Amino Acid Supplementation For People With Poor Digestion

[Amazoniac]

Zeus have picked the indispensable amino acids, excluded the toxins (which happen to have a lower requirement) and suggested to supplement the others. Since BCAAs (underlined) are commonly sold as supplements, often in a ratio of 1 : 1 : 2 (reflecting official recommendations below), he suggested to take such product and add the rest.

- Advanced Nutrition and Human Metabolism (978-1-133-10405-6)

However!

What I suggest instead is to use Cron-o-meter (or an unaffiliated app) and go to 'Settings > Targets > Proteins', leave all visible and define your own individualized targets. It isn't difficult to find information on specific amino acids throughout the foro or Raj's work; when in doubt, go by ratios based on those that you have preset.

Next, after having logged your airplane intakes, I would start to try to adjust according to the digestibility of the protein or your suspicion of assimilation (decreasing the amount to correct for inefficiency, for the example), this way we is left with a more reliable protein diary.

Then, check out the average of a week (Trends > Nutrient Report > Last 7 days). There might be certain amino acids that are off, so it's a good starting place. I would attempt to find the ones that are high, and which meals throughout the week are often imbalanced and major responsibles for such difference, and favor adding specific amino acids in them to make them more balanced. Afterwards you can work the way up or introduce others as wish'd. Perhaps digestion wasn't broken, and all that you needed was a little extra lysine for example.

You can also use the app to evaluate how balanced a food is in terms of amino acids (according to your requirements) by viewing a single food in an amount that's enough to provide the total protein needs of a day (such as 70 g for example). It becomes clear what (in theory) has to be fixed to make the food more complete regarding amino acid profile.

 

[Amazoniac]

And don't forget..
Cron-o-meter, take charge of your life, count on us!

 

[Cirion]

Nice. I will have to do some calculations later to see where I stand relative to these requirements.

It sounds like there's a possible niche product someone can make that has all the AA's in perfect proportion EXCEPT the "poison" AA's, eh?

 

[Amazoniac]

- The Brain’s Response to an Essential Amino Acid-Deficient Diet and the Circuitous Route to a Better Meal

"Given a choice, animals select (balanced) protein within a broad range of concentrations [2]; they avoid both very high (over 75 %) and very low-protein diets [3, 4]. It has long been known that rats will reject a low-protein diet, at 5–6 % or less [5]. Yet, such a low level might only be seen in the diets of fruitarians that avoid grains, seeds, and nuts. In contrast, White [6] showed that animals increase their food intake, becoming hyperphagic, if a diet, with a balanced IAA profile, is just marginally low in protein (8–10 % of the diet) [6–8], a level consistent with vegan-vegetarian diets. In White’s studies, the increases in feeding were associated with changes in orexigenic peptides in the hypothalamus [6]. At this level, the increased food eaten due to the generalized hyperphagia could provide enough protein for maintenance. Animals do not always select foods in a way that would show a “protein appetite” [9]; Morrison et al. [10] note that a mechanism for understanding the maintenance of protein homeostasis is lacking. Nevertheless, both animals [11] and humans [12] are reported to select a higher protein source after eating a low-protein meal; these choices typically are seen in a protein “need state” [13]."

"Rats do not adapt to an IAA devoid diet, which is lethal over time, as survival is similar to that seen with a protein free diet [5]. However, over a period of days, rodents can adapt fully to an IAA-imbalanced diet, which contains at least a small amount of the limiting IAA [5]. The responses to protein and IAA levels are graded; more severe limitation or imbalance causes the most pronounced response (compare feeding on the milder imbalanced diet with the devoid diet in Fig. 4). Such adaptation includes both increasing the activity of amino acid metabolizing enzymes in the liver for those amino acids that are in relative excess [150, 151], and altered feeding patterns [52]. Two recent reports addressing the responses to mild imbalances show adaptation to imbalanced IAA diets.

Using a soy protein diet that is deficient, but not devoid of, sulfur-containing amino acids (SCAA), Sikaladis and Stipanuk [152] showed that rats adapted by altering their feeding patterns, similar to the patterns seen by Leung and colleagues [16], in the imbalanced diet model described by Harper et al. [5]. These soy-fed, mildly SCAA-deficient rats had increased liver levels of P-eIF2α, showing that complete depletion of an IAA is not necessary for the GCN2 response [152], at least in the liver. Methionine (another SCAA) restriction has also been studied recently, over long feeding trials (months). The diets used [153] again closely follow the pattern of Harper’s [5] classical amino acid-imbalanced diets, to which rats adapt within a week (see the controls in ref [117]). Of interest is the reported increase in nighttime energy expenditure in the methionine restricted rats [153]. Rats are nocturnal animals and on an IAA-imbalanced diet they exhibit increased locomotor activity during the dark period, which may be beneficial to the amino acid profile [154]. Increased activity has been shown for water, food and other deprivations, as well [155]. However, in the methionine-restricted animals, interestingly, there was no evidence reported that could link locomotor activity to the increased energy expenditure during the dark period [153]. These authors also report beneficial effects of SCAA restriction, including increased longevity and metabolic changes. Because the effects of this methionine-imbalanced diet can be reversed by the SCAA, cysteine [156], which spares methionine nutritionally, the effects may be due to the limiting of SCAA, or sulfur, in these diets."

"Taken together, we have reviewed findings to show that, with time after sensing IAA limitation, animals can make IAA-relevant choices and associations, aversions and preferences for nutrient selection in the maintenance of IAA, and thus protein homeostasis, and survival. We have also seen how the neuroanatomy serving these behaviors is integrated with sensory, motivational and locomotor centers."​

 

[Amazoniac]

Here's what was suggested above based on Zeus' example:

Spoiler: All-gelatin

Spoiler: BCAA + lysine

Spoiler: Their combination

 

[Cirion]

How did you get all the AA's to show up on cronometer? I don't see some like glycine, arginine, alanine to name a couple on my cronometer.

 

[Amazoniac]

How did you get all the AA's to show up on cronometer? I don't see some like glycine, arginine, alanine to name a couple on my cronometer.

It was comment'd on post #201.

 

[Cirion]

It was comment'd on post #201.

ahh missed that part. Awesome, I was annoyed that cronometer wasn't showing everything, well now it does!

 

[Amazoniac]

The usual digestibility of proteins is surprisingly high:

- Advanced Nutrition and Human Metabolism (978-1-133-10405-6)

"The digestibility of a protein is a measure of the amounts of amino acids that are absorbed following ingestion of the given protein. Animal proteins have been found to be about 90% to 99% digestible, whereas plant proteins are about 70% to 90% digestible. Meat and cheese, for example, have a digestibility of 95%, and eggs are 97% digestible. Cooked split peas are about 70% digestible, and tofu is about 90% digestible. Both the digestibility of a protein and its amino acid content affect protein quality."​

So what's getting in the way of adequate protein synthesis and should explain the poor utilization has be the amino acid composition (because the values provided on the original post are probably based on wealthy people/animals). I don't know much about peptide digestion/adsorption, but it's worth looking into.

Yet check this out:

Their claim of net nitrogen utilization of 99% for their product compared to dietary proteins is suspicious, as is their promotional video.

I'm not sure if fast digestion is always desirable as they imply. Other nutrients have to be present for the synthesis to be ordered and these powders are devoid of nutrition. As you knows, caseid (for example) takes hours to digest, and they mentioned that these amino acids are digest'd in less than 30 min.
On the other hand, it makes us wonder if it's productive to combine isolated amino acids with dietary proteins because there's a chance that they's going to be metabolized at different times.


- Gelatin, stress, longevity

"Most studies of the nutritional requirements for protein have been done for the agricultural industries, and so have been designed to find the cheapest way to get the maximum growth in the shortest time. The industry isn't interested in the longevity, intelligence, or happiness of their pigs, chickens, and lambs."​

Synthetic amino acids might cost more than cheap sources of protein for animal feed. However! If you have an amino acid composition that's so efficient in utilization and can maximize growth, I doubt that the industries wouldn't be favoring such product. What we usually find is cheap proteins with a few supplemental amino acids.


Protein quality/rating system is often based on amino acids composition of a protein. We has a daily theoresical requirement to be met (image above), and another way of presenting that is through leveling them all as 100% of daily needs. Every protein in the diet can be compared to this baseline, and for each food/meal there will be a limiting amino acid; you can only get sufficient protein once you cross the 100% mark for all amino acids, forcing you to exceed on many to get enough of the lowest or adapt to it somehow.

Recommended:
- Protein quality - Wikipedia
- Protein quality evaluation twenty years after the introduction of the protein digestibility corrected amino acid score method
- Protein Quality: Transitions in Food Protein Evaluation (peta.org)

Alternatively , open anesthesiology book ,al there


--
- Advanced Nutrition: Macronutrients, Micronutrients, and Metabolism (978‑1‑4200‑5552‑8)

The savage mode when no methods were available:
"Human protein and amino acid requirements have been studied for well over 100 years using a variety of techniques. Nutrition scientists have collected data on the quantity of protein foods consumed versus health, growth, and weight gain of various populations. The assumption was made that whatever “healthy” people ate was probably what kept them healthy and should, therefore, be used as a standard of comparison for other diets. These standards, with respect to protein, were invariably high for populations having an abundance of meat, milk, poultry, and fish in their diets. Voit and Atwater, around the turn of the century, found intakes of 118 and 125 g of protein per day, respectively, for adult men and termed these intakes as desirable."​

 

[aquaman]

I took glycine powder today for the first time in ages. Immediate running nose/post nasal drip and digestive issues, like cramping and gurgling.

I’ve been using a lot of gelatin and hydrolysate recently and no such issues. Gonna stick to the natural stuff!

 

[Amazoniac]

- Three targets of branched-chain amino acid supplementation in the treatment of liver disease

"Decreased blood concentrations of BCAAs and increased concentrations of aromatic amino acids (AAAs) phenylalanine, tyrosine and tryptophan, and methionine are characteristic of chronic hepatic disease, particularly cirrhosis [25,28,29]. The AAAs increase due to a decreased ability to metabolize these amino acids in a diseased liver. Similarly, the cause of increased methionine concentration is its impaired conversion to S-adenosylmethionine. Therefore, the increase in methionine concentration is frequently associated with decreased levels of its metabolites, such as cysteine and taurine, and impaired synthesis of glutathione. The abnormalities in BCAA and AAA levels in cirrhosis are frequently expressed as a molar ratio (valine + isoleucine + leucine)/(phenylalanine + tyrosine). Physiologically, the ratio is 3.0–3.5, whereas in patients with hepatic cirrhosis it is significantly lower."

"The pathogenesis of decreased plasma BCAA levels in liver cirrhosis has not been clear for many years, and various metabolic abnormalities have been proposed as the cause, including hyperinsulinemia, hyperglucagonemia, catecholamines, hyperammonemia, and starvation [30–34]. Now it seems to be clear that ammonia has the crucial rôle [35]. Hyperammonemia develops typically in cases of portalsystemic shunting, when ammonia generated mostly by bacterial degradation of urea and breakdown of glutamine in the gut escapes detoxification by the liver. In this situation, the muscles take up ammonia from the circulation and detoxify it by the synthesis of glutamine from glutamate. Glutamate deficiency intensifies catabolism of BCAAs associated with enhanced synthesis of glutamate from a-ketoglutarate. These metabolic alterations are responsible for increased glutamine and decreased BCAA and alanine levels in the blood and skeletal muscle after ammonium salt infusion [36]. An inverse alteration in the concentrations of glutamine (increase) and alanine (decrease) indicates an increased demand for glutamate and decreased alanine synthesis from pyruvate (Fig. 3)."

"Hepatic encephalopathy is a serious neuropsychiatric abnormality associated with chronic or acute liver injury. Signs can be impaired cognition, a flapping tremor, and a decreased level of consciousness, including coma, cerebral edema, and ultimately death. In its pathogenesis, changes induced by impaired liver function and portal-systemic shunting interact, resulting in accumulation of substances that are normally removed by the liver. Substances contributing to symptoms of hepatic encephalopathy include mercaptans, short-chain fatty acids, increased concentrations of AAAs, g-aminobutyric acid, "endogenous" benzodiazepines, etc. However, the strongest arguments can be advanced for ammonia, although the exact mechanism by which ammonia causes hepatic encephalopathy is unknown and direct and indirect effects should be considered."

"Presumed mechanisms of the direct effect of hyperammonemia on brain functions include its effect on inhibitory postsynaptic potentials by blocking the chloride pump, impairment of brain adenosine triphosphate synthesis due to depletion of Krebs cycle intermediates, cell swelling by ammonia-induced increased cerebral blood flow and synthesis, and accumulation of glutamine in astrocytes [37–41]."

"Indirectly, hyperammonemia may contribute to hepatic encephalopathy by a decrease in BCAA levels in the blood and by alterations in amino acid transport across the blood–brain barrier, as Fischer and Baldessarini [45] suggested in their "false neurotransmitter" hypothesis. The AAAs flood the central nervous system due to high blood plasma concentrations of AAA and low concentration of BCAAs, which compete for entry by the L-system (system that serves for transport of neutral amino acids) across the blood–brain barrier. Augmented uptake of AAAs could result in an imbalance in the synthesis of dopamine, noradrenaline, and serotonin in the brain. In addition, increased availability of AAAs may cause the formation of "false neurotransmitters" such as octopamine, phenylethanolamine, and tyramine."

"The rationale of BCAAs in the treatment of hepatic encephalopathy was based on assumptions that providing BCAAs would facilitate ammonia detoxification by supporting glutamine synthesis in skeletal muscle and in the brain, normalize plasma amino acid concentrations, and decrease brain influx of AAAs."

"The extensive fatty acid oxidation in a regenerating liver can explain the beneficial effect of carnitine (the essential cofactor in the transfer of fatty acids across the inner mitochondrial membrane) on liver regeneration [64]. Fatty acids also act as a substrate for synthesis of phospholipids and for esterification of cholesterol, important components of newly synthesized cell membranes. The positive effect of exogenous phospholipids on liver regeneration has been demonstrated in animal studies [65] and may explain the therapeutic effect of polyunsaturated phosphatidylcholine in hepatic damage therapy [66]."

"The demands of regenerating hepatic tissue for a supply of amino acids are undoubtedly higher than in a physiologic state. Nevertheless, it seems that it is not necessary to increase the intake of some amino acids with the intent to stimulate liver regeneration or the required amounts can perhaps even be lower. Such amino acids include AAAs, the levels of which are usually increased in hepatic injury, whereas a decreased concentration of some amino acids, particularly taurine, threonine, and BCAA, below control values in the phase of liver recovery indicates increased utilization of these amino acids and the importance of their exogenous supply [26]."

"The beneficial effect of BCAA administration on liver regeneration has been demonstrated in a number of experimental studies [69–71]."

"Several studies have indicated a strong inhibitory effect of ammonia on protein synthesis [93] and its lysosomotropic toxicity [94,95]."

"The contributing complications and infections that are often undiagnosed in patients with cirrhosis may induce a systemic response associated with an enhanced production of cytokines, sympathetic nervous system activation, enhanced cortisol production, etc., followed by a complex of metabolic alterations in the body, particularly by activated proteolysis in skeletal muscle and enhanced BCAA oxidation [9–11]. Because of the enhanced release of BCAAs from muscle proteins, the BCAA deficiency in body fluids may not be observed and/or may disappear. These patients tend to be hypermetabolic and a higher supply of dietary protein may be required to achieve a positive nitrogen balance."

"Several studies have demonstrated that administration of amino acid formulas enriched with BCAAs can reduce protein loss, support protein synthesis, and improve the nutritional status of patients with hepatic illness [17,20,101]. This favorable effect of BCAAs on liver disease development makes liver illness exceptional, particularly in comparison with other proteocatabolic disorders, such as sepsis, burn injury, and cancer, in which positive therapeutic effects of BCAA supplementation are not convincing [15]. One possible explanation may be based on the existence of decreased BCAA levels in liver cirrhosis, which indicates a deficiency of these indispensable amino acids and a clear rationale for BCAA supplementation. However, the decrease in plasma BCAAs is not a constant finding in hepatic illness, particularly in hepatic disease exacerbation and if inflammatory complications develop. In addition, it seems that the inflammatory response blunts the anabolic response after BCAA administration."

"The mechanism of the favorable effect of BCAAs on protein metabolism and nutritional state of patients with hepatic disease is undoubtedly related to their well-known stimulatory effect on protein synthesis and inhibitory effect on proteolysis [1]. Leucine stimulates insulin release from b-cells of the pancreas [103] and there are emerging data that BCAAs, particularly leucine, stimulate protein synthesis through the mTOR signaling pathway and phosphorylation of translation initiation factors and ribosomal proteins [3]. These effects may contribute to the improvement of insulin resistance and b-cell function in patients with chronic liver disease after BCAA treatment [104]. The inhibitory effect of BCAAs on proteolysis is probably mediated by several metabolites of BCAAs, particularly of the BCKAs and b-hydroxy-b-methylbutyrate [1,105,106]."​

 

[Amazoniac]

I took glycine powder today for the first time in ages. Immediate running nose/post nasal drip and digestive issues, like cramping and gurgling.

I’ve been using a lot of gelatin and hydrolysate recently and no such issues. Gonna stick to the natural stuff!

Isn't it odd that commercial hydrolyzed collagen products don't taste funky? Given the composition, it's supposed to after being broken down.

 

[Amazoniac]

- Protein quality evaluation twenty years after the introduction of the protein digestibility corrected amino acid score method

"The 2007 WWO/FAO/UN Expert Consultation on proteins (6) stressed the need to interpret [] classifications with care, as there appears to be an absolute metabolic need for both dispensable and indispensable AA. The efficiency of utilization of IAA is dependent on the total N [Newton] and the form of N in the diet. The higher the dietary total N, the lower the amount of IAA needed to achieve N-balance (6). The report further states that when all or any of the IAA are present in excess of demand, the absorbed mixture is unbalanced and limited by dispensable AA, which would need to be supplied from oxidation of surplus IAA. However, the biological value of a protein is defined in terms of how well the profile of IAA in a protein matches that of the pattern required by body. Some authors have argued that IAA are important at higher intakes than those in the requirement pattern, especially in the case of high quality proteins (e.g. [?] egg, milk, fish and meat protein products) that are used to supplement other low quality proteins (8). Another argument supporting higher intakes of IAA is that their role extends beyond that of supporting growth or N balance (i.e., implications in such diverse functions as lean body mass retention, cell signalling, bone wealth, glucose homeostasis and satiety induction) (7)."​

 

[Amazoniac]

Proportion of BCAAs in proteins of some foods:

Source: the internet.​

Depending on the amount used and timing, it won't be much impacting for someone that eats 100 g of protein a day. Yet for someone whose protein digestion is impair'd or for vegans eating 50 g of protein a day, adsorbing 40 g, and 5% of those being BCAAs (2 g); even small amounts can make a difference.

 

[Amazoniac]

L-Tryptophan: Basic Metabolic Functions, Behavioral Research and Therapeutic Indications

"In humans, tryptophan has relatively low tissue storage[9] and the overall tryptophan concentration in the body is the lowest among all amino acids,[10,11] although only small amounts are necessary for general healthy nutrition.[5,12] While typical intake for many individuals is approximately 900 to 1000 mg daily, the recommended daily allowance for adults is estimated to be between 250 mg/day[5,12,13] and 425 mg/day,[4,14,15] which translates to a dietary intake of 3.5 to 6.0 mg/kg of body weight per day. Some common sources of tryptophan are oats, bananas, dried prunes, milk, tuna fish, cheese, bread, chicken, turkey, peanuts, and chocolate (see Table 1 [and let me know what's going on with whole milch]).[11,16]"

"[..]while tryptophan is found in the smallest concentrations of the 20 amino acids in the human body,[9–11] it has wide-ranging effects and is a critical component of a multitude of essential metabolic functions. While there are three primary functions of tryptophan (i.e. protein, serotonin, and kynurenine synthesis), the focus of the remainder of this discussion is on tryptophan’s role in the synthesis of serotonin in the brain, and the utility of tryptophan for both research and clinical purposes."

"It is estimated that 95% of mammalian serotonin is found within the gastrointestinal tract,[42] and only 3% of dietary tryptophan is used for serotonin synthesis throughout the body.[43] Nevertheless, serotonin synthesis is one of the most important tryptophan pathways and a topic of intense research. It is estimated that only 1% of dietary tryptophan is used for serotonin synthesis in the brain,[12,44] but despite the relatively low concentration of brain serotonin compared to that in the rest of the body, it has a broad impact as a neurotransmitter and neuromodulator and has been implicated in numerous psychiatric conditions and psychological processes."

"Tryptophan is the sole precursor of serotonin[35] and, once consumed, tryptophan is distributed throughout the human body in the circulatory system. Unlike the other 19 amino acids, approximately 75% to 85%[3,65] of circulating tryptophan is bound to albumin, with some estimates as high as 95%.[66] It is primarily the non-bound, free tryptophan that is available for transport across the blood-brain barrier.[3,5,35,66–68] However, since tryptophan has a higher affinity for the blood-brain barrier (BBB) transporter than it does for albumin,[3–69,70] albumin-bound tryptophan that is in close proximity to the BBB will likely dissociate from the albumin to be taken up into the brain.[3] Because of this difference in affinity, some researchers have concluded that up to 75% of albumin-bound tryptophan may be available to cross the blood-brain barrier.[3]"

"In the bloodstream, tryptophan competes with other large neutral amino acids (LNAA; e.g. histidine, isoleucine, leucine, methionine, phenylalanine, threonine, tyrosine, and valine) for the BBB transporter.[3,35,36,71,72] Given that BBB transporter is nearly saturated at normal plasma concentrations of amino acids, it is uniquely susceptible to competitive inhibition.[73] Because of the competitive transport among the LNAAs, the bioavailability of tryptophan for transport across the BBB is best expressed by the ratio of tryptophan to the sum of its competing amino acids.[9,36,66,74] Therefore, changing the ratio of tryptophan to the other competing large neutral amino acids can significantly affect concentrations of brain tryptophan available for serotonin synthesis. This can be accomplished by changing plasma concentrations of tryptophan, or by changing concentrations of the CAAs, either of which affect tryptophan availability and, by extension, serotonin synthesis.[75–78]"

"Although other influences, such as stress, insulin resistance, magnesium or vitamin B6 deficiency, and increasing age, can affect the rate of serotonin synthesis,[79] fluctuations in the tryptophan/CAA ratio and changing tryptophan availability are the two factors most likely to affect this process."

"To some extent, tryptophan availability to the brain can be enhanced by ingestion of carbohydrates and reduced by ingestion of proteins. Carbohydrate ingestion does not change the levels of circulating tryptophan, but it does decrease concentrations of CAAs through activation of insulin,[3,5] which increases the relative availability of tryptophan for transport into the brain.[5,66,80,81] In contrast, protein contains relatively low concentrations of tryptophan and ingestion of a protein meal increases the CAA concentration relative to tryptophan.[5,66] The result is a larger percentage of circulating CAAs, which increases the competitive advantage over tryptophan for crossing the blood-brain barrier. This advantage is reflected in a smaller tryptophan/CAA ratio.[5,66,81,82] Therefore, the ingestion of carbohydrates or proteins has the potential to change the availability of tryptophan for synthesis of brain serotonin; however, even small amounts of protein (as little at 4%) in a carbohydrate meal can prevent the increase in the tryptophan/CAA ratio (Trabis, 2018)."

"The ability of carbohydrate and protein meals to modify tryptophan availability may be dependent on the time of ingestion.[83,84]"

"When taken together, the findings from these studies suggest that changes in tryptophan availability can be manipulated to some extent through dietary intake, although it is unlikely that ordinary changes in dietary tryptophan or the CAAs through protein or carbohydrate manipulations will produce changes substantial enough to have a noticeable impact on behavior in a healthy individual.[5,86]"

"In addition to these dietary factors that affect tryptophan’s availability for synthesis of brain serotonin, acute alcohol consumption has also been shown to decrease the tryptophan/CAA ratio by about 10% at about 30 minutes and 20%–25% at about 1.5 to 2 hours following ingestion.[87,88] This decrease suggests that brain serotonin synthesis is impaired under these conditions.[87,89] Where the average individual is likely to tolerate this level of serotonin depletion without undue effects on their behavior, vulnerable individuals may experience a larger depletion effect (e.g. 50% or more).[90,91]"

"While there are a number of methodologies used to study serotonin dysregulation, one of the most widely used methods is to reduce brain serotonin synthesis, typically by reduction of tryptophan availability. Experimental manipulations of tryptophan are dependent on the two-step process required for serotonin synthesis in the brain.[35] First, brain tryptophan is converted to 5-hydroxytryptophan by the tryptophan hydroxylase enzyme (the rate-limiting step of serotonin synthesis). Second, 5-hydroxytryptophan is converted to serotonin by the aromatic amino acid decarboxylase enzyme. It is the activity of tryptophan hydroxylase that is dependent on the availability of brain tryptophan.[9,35–37,66] Because tryptophan hydroxylase is typically 50% saturated with its tryptophan substrate, an increase or decrease of tryptophan availability in the brain can increase or decrease brain serotonin synthesis.[34,37,78,88,92–94]"

"[A] method for examining the effects of reduced serotonin synthesis is to experimentally restrict dietary intake of tryptophan, which slowly reduces tryptophan availability. However, this method is limited by a relatively lengthy period of dietary restrictions (e.g. up to 10 days), which have shown only 15% to 20% reductions of the plasma total tryptophan with minimal behavioral or neurochemical effects in humans.[5,66,86]"

- Tryptophan, serotonin, and aging

"Malnutrition, and specifically protein deficiency, produces an inflammatory state that involves extreme serotonin dominance. Stress or malnutrition prenatally or in infancy leads to extreme serotonin dominance in adulthood. Other functions of tryptophan are reduced, as more of it is turned into serotonin."​

"Much more pronounced reductions of plasma tryptophan can be obtained using the acute tryptophan depletion methodology, which produces maximal (but transient) tryptophan depletion within 5 to 6 hours. This method typically involves the administration of an amino-acid beverage that contains approximately 100 g of 15 amino acids (see Table 2), but lacks tryptophan.[66,77,102] Consumption of this beverage results in two separate processes that reduce the availability of tryptophan for crossing the blood-brain barrier. First, the intake of the large amount of amino acids stimulates protein synthesis in the liver; however, without a proportionate intake of tryptophan, the protein synthesis clearly reduces the concentration of existing plasma tryptophan.[9,25,26,35–37,66,103] Second, the small amount of plasma tryptophan relative to the high concentration of plasma CAAs further decreases the availability of tryptophan for crossing the blood-brain barrier. Both ongoing protein synthesis and a lower plasma tryptophan/CAA ratio maximize the competitive disadvantage for tryptophan transport into the brain.[36,77] This two-fold effect results in a significant decrease of brain serotonin synthesis in both human and non-human primates,[77,78,104,105] and studies of rat brain have also shown reductions of neuronal serotonin release.[66,106,107]"

"A comparison across studies show'd [need to retest my prolactin levels] an 81% average reduction of plasma tryptophan following consumption of the most commonly used 100 g depletion formulation,[112] with reductions ranging from 55% to 94%.[27,37,77,88,102,104,112–117] Comparable results have been found following administration of a 50 g (i.e. half-size) formulation. For example, relative to pre-drink measures, two time-course studies showed robust depletions of 87% (i.e. free and total tryptophan[112] and 89% (i.e. free tryptophan/CAA ratio[37] maximal reduction of plasma tryptophan following consumption of the 50 g depletion formulation. Likewise, the 50 g and 100 g tryptophan loading formulations have also shown similar results, both of which produce marked increases in plasma tryptophan that range from 300% to 500% of pre-drink measures.[37]"

"A potential limitation of this methodology is that reductions of serotonin synthesis may not be uniform across all brain areas and may not be representative of neuronal release."

"A number of [] studies have reported that healthy women may be more vulnerable to the mood-lowering effects of tryptophan depletion than men,[138,113,141,142] which is supported by imaging studies that provide evidence of sex differences in brain serotonin synthesis.[78,118]"

"The extent of the effects of acute tryptophan depletion on mood appears to be related to varying levels of vulnerability to disturbance of the central serotonin system. Relative to wealthy controls, there is more consistency of mood-lowering effects in wealthy adults who may be vulnerable to serotonin disturbances, such as those with family histories of mood disorders[16,32,135,146,147] or other underlying biological vulnerabilities (e.g. genetic or brain abnormalities).[148,149]"

"In contrast to the typical lack of mood changes in wealthy adults, tryptophan depletion has been demonstrated to affect a variety of cognitive processes in both wealthy individuals and those with a serotonergic vulnerability. Impairments in a variety of learning and memory skills following tryptophan depletion are well documented."

"Tryptophan depletion has also been shown to impair learning on visual discrimination and memory retrieval,[114] episodic memory,[155] stimulus-reward learning,[30] and cognitive flexibility,[160] among other cognitive processes, although more studies are needed to test the reliability of these results. In an editorial commentary on cognitive effects of tryptophan depletion, Riedel[161] notes that there are a number of other physiological effects that may result from tryptophan manipulations that could be involved in the modulation of cognitive functions, such as quinolinic acid (NMDA agonist), and kynurenic acid (NMDA, nicotinic, and glutamatergic antagonist), which should also be considered for measurement.[42]"

"[..]dietary intake alone (i.e. ingestion of food) would seldom influence the availability of tryptophan significantly[.]"​

Acute tryptophan depletion in humans: a review of theoretical, practical and ethical aspects

"[..]serotonin release is not regulated the same way in all brain areas, so trying to extrapolate results from a single area of rat brain to the human brain is unlikely to provide useful insight."

"If the regulation of serotonin function in humans has any similarities to that in experimental animals, ATD may have different effects depending on the environment and the mental state of the human being studied. In experimental animals the rate of firing of serotonin neurons is increased during periods of behavioural arousal and/or motor activity, with subgroups of neurons firing at higher rates during rhythmic motor activities, such as feeding, grooming and increased respiration.[24] Serotonin release, measured by brain microdialysis, is, as expected, increased by factors that increase the firing of serotonin neurons. If ATD decreases release of serotonin, it probably does so by depleting the reserve of serotonin in the pool used for release during neuronal firing. If the firing rate is greater, then there is likely to be greater depletion of the releasable pool. Therefore, a plausible hypothesis is that any effect of ATD on serotonin release is likely to be greater when the participants are in a greater state of arousal. For example, arousal associated with being in a functional magnetic resonance imaging scanner, compared with being in a quiet room filling in rating scales, may cause changes in the effect of ATD on serotonin release."

"If the reserve of serotonin in the releasable pool is a factor in determining the magnitude of any effect of ATD, then effects may be different in different brain areas. Nishizawa and colleagues[16] estimated rates of serotonin synthesis in human brain areas using PET with α-[11C]methyl-L-tryptophan as a tracer. Combining those data with published data on the concentration of serotonin in different brain regions determined postmortem, the study determined that, for example, the time needed to synthesize the amount of serotonin found in the putamen was in the range of 31–48 minutes, but in the cortex the time needed was 0.8–1.3 minutes."

"Van Donkelaar and colleagues[21] pointed out a number of possible changes, other than serotonin synthesis, that might be responsible for the effects of ATD. These include changes in brain nitric oxide (NO), cerebrovascular changes, decreased brain-derived neurotrophic factor (BDNF) and decreased kynurenine pathway metabolites. Other possibilities not mentioned by van Donkelaar and colleagues[21] are effects of amino acid imbalance, direct effects of tryptophan on protein synthesis and on the organic cation transporter 2 (OCT2), effects on melatonin, and side effects and unblinding."

"Tryptophan is unique among the amino acids in that it can alter protein synthesis. Tryptophan supplements can increase protein synthesis in both the rodent liver[48] and brain,[49,50] an effect that seems to be mediated by tryptophan binding on cell nuclei.[51] This raises the possibility that human brain protein synthesis is different after the ingestion of tryptophan-containing and tryptophan-deficient amino acid mixtures. The implications of this are not known."

"The amino acid mixtures used in ATD studies are rather unpalatable despite various strategies used to diminish their unpalatability. These strategies include adding strong flavours, such as chocolate, to the amino acid suspension, putting the worst tasting amino acids (arginine, cysteine and methionine) in capsules, or, in the case of lysine, using the monohydrochloride instead of the free base.[14,59] Administering the mixture very cold will also help as it will decrease the taste of the amino acids by lowering the amount that dissolves in the water, and it will decrease the amount that volatilizes thereby diminishing the smell. However, whatever strategies are used, side effects will occur. Ingestion of the mixture results in up to 100 g of crystalline amino acids sitting in the stomach until the acid environment of the stomach dissolves them. As might be expected in these circumstances, both nausea and vomiting can occur. However, side effects have not often been studied. When they are, often there is no difference in side effects between ATD and control conditions, as found, for example, by Klaassen and colleagues.[60] However, aan het Rot and colleagues[61] found that dizziness, headache and nausea were all worse after ATD than after the placebo treatment. Furthermore, bright light, which prevented the lowering of mood in the ATD group, also diminished dizziness and nausea in that group. Serotonin receptors involved in emesis are present in both the gut and brain,[62] and the effect of bright light suggests that brain receptors contribute to the nausea and dizziness."

"An important objective of most ATD studies is to lower tryptophan levels as much as possible. Evidence to date suggests that the decline in plasma tryptophan has to be around 60% or greater to see any effect on mood.[68] Presumably, with a smaller lowering of tryptophan levels any effect on serotonin function is below the threshold needed to alter mood. The large decline in tryptophan levels that is needed may be related to the regulation of serotonin release."

"Another tryptophan-deficient amino acid mixture that has been used is collagen-based.[84] Collagen is a protein that is naturally free of tryptophan. Compared with the formula based on human milk, it has much higher levels of glycine and much lower levels of methionine, and it includes hydroxyproline. It lowered human plasma tryptophan levels by 74%. As with the mixture lacking non-essential amino acids, a direct comparison is needed of the ability of this mixture to lower plasma tryptophan and minimize side effects relative to the other mixtures discussed here."

"Badawy and colleagues[85] have criticized the ATD mixture formulation used by my colleagues and I[13] on the grounds that it may decrease the synthesis of catecholamines. They concluded this by looking at the ratio of the plasma level of phenylalanine plus tyrosine to the sum of the plasma level of the branched chain amino acids. With the ATD mixture, this ratio decreased by about 50%, suggesting that catecholamine synthesis was lowered. The rationale for this ratio is that all LNAAs are transported into the brain by the same transporter and compete with each other for uptake into the brain.[36] However, although phenylalanine is a substrate for tyrosine hydroxylase, it is not hydroxylated as efficiently as tyrosine, which is why untreated phenylketonuria is associated with large decreases, rather than increases, in catecholamine synthesis.[86] When using the more appropriate ratio of plasma tyrosine to the sum of all the other LNAAs, ATD causes the ratio to decrease slightly[63] or not at all.[87] Small changes in the tyrosine ratio are not a concern."

"Human plasma amino acids vary throughout the day by as much as 50% from minimum to maximum, due to diurnal rhythms and, more important, to protein intake.[88] Ratios of tyrosine or tryptophan to other LNAAs also vary, although to a lesser extent than the individual amino acids. The important issue is that large changes are needed in tryptophan (or tyrosine) to cause changes in biogenic amine function. Therefore, changes in the availability to the brain of the biogenic amine precursors that are not much greater than their normal physiologic variation are probably not functionally significant."

"Another important issue is the dose of mixture to use in ATD studies. My colleagues and I[89] found that 25 g, 50 g, 75 g and 100 g mixtures reduced human plasma tryptophan by 42%, 60%, 65% and 64%, respectively. Dougherty and colleagues[90] also found a more robust depletion with a 100 g mixture than a 50 g mixture. However, the 2 mixtures caused similar lowing of mood — the 100 g mixture caused greater attrition — even though ratings of somatic symptoms were similar in the 2 groups. The widespread use of higher doses is probably prompted by the normal concern of researchers to maximize the chances of seeing an effect. However, in some circumstances a lower dose may be better. For example, Hayward and colleagues,[80] using a 31 g ATD mixture, found changes in cognitive process with no change in mood in recovered depressed patients. This showed that the cognitive changes were not mediated by lowered mood. If a higher dose had been used, mood changes might have occurred, eliminating the possibility of concluding that mood changes did not mediate the cognitive changes."

"Any protein meal will lower the plasma tryptophan ratio, and yet a protein meal causes little or no decline in levels of the tryptophan or the serotonin metabolite 5-HIAA in human CSF.[94]"

"Krahn and colleagues55 compared the effect of 100 g and 25 g tryptophan-deficient amino acid mixtures. They confirmed the finding of my colleagues and I[89] that the 25 g mixture caused a much smaller decline in tryptophan availability and reported that the 8 participants who received both mixtures could not distinguish between them."

"[An] experience of a recovered depressed patient from the ATD study of Delgado and colleagues:[14]

She began to cry inconsolably and described her emotions as being 'out of control.' She said that she did not know why she was crying but could not stop. She also described psychic anxiety, difficulty concentrating, loss of energy, loss of self-confidence, and a sense that nothing was worthwhile. She felt as if all the gains she had made over the past few weeks had 'evaporated.'"​

 

[Cirion]

So I think this probably may have been answered already. But if I want to use essentially the amino acid full replacement strategy (IE, zero consumption of animal products). What would I need to supplement to avoid long-term deficiencies and in what dosages?

Like, B12 being a common one that will be low on a zero animal product diet.

 

[LiveWire]

I find this whole thread a bit ridiculous. Why not just have a cup of nonfat cottage cheese, instead of trying to imitate food with these powders cooked in some Chinese basements out of god knows what?

It’s more expensive than actual food, it tastes disgusting, quality has to be assumed to be abysmal, contamination has to be assumed to be substantial, its effects and even just the body’s ability to even recognize it as actual aminos is questionable at best, ratios and compositions are arbitrary and just pulled out of someone’s ****...so why do it?

Aaah wait...it’s for people with ‘poor digestion’. Well, aside from the fact that almost none of the posters seem to have mentioned anything about poor digestion, even if it was the case, yes, what a way to fix it!

I’m not dismissing AA supplementation as such. A little glycine or taurine here and there on top of actual food, as non Peaty as it is, why not.

But most of this thread is about replacing food with this garbage...I can’t believe I’m in Ray Peat Forum. Someone tell me this is just a parody thread.

 

[LiveWire]

So I think this probably may have been answered already. But if I want to use essentially the amino acid full replacement strategy (IE, zero consumption of animal products). What would I need to supplement to avoid long-term deficiencies and in what dosages?

Like, B12 being a common one that will be low on a zero animal product diet.

Pea or soy protein. Don’t like it? Eat animal products.

 

[Amazoniac]

Humans likely do not need more than 2mg/kg methionine daily. Anything more than that is excess. I don't think all excess is degraded but even if the extra is simply converted to more SAM-E and cysteine that's probably not desirable. Most people consume WAY more than 2mg/kg methionine daily.
The Impact of Dietary Methionine Restriction on Biomarkers of Metabolic Health
"...Calorie restriction without malnutrition, commonly referred to as dietary restriction (DR), results in a well-documented extension of life span. DR also produces significant, long-lasting improvements in biomarkers of metabolic health that begin to accrue soon after its introduction. The improvements are attributable in part to the effects of DR on energy balance, which limit fat accumulation through reduction in energy intake. Accumulation of excess body fat occurs when energy intake chronically exceeds the energy costs for growth and maintenance of existing tissue. The resulting obesity promotes the development of insulin resistance, disordered lipid metabolism, and increased expression of inflammatory markers in peripheral tissues. The link between the life-extending effects of DR and adiposity is the subject of an ongoing debate, but it is clear that decreased fat accumulation improves insulin sensitivity and produces beneficial effects on overall metabolic health. Over the last 20 years, dietary methionine restriction (MR) has emerged as a promising DR mimetic because it produces a comparable extension in life span, but surprisingly, does not require food restriction. Dietary MR also reduces adiposity but does so through a paradoxical increase in both energy intake and expenditure. The increase in energy expenditure fully compensates for increased energy intake and effectively limits fat deposition. Perhaps more importantly, the diet increases metabolic flexibility and overall insulin sensitivity and improves lipid metabolism while decreasing systemic inflammation. In this chapter, we describe recent advances in our understanding of the mechanisms and effects of dietary MR and discuss the remaining obstacles to implementing MR as a treatment for metabolic disease."
Methionine-Restriction Diet (MRD) in Obese Adults With Metabolic Syndrome - Full Text View - ClinicalTrials.gov

Guru, I went for a more careful read of your previous classes on this minimum requirement. Here's one of the publications that thou post'd:

- Dietary Methionine Restriction Increases Fat Oxidation in Obese Adults with Metabolic Syndrome

It's interesting. Hopefully divine forces draw Daniel Wich here for him to opine about the 'plasma methionid' test.

Anyway, your experiment led me to everything that follows..


From what I understand, below they used a method that judges sufficiency by enough protein synthesis when the required amino acids are present. If there are missing ones, those that is in excess will disposed by burning them for energy. They pick phenylalanine for this purpose and radiolabel a part of it to detect its excretion (that should've been incorported instead).

- Total sulfur amino acid requirement in young men as determined by indicator amino acid oxidation with l-[1-13C]phenylalanine

"Total sulfur amino acids (SAAs) are the first limiting amino acids in several foods (9); therefore, knowledge of the mean requirement and population-safe intake of SAAs is important for making recommendations about protein and amino acid intakes in humans."

"[..]because nitrogen balance tends to underestimate nitrogen losses and is influenced by excess energy intake, amino acid requirements are susceptible to underestimation (12–16)."

"The first published estimates of total SAA requirements were based on the nitrogen balances of 6 men (11). The current population-safe intake of SAAs for adults recommended by the FAO/WHO/UNU is 13 mg·kg−1·d−1 (10), which is based on the highest estimated individual requirement to achieve positive nitrogen balance in studies carried out by Rose et al (11) in men and by Reynolds et al (36) in women. Human nutrient requirements, except for energy, are set according to a statistical model that uses the mean requirement plus 2 SDs to determine a population-safe intake for a given nutrient (37). In nitrogen balance studies used to estimate total SAA requirements, one can easily calculate a mean requirement and an SD because individual data are provided for each of the 6 subjects in the original paper by Rose et al (11). When we recalculated this nitrogen balance data, we found a mean requirement of 13.2 mg·kg−1·d−1. To this new mean, we added 2 times the SD to arrive at an estimated population-safe total SAA intake of 18 mg·kg−1·d−1. This value is similar to the population-safe intake found in the present study (21 mg·kg−1·d−1) and is consistent with the 24-h balance estimates discussed below (17,38)."

"Given the complexity of SAA metabolism, estimating total SAA requirements by direct oxidation tracer methods is extremely difficult. This is because the carboxyl carbon of methionine is not directly lost to the bicarbonate pool, nor is it irreversibly oxidized to carbon dioxide during degradation; a condition that must be met for the principles of direct oxidation to apply (15). However, Young et al (17) suggested that the current FAO/WHO/UNU population-safe SAA intake of 13 mg·kg−1·d−1 is too low on the basis of 24-h balance studies using l-[methyl-2H3,1-13C]methionine as a tracer. In that study, 5 men were fed 13 mg SAAs·kg−1·d−1 and tracer oxidation was monitored over 24 h. Although all of the subjects did not achieve balance at that intake, some subjects were close enough to zero balance for the authors to conclude that the true mean total SAA requirement was not much different from the FAO/WHO/UNU population-safe intake (17). The authors also suggested that for all subjects to achieve methionine balance, the population-safe intake should be set at ≈25 mg·kg−1·d−1. These results were confirmed in a later study (38)."

"IAAO is an independent method of estimating indispensable amino acid requirements in humans. Since its first applications in humans (23), IAAO has evolved into a relatively noninvasive and efficient means of elucidating the indispensable amino acid needs of children and adults (26,28). The technique monitors the oxidation of an independent, indispensable indicator amino acid in response to graded intakes of an indispensable test amino acid. As the intake of the test amino acid approaches its requirement, the oxidation of the indicator decreases such that further increments in the test amino acid will have no effect on the oxidation of the indicator amino acid (25)."

"In the present study, we found a mean total SAA requirement of 12.6 mg·kg−1·d−1, with a population-safe intake of 21.0 mg·kg−1·d−1. This latter amount is 60% greater than the current recommended total SAA requirement of 13.0 mg·kg−1·d−1 (10). Both the mean and safe IAAO-determined values agree with values predicted from 24-h balance data (17,38) and values recalculated from early nitrogen balance data (11). We conclude that 12.6 mg·kg−1·d−1 is a reasonable estimate of the average SAA requirement (37,40). Setting a dietary reference intake for total SAAs will depend on the analysis of more individual data, which may modify our current estimated population requirement of 21 mg·kg−1·d−1."

"Ensuring adequate B-vitamin nutriture when attempting to study SAA metabolism is of the utmost importance."

"Each subject randomly received each of 6 dietary methionine intakes: 0, 6.5, 13.0, 19.5, 26.0, and 32.0 mg·kg−1·d−1. Each study consisted of a 2-d adaptation period to a prescribed diet. The diet provided 1.0 g protein·kg−1·d−1 and was followed by a single study day on which phenylalanine kinetics were measured with the use of l-[1-13C]phenylalanine at 1 of the 6 dietary methionine intakes and a crystalline amino acid intake of 1.0 g·kg−1·d−1. The dietary study periods were separated by ≥1 wk; all subjects completed all 6 studies within 3 mo."

There's a cavern by them that it's possible for others needs to not be met in spite of the adequate protein synthesis, but the experiment was on requirements for methionine dispensing the need for cysteine. When cysteine is not present, the mean minimum requirement of these pimps was about 12.5 mg/kg/d, and more (21 mg/kg/d) if they was to cover most people (just like it happens when you have to generalize recommendations for a larger population). If both are present, needs should be reduced.

The next publication is the 2 mg/kg/d experiment that seems to be the source of your suggestion. It was on people dealing with cancre and the restriction was a form of starvation where tumors are more impacted than the person, and this should have an overall positive effect.

- Nutrient Intake and Nutritional Indexes in Adults With Metastatic Cancer on a Phase I Clinical Trial of Dietary Methionine Restriction

"Although [methionine's regenerating] enzymes [dependent on folate/cobalamin and betaine] are functional in some tumors (4), most tumors are dependent on exogenous, preformed methionine and, therefore, fail to grow, even in the presence of homocysteine (5–8)."

"The selective antitumor activity of methionine restriction is not due to an absolute difference between benign and malignant tissues, because neither can survive for long in the complete absence of methionine. Rather, tumors are more sensitive than normal tissues to methionine restriction; just as many tumors are more sensitive to chemotherapy and radiation therapy. In contrast, restriction of other essential amino acids is either very toxic or ineffective (19). Methionine restriction, therefore, does not represent indiscriminate 'starvation.'"

"The protocol for implementing the dietary methionine restriction was modified over the course of the study to develop a dietary pattern that could best be used by free-living cancer patients. All patients were placed on Hominex-2 Amino Acid-Modified Medical Food (Ross Products Division, Abbott Laboratories, Columbus, OH), which is approved for treatment of patients with homocystinuria (Table 2). Hominex-2 contains essentially no methionine (Table 3). The quantity of Hominex-2 consumed daily by each patient was calculated to provide 0.6–0.8 g protein/kg body wt. Hominex-2 dose and energy intake were maintained at baseline levels throughout participation, rather than reduced as patients lost weight. Hominex-2 served as the primary dietary protein source for all patients."

Spoiler

"Weight loss was the only side effect of the diet, and all but one patient regained weight on resumption of a normal diet. The only patient who failed to regain weight after discontinuing the study had cancer cachexia related to pancreatic adenocarcinoma even before his enrollment. Plasma methionine levels and food records indicated that patients adhered to the diet."

"After observing weight loss in Patients 1–4, we refined the diet to provide increased energy and protein intake. Nonetheless, Patients 5–8, who maintained energy intakes considerably above baseline and protein intakes above the RDA, still lost weight at the same rate as Patients 1–4. One possible explanation for this observation is that 35 kcal/kg/ day, which was consumed by Patients 5–8, was still inadequate to maintain positive nitrogen balance. This possibility is supported by early studies showing that energy requirements are considerably higher for patients whose sole nitrogen source consists of purified amino acids than for those who consume intact proteins (21)."

"Alternatively, weight loss experienced by patients in the trial may have been independent of energy intake but, rather, attributable to 'obligatory' muscle catabolism related to methionine restriction per se. A recent study designed to quantify dietary methionine requirements in normal subjects sheds light on this issue (22). In that study, stable isotope methods were used to measure obligatory methionine oxidation in normal subjects on a diet completely devoid of sulfur amino acids (methionine and cysteine) for 5 days. Although somewhat controversial (23), obligatory oxidation rates are considered by many to represent the minimum requirement for amino acids, that is, the amount that is oxidized despite maximal body conservation. The obligatory oxidative loss of methionine was 13 mg/kg/day in that study (22). Patients in our trial, who were restricted to 2 mg methionine/kg/day, therefore, consumed 11 mg/kg/day less than the minimum requirement. However, they consumed adequate amounts of cysteine, which is present in Hominex-2. They therefore may have had obligatory methionine oxidation rates 13 mg/kg/day. The fact that all patients reversibly lost weight, despite what would normally be considered adequate energy and protein intake, may actually be encouraging, since it confirms that patients adhered to the diet. The basic premise of this strategy is that dietary methionine restriction will have a greater deleterious effect on tumors than on normal host tissues."​

It wasn't low in cysteine. You'll find various other experiments that require methionine restriction using that product (Hominex-2 by Abbott), and its composition makes up for the lowered methionine content. It's the opposite of casein, that happens to be high in methionine and low in cysteine. Check this out:

Therefore I don't think it's a reliable reference for minimum requirements.

Regarding this sparing effect..

- Dietary cysteine reduces the methionine requirement in men

"The current FAO/WHO/UNU population-safe intake of total sulfur amino acids (SAAs) in healthy adults, based on early nitrogen balance studies (1–3), is 13 mg·kg−1·d−1 (4). We previously reported that this value is 60% lower than the population-safe intake found in a study of men by indicator amino acid oxidation (IAAO) (5[↑↑]). Using l-[1-13C]phenylalanine as an indicator, we found that the mean methionine requirement of 6 men in the absence of dietary cysteine was 12.6 mg·kg−1·d−1 and the upper limit of the 95% CI of this mean, which is an estimate of the population-safe intake, was 21 mg·kg−1·d−1 (5). Recent studies of SAA kinetics in humans confirmed, with the use of labeled methionine tracers (6,7), that the current FAO/WHO/UNU recommendations for total SAA intake (4) are too low. In addition, using individual data provided in the early nitrogen balance study by Rose et al (1), we recalculated the mean and population-safe intake of total SAAs to be 13.2 and 18 mg·kg−1·d−1, respectively. Both of these recalculated values are similar to those found in our previous IAAO study (5) and further confirm that the population-safe intake of SAA is greater than the published FAO/WHO/UNU value of 13 mg·kg−1·d−1 (4)."

"The ability of cysteine to reduce the quantitative requirement for methionine in humans was reported in early studies (2,8–10). In contrast, a more recent series of reports on methionine kinetics using methionine and cysteine tracers suggests that cysteine has no sparing effect on methionine requirements in humans (7,11–15). However, the failure to detect a sparing effect in these recent experiments may have resulted from the investigators unknowingly supplying inadequate dietary SAA intakes. The test diets adopted in these kinetic studies were based on the FAO/WHO/UNU estimates, which we (5) and others (6,7) maintain are too low. To detect a cysteine sparing effect on methionine requirements, cysteine must be present in amounts adequate to completely, or largely, arrest the flow of metabolites through the transsulfuration pathway, whereas methionine must be present in amounts adequate to meet all its other metabolic functions, including protein synthesis, transmethylation, and the provision of homocysteine for remethylation reactions necessary for folate and betaine metabolism. Unless the total SAA needs of all subjects are met, addition of cysteine to the diet will lead to an immeasurably small sparing effect on methionine requirements (13,14)."

"Each subject randomly received each of 6 dietary methionine intakes: 0, 2.5, 5.0, 7.5, 10.0, and 13.0 mg·kg−1·d−1. Dietary cysteine was held constant at an intake of 21 mg·kg−1·d−1. Each study consisted of a 2-d adaptation period to a prescribed diet (17). The diet provided 1.0 g protein·kg−1·d−1 and was followed by a single study day on which phenylalanine kinetics were measured with the use of l-[1-13C]phenylalanine at 1 of the 6 dietary methionine intakes and a protein intake of 1.0 g·kg−1·d−1. The study dietary periods were separated by ≥1 wk; all subjects completed all 6 studies within 3 mo."

"In the current experiment we found a mean methionine requirement of 4.5 mg·kg−1·d−1 and a population-safe intake of 10.1 mg·kg−1·d−1 when cysteine was fed at an excess of 21 mg·kg−1·d−1."

Less methionine to reach the breakpoint this time, so needs are reduced and lower amounts are enough to prevent other amino acids from being wasted.

"The evidence in support of cysteine having a sparing effect on methionine requirements in humans and animals is substantial. As early as 1941, Womack and Rose (8) showed a 17% sparing effect of cysteine on methionine requirements in rats when growth rates were used as an indicator. Shortly thereafter, a series of nitrogen balance studies in men and women showed a sparing effect ranging from 48% to 89% (2,9,10). In addition to these studies, subsequent studies showed that dietary cysteine suppresses transsulfuration in rats (26,27) and humans (11), thus providing a metabolic basis for the sparing effect of cysteine on methionine requirements."

"The available evidence indicates that the sparing effect of cysteine is based on a repartitioning of homocysteine between competing pathways. Although no change appears to occur in the rate of homocysteine remethylation to methionine by either of the available remethylation pathways (11,26,27), there is a clear reduction in the rate of transsulfuration. The net result is that the fractional remethylation of homocysteine increases while that portion metabolized by transsulfuration decreases."​

The protein consumption in these experiments wasn't extreme, around the 0.8 g/kg/d standard recommendation and up to 1 g. I'm mentioning this because I was wondering if it wasn't a matter of having shoved down amino acids on these guys and increasing their requirement for methionid along.

There were subjects needing more or less but the mean value was 4.5 mg/kg/d conditioned to the higher cysteine intake. I'm not aware of foods being able to provide this much cysteine without methionine.

It seems to me that the 2 mg/kg/d value is too low even for cultures that eat little animal protein, are skinny and small, simpler lives, no stimulants, low calories, and so on; all supportive for reducing the need for it. According to such figure, a person weighing 55 kg would require at least 110 mg, but they certainly obtain this from diet, possibly more than double, making it difficult to judge how low you can go without issues.

Contrary to that, liver challenges, military stress, generalized malnutrition making the person unable to compensate for the lack of methionine, wasting, etc, should all increase the requirements above normal.

I'm sure you remember the quotes below, they mention the accumulation, yet in some cases still find it useful to give more.

- Treatment Of Cirrhosis Of The Liver By A Nutritious Diet And Supplements Rich In Vitamin B Complex

"although the choline and methionine content in the cirrhotic liver may be normal or actually higher than normal,[8a] these factors are not available for utilization"

"Experimental studies demonstrated that an inadequate level of methionine cannot be compensated for by excessive levels of choline and cystine.[10] It was further demonstrated that when methionine was added to choline in experimental hepatic damage and growth, a 50 per cent improvement in therapeutic results occurred.[10,15] The damaged liver thus appears to have lost its transmethylation ability and requires both synthetic methionine and choline until normal transmethylation can take place from the ingested food."

"It has been suggested that the lipotropic agent methionine could enhance in a synergistic way the lipotropic (or fatty-cirrhosis-preventing) activity of choline.[7] Animal experiments revealed further that in hepatic damage choline would largely prevent the cirrhosis but not the necrosis and hemorrhage. Methionine was found to effectively prevent both types of damage to the liver. Experimental studies also showed that the cirrhotic symptoms due to choline deficiency result from lack of a methyl-containing essential other than choline and that methionine can directly supply this lack.[8] It is now apparent that although diets may contain an adequate supply of choline, an imbalance or deficiency of other dietary constituents can nullify the lipotropic action of the choline.[9]"

"The high protein diet which I prescribed consisted not only of a high casein source of proteins by the use of skimmed milk feedings and cottage cheese but also of servings of meat three times a day wherever possible. The importance of a high protein diet in cirrhosis of the liver is now thoroughly established[13] and takes precedence over dietary carbohydrate in therapeutic importance. The maximum use of meat in this diet appeared to be advisable because of the necessity for providing the essential amino acids which contain the basic methyl groups, with and without the sulfur radical. These methyl groups are required by the liver for the transmethylation function which institutes regeneration and healing in cirrhosis. As has previously been stated, cirrhosis of the liver when produced experimentally is now regarded as a methyl-group deficiency disease."

"Second, in a controlled series of 62 patients over an eight year period,[11] therapeutic results suggested that the combination of methionine and choline resulted in a better therapeutic response than did various other combinations of amino acids, diet, liver and vitamin supplements in the treatment of hepatic cirrhosis. Methionine was taken orally in capsule form, the dosage being 2 Gm. daily. Similarly, choline chloride was administered orally in a daily dosage of 2 Gm.[10d]"​

- Protective CO2 and aging

"The age accelerating effect of methionine might be related to disturbing the methylation balance, inappropriately suppressing cellular activity."​

Collagen should buffer it and avoid the inappropriate effect. Those researchers mentioned gelatin in their articles, they've considered it (and some used it). To me it doesn't look like increasing everything but methionine and choline would lead to better outcomes. Do you think that they would had fared better if these were cut to the minimum consistently? When do you think that more is desirable?

If anything, it's the uncompensated prolonged restriction that is concerning the most:

- Treatment Of Cirrhosis Of The Liver By A Nutritious Diet And Supplements Rich In Vitamin B Complex

"Interestingly, in contrast to pure methionine restriction, combined methionine and choline restriction have prooxidant, proinflammatory effects in the liver [92,93] and may even promote the development of liver cirrhosis [94] and hepatocellular carcinoma [95]. Methionine- and choline-deficient (MCD) diet in mice also induces liver steatosis and may be used as a suitable model for investigation of the pathophysiological mechanisms of NAFLD [96]. In 2 weeks MCD diet induces focal microvesicular liver steatosis, while in 6 weeks inflammation accompanies diffuse micro- to macrovesicular steatosis with increased serum level of C-reactive protein [93]. These changes are associated with increased levels of malondialdehyde and nitrites+nitrates and reduced GSH level, thus indicating that MCD diet causes oxidative and nitrosative stress in the liver. Additionally, the antioxidative capacity of the liver was found to be decreased by MCD diet due to the reduction of superoxide dismutase and catalase activities, the reduction being the most extensive after 4 week-treatment with MCD diet [93]. Lack of methionine and choline in the diet was also found to cause alterations in free fatty acid profile in the liver [92]. Within 2 weeks it causes a decline in palmitic, stearic, arachidonic and docosahexaenoic acid (DHA). The significance of this finding should be further investigated, but a decrease in DHA level may at least partially contribute to the proinflammatory effect of MCD diet on the liver [92]. All of these changes are dominantly caused by choline deficiency. However, although choline deficiency is sufficient for the development of steatosis, both methionine and choline deficiency are essential for the development of inflammation in the liver [97]. These findings clearly indicate, that adequate intake of micronutrients according to daily requirements is a prerequisite for beneficial effects of dietary methionine restriction on metabolic processes and function of the liver."​

 

[Amazoniac]

Something occurred to me.

In the 'Dietary cysteine reduces the methionine requirement in men' experiment, it was 21 mg/kg/d of cysteine, so about 1.5 g cysteine a day. Whereas in the cancre experiment..

"By consuming four to five shakes per day, patients met 100% of their protein requirements (0.8 g protein/kg) and ~75% of their energy requirements. Regular food was then used to provide up to 2 mg methionine/kg/day as well as the remaining energy needs. After the reformulation of the beverage, patients were able to consume up to 35 kcal/ kg/day.

Methionine is present in most foods as an integral component of dietary protein. After the reformulation of Hominex-2 beverages, dietary methionine exchange lists were developed that allowed patients to select and consume a variety of foods up to their targeted dietary methionine level. Patients could choose small portions of dietary starches (e.g., cereals, potatoes, breads, crackers, canned soups, cookies) and ample portions of fruits and vegetables. Use of protein-free beverages, candies, ices, margarines, and cooking oils served to boost energy intake into target ranges. Patients were counseled not to eat any foods containing animal protein, which is rich in methionine."​

.. it was 0.9% of (for example) 56 g of protein/d, so 0.5 g + what diet provided. This had no marked sparing effect according to what the guys mention'd.
I have no idea how they were able to keep methionine (and so cysteine) intake as low as 2 mg/kg/d if ample portions of fruits and vegetables were allowed. Just one small serving of spinach, 2 cups of orange juice and an apple already provide you that.