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Hi all,

I'm starting this thread which is another offshoot of my mTOR obsession.

I find this protein more fascinating than ever. It has been described as an ON/OFF switch, but actually it's more like a DIMMER. It can be downregulated, emanating a soft, pale light (activity) whereas it can be upregulated, providing a bright light.

In scientific terms, it's activity is measured by the phoshorylation ratio (phosphorylated/unphosphorylated mTOR proteins) in every single organ/tissue.


Chronical downregulation or upregulation can be bad and result in sickness or degenerative or neoplastic disease. Whereas a wise tweaking of such a metabolic dimmer can result in more healthspan and longevity.


In the central nervous system (CNS) a fair level of mTOR activity is believed to mantain neurogenesis and prevent cognitive impairment.


I'm going to post some literature and some practical consideration upon the literature.


We've seen that we can upregulate mTOR in skeletal muscles by exercise thru the mechanoreceptors signal and make muscles grow, or preventing them from atrophying.


We've seen that we can upregulate mTOR in the BAT tissue by cold exposure thru the norepinephrine receptors signal, making BAT increase in mass and reaping the beneficial results.


How can we upregulate mTOR in the CNS?


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This article (which might well be in AlPater's lists) proposes some interesting insights:


Front Mol Neurosci. 2014; 7: 28.
Published online 2014 Apr 23. doi:  10.3389/fnmol.2014.00028
PMCID: PMC4005960

mTOR signaling and its roles in normal and abnormal brain development


It displays a list of upregulating signals, among which, according to the authors, one of the most potent is the BDNF (Brain derived Neurotroipic Factor).


It appears, quoting Wikipedia, that BDNF production is stimulated by physical exercise.

According to the references, aerobic exercise increases 3 times serum concentration of BDNF.


A preliminary point which might come out of this is that we should alternate aerobic exercise (mTOR↑ in brain) and resistance exercise (mTOR↑ in muscles), while practicing regularly cold exposure (mTOR↑ in BAT). Swimming in coldish water kills two birds with a stone, since that's an aerobic exercise with CE. Resistance exercise also kills two birds with a stone, since the 4th bird, mTOR bone tissue, is known to be upregulated by static or dynamic loading.





BDNF signaling[edit]

One of the most significant effects of exercise on the brain is the increased synthesis and expression of BDNF, a neuropeptide hormone, in the brain and periphery, resulting in increased signaling through its tyrosine kinase receptortropomyosin receptor kinase B (TrkB).[4][43][44] Since BDNF is capable of crossing the blood–brain barrier, higher peripheral BDNF synthesis also increases BDNF signaling in the brain.[38] Exercise-induced increases in brain BDNF signaling are associated with beneficial epigenetic changes, improved cognitive function, improved mood, and improved memory.[4][8][17][43] Furthermore, research has provided a great deal of support for the role of BDNF in hippocampal neurogenesis, synaptic plasticity, and neural repair.[5][43] Engaging in moderate-high intensity aerobic exercise such as running, swimming, and cycling increases BDNF biosynthesis through myokine signaling, resulting in up to a threefold increase in blood plasma and brain BDNF levels;[4][43][44] exercise intensity is positively correlated with the magnitude of increased BDNF biosynthesis and expression.[4][43][44] A meta-analysis of studies involving the effect of exercise on BDNF levels found that consistent exercise modestly increases resting BDNF levels as well.[17]

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Mccoy,  I'm looking forward to see how this thread develops.


Here's a general overview that stresses the importance of BDNF as well:


Successful brain aging: plasticity, environmental enrichment, and lifestyle


PMCID: PMC3622468



Interestingly, the effects of aerobic physical exercise, caloric restriction, and enriched environments ail seem to converge in terms of their abilities to enhance neuronal plasticity via a mechanism involving BDNF.67 More specifically, flavonoids and exercise may both enhance synaptic plasticity and learning by increasing BDNF levels and activating similar molecular pathways.68 In summary, it can be stated that aerobic exercise and dietary restriction, through similar molecular mechanisms, may make neurons more resistant to oxidative stress and less susceptible to mitochondrial impairment: therefore both of these factors may protect against neurodegenerative diseases.  [emphasis added]


Of special relevance for aging of the brain are the effects mediated by glucocorticoids in the hippocampus,11,73 where they seem to be neurotoxic, affecting neuronal energy balance and the neuronal substrates for learning and memory.73 Moreover, the reduction in the number of neurons in this area of the brain produced by glucocorticoids has been correlated with a decline in cognitive functions.74 Interestingly, environmental enrichment is effective in attenuating the increases of glucocorticoids produced by acute stress in the prefrontal cortex of adult rats.1,11


Recent experimental findings are relevant for further understand the chronic effects of stress and glucocorticoids, with particular implications for the aged brain. Up until recently the deleterious effects of glucocorticoids, particularly in the hippocampus, were mainly ascribed to the effects mediated by their elevated levels that result as a consequence of acute stress, rather than to chronic increases in the basal levels of these steroids. However, we and others have proposed that a permanent increase of the “basal” levels of glucocorticoids that results from a stressful lifestyle could also contribute to the neuronal damage that occurs in the these areas of the brain during aging.11,71

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Re:  phytochemicals, BDNF,  etc.:



Dietary phytochemicals and neuro-inflammaging: from mechanistic insights to translational challenges

[curcumin, anthocyanins, flavanols:catechin and epcatechin, EVOO: oleuropein and hydroxytyrsol]



Dietary Phytochemicals in Neuroimmunoaging: A New Therapeutic Possibility for Humans?

[ferulic acid, green tea, blueberry and strawberry, curcumin, sulforaphane, resveratrol]



Nutraceuticals in cognitive impairment and Alzheimer’s disease

[flavonoids; Flavanols: Catechin, Epicatechin, Epigallocatechin, Epigallocathechin Gallate; Flavonols: Quercetin, Kaempferol; Flavones: Luteolin, Apigenin; Isoflavones: Soy - Genistein, Daidzein, Glycitin; Anthocyanidins: Pelargonidin, Cyanidine, Malvidin; resveratrol, curcumin; carotenoids; crocin-saffron; B-Vitamins: Folate, Cobalamin, Pyridoxin; Diterpenes: Carnosic Acid, and Rosmarinic Acid]


Blueberry, bilberry, cranberry, elderberry, raspberry seeds, and strawberry are sources of natural anthocyanin antioxidants. Proanthocyanidins extracted from grape seeds (the bark of the Chinese Scutellaria baicalensis herb) exert potent anti-inflammatory, antioxidant, antinociceptive, and vasodilatative effects and may show antidepressant properties (Ogle et al., 2013). Berry anthocyanins also improve neuronal and cognitive brain function, ocular health as well as protect genomic DNA integrity (Zafra-Stone et al., 2007). However, blueberries also contain significant amounts of flavanols, flavonols, and other phenolics which may justify their role in increasing their beneficial effects (Harnly et al., 2006).


After blueberries feeding, anthocyanidins are found in specific cerebral sites, including hippocampus and neocortex (Andres-Lacueva et al., 2005). Neurogenesis acting on hippocampus may represent one mechanism by which blueberry flavonoids improve memory. There is strong evidence suggesting that blueberry can improve memory and learning in aged animals. These improvements seem linked to the modulation of important structural and synaptic plasticity markers (Rendeiro et al., 2012). One of the role of anthocyanins in neuroprotection could be mediated through phospholipase A2 inhibition (Frisardi et al., 2010), which is negatively involved in a complex network of signaling pathways linking receptor agonists, oxidants, and proinflammatory cytokines to the release of arachidonic acid and eicosanoid synthesis (Sun et al., 2004).


Memory performance has been demonstrated to be linked to the modulation of the expression of particular proteins like CREB (cAMP-response element-binding protein), which is a pathway known to be activated in response to Aβ and brain-derived neurotrophic factor (BDNF). Changes in CREB and BDNF in berry-feed animals were accompanied by increases in the phosphorylation state of the protein factor ERK, very important for synaptic plasticity and memory formation (Williams et al., 2008). Furthermore, blueberry seems to have a more significant effect on short-term memory than long-term memory, as demonstrated by improved performance in several memory maze tasks (Ramirez et al., 2005; Williams et al., 2008; Rendeiro et al., 2012).


Another study (Fuentealba et al., 2011) that underlines the role of berries-extract against Aβ shows how these extracts could partially antagonize two newly found effects of Aβ: the decrease in intracellular Ca2+ activity, an important element in neurodegenerative processes and ATP leakage, an effect of aggregated Aβ (Petrozzi et al., 2007). Short-time blueberry diet might produce benefits on memory in aged rats (Malin et al., 2011) by a suggested alteration of ROS signaling through CREB and MAP-kinase (Brewer et al., 2010). Inflammation pathways and modulation of the expression of inflammatory genes might also be involved (Shukitt-Hale et al., 2008). Finally, there is evidence that anthocyanins have insulin-like and glitazone-like properties which may contribute to improve metabolic function and lipid lowering effects (Kalt et al., 2008; Tsuda, 2008; Krikorian et al., 2010b) as well as to improve memory and reduce depressive symptoms (Krikorian et al., 2010b).


Diet-Induced Cognitive Deficits: The Role of Fat and Sugar, Potential Mechanisms and Nutritional Interventions

PMCID: PMC4555146

It is of vital importance to understand how the foods which are making us fat also act to impair cognition. In this review, we compare the effects of acute and chronic exposure to high-energy diets on cognition and examine the relative contributions of fat (saturated and polyunsaturated) and sugar to these deficits. Hippocampal-dependent memory appears to be particularly vulnerable to the effects of high-energy diets and these deficits can occur rapidly and prior to weight gain. More chronic diet exposure seems necessary however to impair other sorts of memory. Many potential mechanisms have been proposed to underlie diet-induced cognitive decline and we will focus on inflammation and the neurotrophic factor, brain-derived neurotrophic factor (BDNF). Finally, given supplementation of diets with omega-3 and curcumin has been shown to have positive effects on cognitive function in healthy ageing humans and in disease states, we will discuss how these nutritional interventions may attenuate diet-induced cognitive decline. We hope this approach will provide important insights into the causes of diet-induced cognitive deficits, and inform the development of novel therapeutics to prevent or ameliorate such memory impairments.


There are several mechanisms that are likely to regulate improved cognition following DHA supplementation. DHA can cross the blood brain barrier and is highly concentrated in the adult brain. In rodents, for example, it represents about 15%–20% of the total brain lipids [112]. DHA can affect neuronal differentiation by promoting neurite growth in hippocampal neurons [113,114] and hence has the potential to increase neurogenesis. Omega-3 supplementation increases molecular markers involved in plasticity including BDNF and tropomyosin receptor kinase B (TrkB) [80]. Omega-3 supplementation also works through preventing neuroinflammatory processes.


Curcumin’s effect on cognitive performance may involve several mechanisms or pathways. For instance, curcumin has been shown to improve cognition via its effect on synaptic plasticity [83,120,121]. Curcumin improves synaptic plasticity through alterations in key proteins such as calcium/calmodulin-dependent kinase II (CaMKII) and N-methyl-d-aspartate receptor (NMDAR) [121]. Curcumin can also reduce oxidative stress, which is associated with improved cognition [119,122]. A very recent study demonstrated that curcumin promotes the synthesis of DHA from its precursor, α-linolenic acid (C18:3 n-3; ALA) and increased the activity of enzymes involved in the synthesis of DHA such as fatty acid desaturase 2 (FADS2) and elongase 2 in the brain [123]. The same research group has previously demonstrated beneficial effect of curcumin in preventing reduced brain DHA levels after brain trauma [124].


Putative Role of Red Wine Polyphenols against Brain Pathology in Alzheimer’s and Parkinson’s Disease

Red Wine Polyphenols Modulate Signaling Pathways

It has become evident that RWP and their corresponding in vivo metabolites elicit their neuroprotective effects not by simply acting as antioxidants, but rather by interacting with various signaling cascades involved in adaptive stress responses (93). Selective inhibitory or stimulatory actions of RWP on neuronal and glial kinase signaling cascades have been studied, including (i) phosphoinositide 3-kinase (PI3K)/protein kinase B (Akt); (ii) mitogen-activated protein kinase (MAPK) and extracellular signal-regulated protein kinase (ERK1/2); (iii) nuclear factor erythroid 2-related factor 2 (Nrf2); and (iv) nuclear factor kappa B (NFkB) (93). Inhibition or stimulation of these pathways by RWP is likely to profoundly affect cellular function by altering the phosphorylation state of target molecules and/or by modulating gene expression (94). Such actions will be highlighted in relation to the pathogenesis of AD and PD (Table (Table22).


The best-characterized MAPK pathways are the mitogenic ERK and the stress activated c-Jun N-terminal kinase (JNK) signaling pathways (94). The potential modulation of MAPK signaling by RWP is significant, as ERK1/2 and JNK are involved in neuronal growth factor-induced mitogenesis, differentiation, apoptosis, and neuronal plasticity (108). Investigations have indicated that individual RWP and/or their metabolites may interact selectively within the MAPK signaling pathways (109).


For example, through the activation of ERK1/2, resveratrol and ferulic acid significantly enhance mammalian neurotrophins, such as nerve growth factor (NGF) and brain-derived neurotrophic factor (BDNF) in neuronal cell lines (9799). Modulation of neurotrophin signaling is crucial to support neuronal survival and maintain synaptic plasticity, hence, might provide a therapeutic strategy in AD and PD (110). Interestingly, the ability of resveratrol to protect hippocampal cells against Aβ-induced toxicity correlated strongly with its affinity to “receptor” binding sites at the level of the cellular plasmalemma in rat brain (111). Epicatechin and one of its major in vivo metabolites, 3′-O–methyl-(−)-epicatechin, stimulated phosphorylation of ERK1/2 at physiologically relevant concentrations thereby protecting neurons against OS-induced apoptosis via a mechanism involving the suppression of JNK (100, 101). On the other hand, neither quercetin nor its O-methylated metabolites had a measurable effect on JNK phosphorylation (102).


Cinnamon: A Multifaceted Medicinal Plant



Parkinson’s disease (PD) is the second major widespread neurodegenerative disorder after Alzheimer’s disease, with a prevalence of 2% in people 65 years and older [95]. PD protein 7 (PARK7) is an autosomal recessive form of early-onset parkinsonism caused by alterations in the DJ-1 gene [96]. Khasnavis and Pahan reported that sodium benzoate, a cinnamon metabolite, upregulates DJ-1 by modulating mevalonate metabolites [97, 98].Cinnamon and its metabolite sodium benzoate also upregulate the neurotropic factors BDNF (brain-derived neurotropic factors) as well as neurotrophin-3 (NT-3) in the mouse central nervous system [99]. PARK7 is one of the main neuroprotective proteins that protects cells from damage and from the further detrimental effects of oxidative stress; therefore, this protein may be an effective molecule that can be incorporated into the therapeutic intervention of Parkinson’s disease [98].

A natural compound isolated from cinnamon extract (CEppt) significantly reduces the formation of toxic β-amyloid polypeptide (Aβ) oligomers and prevents its toxicity on neuronal pheochromocytoma (PC12) cells [100]. The study indicated that CEppt resolved the reduced permanence, fully improved deficiencies in locomotion, and totally eradicated the tetrameric species of Aβ in the brain of the fly model of Alzheimer’s disease, leading to a noticeable reduction in the 56 kDa Aβ oligomers, reducing plaques and improving the cognitive performance of transgenic mice models [100].

Another study reported that the aqueous extract of C. zeylanicum can reduce tau aggregation and filament formation, two of the main features of Alzheimer's disease. The extract can also encourage the complete fragmentation of recombinant tau filaments and cause the considerable modification of the morphology of paired helical filaments from Alzheimer’s disease brain [101], indicating the potential of cinnamon in the treatment of Alzheimer’s disease.
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I found interesting figure 3 from one of the publications you posted or the references therein:


Published online 2010 Oct 18. doi:  10.1016/j.tins.2010.09.003
PMCID: PMC2981641
When Neurogenesis Encounters Aging and Disease






A high-energy diet may adversely affect neurogenesis and cognitive function by increasing levels of systemic stress (hyperactivation of the hypothalamic - pituitary - adrenal axis) and intrinsic oxidative and inflammatory stress in neurons, and by reducing the production of brain derived neurotrophic factor (BDNF), protein chaperones and antioxidant enzymes [8586] (Figure 3b). 



Intellectual enrichment/stimulation is what most of us are doing here, dealing with cell metabolism, biochemistry and biology with no prior knowledge of the field.


I saw some publications with more rigorous definitions on this enrichment issue, I'll try to post some references.


Preliminary shoplist to increase  BDNF→ mTOR activity in the CNS, pls add to it if I missed something.


  • Caloric restriction
  • Aerobic exercise
  • Intellectual stimuli
  • DHA
  • phytochemicals from berries, curcumin, cinnamon and fruit & vegetables in general


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Sibiriak, yes, they are picturesque terms...


This article is interesting because it contends that specialization into a specific field in adulthood causes cognitive decline.

The authors propose a strategy which triggers cognitive development in adults, by  sort of mimicking the cognitive pattern in children.

The 'triggering' is probably the stimulus which causes among other things an increase in BDNF.


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Guest Sibiriak

Mccoy,   thanks for the cognitive development link.  I'm  thinking my move Siberia, new culture, new climate, having to learn a new language etc. might be stimulating a BDNF increase!



Huperzine A appears on a lot of lists, along with other agents:


Phytochemicals That Regulate Neurodegenerative Disease by Targeting Neurotrophins: A Comprehensive Review




Health Protocols:  Age-Related Cognitive Decline


Best Supplements to Stimulate Neurotrophic Factors





BDNF-based synaptic repair as a disease-modifying strategy for neurodegenerative diseases



Health Protocols:  Age-Related Cognitive Decline




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Schematic diagram representing cinnamon-mediated protection of dopaminergic neurons.











Caffeine-mediated BDNF release regulates long-term  synaptic plasticity through activation of IRS2 signaling



[..]Various intercellular signaling molecules can trigger lasting changes in the ability of synapses to express plasticity and BDNF-mediated activation of the TrkB pathway has been implicated in this process. In particular, the neuronal activity-dependent secretion of BDNF plays a fundamental role in the classical LTP induced by electrical stimulation protocols (Gärtner & Staiger 2002; Rex et al. 2007). Interestingly, caffeine increases BDNF levels  (Costa et al. 2008; Sallaberry et al. 2013) and BDNF can induce NMDAR-independent LTP (Kang & Schuman 1995). Our present results provide the first experimental demonstration that caffeine, at moderate to high concentration, evokes an increase of calcium and neuronal activity-dependent BDNF secretion during CAFLTP in the hippocampus.


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Hi all,

I'm starting this thread which is another offshoot of my mTOR obsession.


Chronical downregulation or upregulation can be bad and result in sickness or degenerative or neoplastic disease. Whereas a wise tweaking of such a metabolic dimmer can result in more healthspan and longevity.


What would you cite as evidence for a practical intervention that successfully tweaks mTOR in a way that results in more healthspan and longevity? I don't mean a short-term study with a short-term benefit: I mean a lifespan study, or a very long-term prospective epidemiological study.


The only real evidence on the modulation of mTOR to extend health- and lifespan of which I'm aware is for (a) rapamycin, the first and still the best-demonstrated drug to retard aging in mammals, and (b) CR, the first and still the best-demonstrated intervention of any kind to retard aging in mammals. Both of these interventions chronically downregulate mTOR signaling.


Yes, yes, people will find a zillion studies showing short-term benefits of mTOR-enhancing interventions. I could find the same for anabolic steroids ...

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Hi Michael, glad you chimed in on this subject, your scientific rigour is very much welcome!


First of all, definitions: I'm aware that 'chronical downregulation' is a qualitative expression that can be construed in arbitrary ways.


By 'chronical downregulation' in the above post, I meant something detrimental to health, a suppression of mTOR activity below a safe threshold. I'm not aware that there is a numerical value for the lower safe threshold of mTOR phoshorylation ratio (phosphorylated/unphosphorylated mTOR proteins) in single organs/tissue.


On the other side, you define 'chronical downregulation' as a beneficial state where the  phoshorylation ratio is low enough to allow metabolic pathways beneficial to longevity and prevent those deleterious to longevity.


AFAIK, too low of a phoshorylation ratio of mTOR can be very detrimental (for example, it suppresses the immune system by preventing proliferation of macrophages and so on). mTOR is completely turned off at death.


So maybe we should agree on some definition which implies a safe downregulation, above the detrimental lower threshold whose value I'm not aware of. Something like 'appropriate downregulation for longevity purposes'.


Since mTOR is by pure definition the Target Of Rapamycin, of course such compound lowers the phoshorylation ratio and is used to mimick CR (with potential serious collateral problems)


CR AFAIK lowers the signals which activate mTOR (increase its intra-cellular phoshorylation ratio) hence it constitutes an  'appropriate downregulation for longevity purposes'.


Other ways to achieve an 'appropriate downregulation for longevity purposes' may be leucine and methionine control for example, carbs restriction, and so on.


The important issue in the context of this thread is that, as far as CNS goes, cognitive functions seem to need a pretty upregulated mTOR phoshorylation ratio to regenerate brain cells.


Some other tissues, like skeletal mucle and BAT also would seem to benefit from an upregulated (or at least a cyclically upregulated) mTOR phoshorylation ratio. In elders, muscle growth is good since it avoids sarcopenia. Bone cells growth is likewise good, ditto BAT.


In other organs growth might not be such a desirable situation, and I'm aware that growth and regeneration are both necessary in any context and a balance is needed.


Sounds confusing, but my understanding now is that CR tends to chornically downregulate mTOR phoshorylation ratio in the system, allowing at the same time some local cycles of upregulation (organ regenerations), necessary to survival. Probably, it shifts the growth-regeneration balance downward.


The above though, without local interventions (for example physical exercise), may imply problems such as sarcopenia or decline in cognitive function which may be themselves detrimental to longevity.

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  • 7 months later...

Intermittent metabolic switching, neuroplasticity and brain health

Mattson MP, Moehl K, Ghena N, Schmaedick M, Cheng A.
Nat Rev Neurosci. 2018 Jan 11. doi: 10.1038/nrn.2017.156. [Epub ahead of print] Review.
PMID: 29321682




(Thanks to Al Pater!!!)


Brain evolution, including higher cortical functions of humans (imagination, creativity and language), was driven by the necessity of sustaining high levels of performance in a food-deprived (fasted) state Intermittent metabolic switching (IMS) occurs when eating and exercise patterns result in periodic depletion of liver glycogen stores and the associated production of ketones from fatty acids. IMS occurs rarely or not at all in individuals who eat three or more meals per day and who are fairly sedentary The ketone β-hydroxybutyrate (BHB) is transported into the brain and into neuronal mitochondria, where it is used to generate acetyl CoA and ATP. BHB also acts as a signalling molecule in neurons that can induce the expression of brain-derived neurotrophic factor and thereby promote synaptic plasticity and cellular stress resistance


During fasting and extended exercise, adaptive cellular stress-response signalling pathways are activated and autophagy is stimulated, whereas overall protein synthesis is reduced. Upon refeeding, rest and sleep, protein synthesis is upregulated and mitochondrial biogenesis occurs, enabling neurogenesis and synaptogenesis




Conclusions and future directions

The evidence reviewed in this article leads to several general conclusions regarding IMS  [intermittent metabolic switching] and neuroplasticity.


First, cognition, sensory–motor function and physical performance can be enhanced by IMS protocols involving IF and/or vigorous exercise.


Second, by providing an alternative energy source and activating signalling pathways involved in neuroplasticity and cellular stress resistance, the ketone BHB [β-hydroxybutyrate] plays a particularly important role in neuronal adaptations to fasting and exercise.


Third, neurons respond to the G-to-K switch [ the transition from utilization of carbohydrates and glucose to fatty acids and ketones as the major cellular fuel source] by engaging a 'cell-preservation mode' and adopt a 'cell-growth mode' by activation of certain signalling pathways when the switch is off (food, rest and sleep).


Fourth, fasting and exercise upregulate neurotrophic factor signalling, antioxidant and DNA repair enzymes, protein deacetylases and autophagy, which protects neurons against stress and sets the stage for mitochondrial biogenesis and cell growth and plasticity during recovery periods (Fig. 3).


Fifth, lifestyles characterized by little or no IMS (three meals per day plus snacks and negligible exercise) result in suboptimal brain functionality and increase the risk of major neurodegenerative and psychiatric disorders.


Sixth, many different IMS regimens are likely to improve brain health such that individuals may choose an approach that suits their particular daily and weekly schedules.



More details here:


Adaptive Responses of Neuronal Mitochondria to Bioenergetic Challenges: Roles in Neuroplasticity and Disease Resistance



An important concept in neurobiology is “neurons that fire together, wire together” which means that the formation and maintenance of synapses is promoted by activation of those synapses. Very similar to the effects of the stress of exercise on muscle cells, emerging findings suggest that neurons respond to activity by activating signaling pathways (e.g., Ca2+, CREB, PGC-1α, NF-κB) that stimulate mitochondrial biogenesis and cellular stress resistance. These pathways are also activated by aerobic exercise and food deprivation, two bioenergetic challenges of fundamental importance in the evolution of the brains of all mammals, including humans. The metabolic ‘switch’ in fuel source from liver glycogen store-derived glucose to adipose cell-derived fatty acids and their ketone metabolites during fasting and sustained exercise, appears to be a pivotal trigger of both brain-intrinsic and peripheral organ-derived signals that enhance learning and memory and underlying synaptic plasticity and neurogenesis. Brain-intrinsic extracellular signals include the excitatory neurotransmitter glutamate and the neurotrophic factor BDNF, and peripheral signals may include the liver-derived ketone 3-hydroxybutyrate and the muscle cell-derived protein irisin. Emerging findings suggest that fasting, exercise and an intellectually challenging lifestyle can protect neurons against the dysfunction and degeneration that they would otherwise suffer in acute brain injuries (stroke and head trauma) and neurodegenerative disorders including Alzheimer’s, Parkinson’s and Huntington’s disease. Among the prominent intracellular responses of neurons to these bioenergetic challenges are up-regulation of antioxidant defenses, autophagy/mitophagy and DNA repair. A better understanding of such fundamental hormesis-based adaptive neuronal response mechanisms is expected to result in the development and implementation of novel interventions to promote optimal brain function and healthy brain aging.




As described above, emerging findings suggest that neurons respond to the three most common and evolutionarily meaningful physiological bioenergetic challenges –food deprivation/fasting, physical exertion, and intellectual challenges – by increasing both the number of healthy mitochondria they contain and the stress resistance of individual mitochondria. The intercellular signals that mediate these mitochondria-centered adaptive responses include brain cell-intrinsic neurotransmitters (particularly glutamate) and neurotrophic factors (BDNF, FGF2), and signaling molecules emanating from peripheral organs (particularly liver and muscle) including the ketone 3OHB, irisin [200] and cathepsin B [201]. Interestingly, all three of the latter peripheral organ-derived factors have been shown to increase BDNF expression in brain cells [91, 200, 201].


Because BDNF has been shown to stimulate mitochondrial biogenesis in neurons [35] and to increase resistance of neurons to metabolic and excitotoxic stress [44], BDNF signaling may be particularly important in the beneficial effects of exercise on neuroplasticity and neuronal stress resistance. Studies of animal models have shown that intermittent fasting is highly effective in protecting the brain against a range of stressors that are known to cause neuronal degeneration by impairing mitochondrial function [1, 12]. The underlying cellular and molecular mechanisms appear to be generally similar to those of exercise, and involve both increases in neuronal network activity and signals from the periphery, most notably 3OHB.


While the data from studies of animal models are compelling, and evidence from epidemiological studies and some intervention trials are consistent with beneficial effects of fasting, exercise, and intellectual engagement on brain function and resilience, studies aimed at determining the optimal ‘doses’ and timing of these interventions in specific neurological disorders is lacking.


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Yet again we have hormetic mechanisms at the base of the beneficial signalling:


  1. Metabolic hormesis (Nutrient deprivation)
  2. Energetic hormesis (exercise)
  3. Cognitive hormesis (learning)


Re #3 above, it is evidently beneficial to challenge the brain by the study of different subjects and aspects, even the most complex ones. Just reading easy things with no cognitive challenge does not constitute hormesis. The 'easy' adjective is obviously subjective, what's challenging to me may be ridiculously easy and unchallenging to another.



Those who have an intellectual job usually enjoy cognitive hormesis but not energetic hormesis and vice-versa, so everyone should try and score in all three hormetic areas.

#1 is applicable by everyone (CR, IF, FMD, fully-fledged fast).

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  • 4 weeks later...

Does anyone know how mTOR and Arc interact?


They seem to interact in some ways, like described in the following article. mTOR overamplification in the hypothalamus signals abundance of nutrients hence less need of hunger, and viceversa. 


Hypothalamic mTOR Signaling Regulates Food Intake
  1. Daniela Cota1
  2. Karine Proulx1
  3. Kathi A. Blake Smith1
  4. Sara C. Kozma2
  5. George Thomas2
  6. Stephen C. Woods1
  7. Randy J. Seeley1,*

 See all authors and affiliations

Science  12 May 2006:

Vol. 312, Issue 5775, pp. 927-930

DOI: 10.1126/science.1124147


The mammalian Target of Rapamycin (mTOR) protein is a serine-threonine kinase that regulates cell-cycle progression and growth by sensing changes in energy status. We demonstrated that mTOR signaling plays a role in the brain mechanisms that respond to nutrient availability, regulating energy balance. In the rat, mTOR signaling is controlled by energy status in specific regions of the hypothalamus and colocalizes with neuropeptide Y and proopiomelanocortin neurons in the arcuate nucleus. Central administration of leucine increases hypothalamic mTOR signaling and decreases food intake and body weight. The hormone leptin increases hypothalamic mTOR activity, and the inhibition of mTOR signaling blunts leptin's anorectic effect. Thus, mTOR is a cellular fuel sensor whose hypothalamic activity is directly tied to the regulation of energy intake.

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  • 2 years later...


Neurobiological effects of the green tea constituent theanine and its potential role in the treatment of psychiatric and neurodegenerative disorders (2013)




Theanine (n-ethylglutamic acid), a non-proteinaceous amino acid component of green and black teas, has received growing attention in recent years due to its reported effects on the central nervous system. It readily crosses the blood-brain barrier where it exerts a variety of neurophysiological and pharmacological effects. Its most well-documented effect has been its apparent anxiolytic and calming effect due to its up-regulation of inhibitory neurotransmitters and possible modulation of serotonin and dopamine in selected areas.

It has also recently been shown to increase levels of brain-derived neurotrophic factor. An increasing number of studies demonstrate a neuroprotective effects following cerebral infarct and injury, although the exact molecular mechanisms remain to be fully elucidated. Theanine also elicits improvements in cognitive function including learning and memory, in human and animal studies, possibly via a decrease in NMDA-dependent CA1 long-term potentiation (LTP) and increase in NMDA-independent CA1-LTP.

Furthermore, theanine administration elicits selective changes in alpha brain wave activity with concomitant increases in selective attention during the execution of mental tasks. Emerging studies also demonstrate a promising role for theanine in augmentation therapy for schizophrenia, while animal models of depression report positive improvements following theanine administration. A handful of studies are beginning to examine a putative role in attention deficit hyperactivity disorder, and theoretical extrapolations to a therapeutic role for theanine in other psychiatric disorders such as anxiety disorders, panic disorder, obsessive compulsive disorder (OCD), and bipolar disorder are discussed.


There already exists a significant body of literature on the potential neuroprotective effects of the green tea catechins by Youdim, Mandel, and others (for reviews, see refs.72,73). These effects appear to involve a myriad of cellular mechanisms including iron chelation, anti-oxidant activity via scavenging of free radicals, and modulation of specific cellular survival and signal transduction pathways such as the protein kinases.

The mechanisms by which theanine exerts its neuroprotective effects appear to differ primarily from those of the catechins; there is now a significant body of evidence demonstrating the direct or indirect antagonism of glutamate metabolism and neurotransmission within the CNS, alongside a possible further up-regulation of inhibitory neurotransmitters such as GABA and glycine, and increases in BDNF.

However, further cellular downstream effects of Ltheanine are now beginning to emerge as a result of the recent in vivo and in vitro studies of Di, Kim, and Cho.24,32,34 Their collective findings suggest that notwithstanding the down-regulation of brain glutamate metabolism, L-theanine is also capable of interfering to some degree, with harmful activities such as DNA fragmentation, amyloid-induced cell death and apoptosis. Its ability to inhibit the suppression of a  myriad of cellular proteins such as C Jun Kinase,  Caspase 3 plus NOS and haem oxygenase production, all implicated with neurodegeneration and cell cycle regulation and survival, may suggest further means by which theanine exerts neuroprotective activity.

Furthermore, its ability to inhibit the ERK and MAP kinases, would appear to play a role in its prevention of amyloid β-induced cell death. Its ability to alter the cell protein kinases is shared by the catechins; whether the overall effects within the context of green tea consumption are additive or not is presently unknown.

Overall, however, the positive findings to date regarding theanine are providing additional support for the efficaciousness of green tea consumption apropos of cognitive function and neuroprotection. Given the positive experimental outcomes following treatment with theanine post-cerebral infarction in animals, further studies on L-theanine supplementation in humans following cerebral infarction and injury seem justified.

There is also an increasing body of evidence to support a role for L-theanine in the partial prevention of Alzheimer’s disease and cognitive decline in humans partly due to its effect on CA1 neurons. The increase in brain levels of BDNF following L-theanine administration to animals point to a further possible role for this amino acid in neurogenesis and memory formation.

Given the role of BDNF in synaptic plasticity and learning via its effects on late phase LTP, one correlation that merits further attention is that between BDNF and L-theanine. Whether or not its ability to increase levels of BDNF might play a further indirect role in the treatment of psychiatric disorders such as depression, bipolar disorder, and OCD, remain speculative at present but worthy of investigation. It is worth reiterating the findings of Takeda et al.55 regarding the positive effect of theanine on NMDA-independent CA1LTP in rats. The latter phenomenon is now thought to play a part in spatial memory formation within the hippocampus.74 In light of the positive effects of L-theanine administration on cognitive function in rats involving spatial awareness such as the water maze task, it is interesting to speculate on whether theanine may partly exert its effects via this mechanism. It is also worth noting that theanine appears capable of both NMDA receptor dependent and independent effects. BDNF has also been implicated in the aetiology of Alzheimer’s disease; it has been suggested that the early memory dysfunction seen in AD may be related to BDNF levels within the hippocampus.75 [...]


 See also this broad but rather shallow review discussing a wide range of potential dietary, herbal and synthetic nootropic substances, their possible mechanisms,  and the (lack of) evidence supporting their use.

Brain Ageing, Cognition and Diet: A Review of the Emerging Roles of Food-Based Nootropics in Mitigating Age-Related Memory Decline (2019)


Edited by Sibiriak
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  • 2 years later...

How fasting affects mTOR and neurons.  The study was done with a focus epilepsy.

Why does fasting reduce seizures?

Studies by others had shown that mTORC activity is inhibited by acute fasting, though these studies didn't look at the brain.

In the new study, they showed in a mouse seizure model that mTOR signaling was reduced in the brain after fasting. Additional studies of cultured rat neurons in a dish suggest that this fasting effect is primarily driven by the lack of three amino acids (leucine, arginine, and glutamine).

Yuskaitis and colleagues now want to try diets in animal models that eliminate specific amino acids and observe the effects on seizures. They also want to explore how the ketogenic diet, a popular approach to treating epilepsy, helps curb seizures. No one currently knows why this low-carbohydrate, high-fat diet works.

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Thanks for having resuscitated this thread, I vaguely remembered about it was good to read it again.

The importance of physical exercise to boost the cognitive function (by BDNF release) has been recently discussed by Peter Attia. He contends this is the single most important factor.

Nevertheless, I believe that cognitive stimulation plays its nontrivial contribute. Lately I've been interested in various topics (which I had no previous occasions to deepen) like astronomy, particle physics, neurobiology, psychopharmacology and don't remember now what else. I find it improves brain efficiency with a double effect: the cognitive challenge itself and the satisfaction/pleasure deriving from understanding, which constitutes a balanced, brain-nourishing dopaminergic effect. I confess I don't know whether optimal dopamine release in some neuronal circuits is associated with BDNF release.

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