Cognitive Benefits Of Caloric Restriction Are Due To Reduced Tryptophan/Serotonin/mTOR Signalling

Limon9

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It seems that consuming pure egg white will indeed make you stupid enough to consume pure egg white.

Key Points
- Calorie restriction improves mental test performance in mice.
- Adding tryptophan into calorie-restricted diet abolished memory benefits.
- Giving C.R. mice the serotonergic drug fenfluramine abolished memory benefits.
- Serotonin receptor 5HT6 and mTORC1 (which, in the brain, is tightly associated with that receptor) were indispensible for this effect as shown by loss-of-function testing.
- Giving a rapamycin analog mimicked the memory benefits when given to an ad-libitum group.
- Adding more fat or carbohydrate to the diet did not degrade memory performance, despite increased bodyweight.

"Unpeaty" Things
- Authors think this is due to chronically mildly elevated corticosterone (the rodent equivalent of cortisol).
- Authors note that calorie restriction increases NMDA, which is often a red flag biological event in Peat-World.

Since brain-serotonin is strongly dependent on the balance of circulating amino acids, such a result should not be equated with eating meat or dairy products, which all contain a "natural" balance that shouldn't affect things too much (at least in moderation). A fair comparison would be with taking supplemental tryptophan, eating way over one's protein requirement, or eating way too much granulated dextrose/sucrose/junkfood. Gelatin alters the serum ratio so as to reduce brain serotonin by providing a decent amount of nonpolar amino acids without tryptophan, which I hope would help to provide advantages in long-term mental plasticity.

Higher Serotonin Availability May Be The Cause Of Cognitive Impairment / Dementia

Serotonin receptor HTR6-mediated mTORC1 signaling regulates dietary restriction-induced memory enhancement
PLoS Biol. 2019 Mar 18;17(3):e2007097. Teng L et al.

Highlights
"An adequate but reduced dietary intake, such as dietary restriction (DR; 20%–40% reduction in total daily caloric intake without malnutrition), has been recognized to be the most effective anti-aging intervention, not only improving cognitive performance in elderly humans but also prolonging healthy life span in several model organisms [4, 5]. Studies investigating the nutritional basis of DR benefits have revealed that reduced dietary intake of protein as well as of certain amino acids, including tryptophan, can improve surgical stress resistance and extend life span in rodents [6, 7]."
"HTR6 stimulates Gs and adenylyl cyclase, which are generally known to have a positive influence on cognitive functions [12]. However, accumulating evidence in both rodent and human studies suggests that pharmacological blockade of HTR6 signaling improves memory performance [13–18]. This discrepancy has highlighted alternative pathways that mediate the procognitive effect of HTR6 inhibition. Despite an enhanced corticolimbic release of acetylcholine, glutamate, and monoamines that favors cognitive processes [19], the disrupted recruitment of mechanistic target of rapamycin (mTOR) signaling that occurs upon HTR6 inhibition is postulated as a mechanism mitigating cognitive deficits in animal models of schizophrenia [20]."

[This part was worded very obtusely. What I've gathered from other research suggests that mTOR is pathologically overactivated in schizophrenia, and that blockade of it or of 5HT6 in the brain is therapeutic. Prepare for acronyms:]
"... our results demonstrate that dietary tryptophan is a major contributor in limiting DR-induced memory enhancement. The serotonin receptor HTR6 is indispensable for this process,"
"Our results demonstrated that adding back tryptophan, but not glutamate, cysteine, or tyrosine, attenuated DR-induced memory retention (Fig 2B). Tryptophan alone is thus limiting for memory retention during DR. Although adding back carbohydrate and fat, but not protein or individual amino acids, significantly increased the body weight of DR mice (S2A and S2D Fig), none of these dietary manipulations affected general locomotor activity or total time spent on object exploration, compared to either the AL [ad libitum] or DR group in the open field test or NOR [novel object recognition] test, respectively (S2B, S2C, S2E and S2F Fig)."
"We found that fenfluramine abolished DR-induced memory enhancement (Fig 2C), suggesting that DR may induce reduced serotonergic signaling and that an acute increase in serotonin transmission interferes with DR improvement of memory performance."
"DR induced down-regulation of HTR6 mRNA expression is likely to work through an elevated level of circulating corticosterone, as suggested in previous studies [28, 29]. In agreement with this, we found a higher level of serum corticosterone in DR (compared with AL) mice (Fig 2I), and chronic supplementation with a low dose of corticosterone (10 μg/ml in drinking water for 6weeks) significantly repressed hippocampal HTR6 mRNA expression (Fig 2J) and improved memory performance (Fig 2K)."
"... supplementation of food with an mTORC1 inhibitor (everolimus, rapamycin analog [RA]) mimicked but did not further enhance the memory performance of DR and HTR6 KO [knockout] mice (Fig 5M). Supplementation with the mTORC1 inhibitor also prevented mTORC1 activator–induced memory impairment in the DR mice (Fig 5M). Neither mTORC1 activator nor inhibitor treatment affected feeding behavior, body weight, or locomotor activity of mice (S6A–S6C Fig)."
"Previous studies have demonstrated a biphasic effect of corticosterone on cognitive function. Whereas enhanced memory and LTP [long-term potentiation] occur when the level of corticosterone is mildly increased (predominantly MR activation), impaired memory and LTP appear when the corticosterone level is greatly increased (both MR [mineralocorticoid receptor] and GR [glucocorticoid receptor] activation) [44–46]. This biphasic effect of corticosterone is also observed in the regulation of hippocampal neurogenesis, which is known to be associated with DR-induced memory formation [47, 48]. A low dose of corticosterone treatment, similar to that used in our study, does not induce stress responses in mice [49], but the improved memory performance and LTP observed in our study are largely in agreement with previous studies discussed above."
"It is of particular interest that DR up-regulates N-methyl D aspartate receptor [:grimacing:] and brain-derived neurotrophic factor/tropomyosin receptor kinase B signaling, which may result in the increased CREB-1 activity observed in the brain of the DR mice [30, 59]. Accordingly, creating an in vitro cell culture environment mimicking chronic DR and a real-time monitor for protein (kinase) activity during memory behaviors will be important for future studies to establish which signaling networks are influenced by DR. mTOR exerts a critical role in the regulation of dendritic protein synthesis, which is essential for long-lasting synaptic plasticity [60]. Current concepts of neuroplasticity and memory regulation refer to mTOR as a rheostat rather than an on–off switch. Whereas acute and complete inhibition of mTOR abolishes synaptic plasticity, chronic partial reduction of mTOR signaling may result in DR-mimicking effects, leading to the enhanced memory performance in animals observed in this study and consistent with previous reports [61, 62]."
 
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proteome

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Authors think this is due to chronically mildly elevated corticosterone (the rodent equivalent of cortisol).
How chronically?

One of Peat's points is that certain things that have only benefits for years can cause problems later, e.g. elevated tryptophan in young mammals causing higher growth rates.

Also, I'm a bit confused by this:

"- Adding more fat or carbohydrate to the diet did not degrade memory performance, despite increased bodyweight."

Does that still mean that a 20% reduction improves memory performance?
 

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