studies are pointing towards rapamycin as being safe at low dosages (say 1-2mg/d) as an anti aging pill. The immunosuppressory effects seem to have been exaggerated, and primate studies have been promising. Not conclusive yet, but keep your eyes open.

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  13. My comment is about high doses of branched-chain amino acids for autism, but wasn’t sure where to post it.

    Impaired amino acid transport across the BBB is one possible cause of autism, as apparently patients with SLC7A5 mutations have autism and motor delay. Slc7a5 is critical for maintaining normal brain BCAA levels. This newly published study was in mice and it demonstrated how brain BCAA deficiency triggers neurobehavioral alterations in mice. Most interestingly Slc7a5 mutant mouse behavior was partially corrected by intracerebroventricular BCAA injections. http://www.cell.com/cell/abstract/S0092-8674(16)31534-3

    My question would be if SLC7a5 would be worth ruling out in every case, esp where a child is a non-reponder and where there is a pronounced motor dysfunction? In case of positive results would high dose of BCAA taken orally be worth trialing at all, since whatever is taken orally might not get transported to the brain?

    Mutations in BCKDK gene can also result in autism (accompanied by intellectual disability and epilepsy), and there is positive dietary response to an overload of branched-chain amino acids in the mouse model of that same mutation. Not sure if anyone is trialling BCAA overload in humans with BCKDK and autism? http://science.sciencemag.org/content/338/6105/394

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