Amino-Acid Nutrition

Abstract

The twenty proteinogenic amino acids are not interchangeable nutrients. Nine are indispensable in healthy adults; several more become conditionally indispensable in growth, pregnancy, or catabolic illness; the remainder can be made from other carbon skeletons if nitrogen is available. After a meal, a large and amino-acid-specific fraction is extracted by the splanchnic bed before any peripheral tissue sees it. What remains is used for protein synthesis, transaminated, oxidised, or converted to urea. Those fates are regulated by energy status, protein status, and amino-acid sensing systems of which mTORC1 is the most discussed and the most over-read.

Human indispensable-amino-acid requirements were first estimated by nitrogen balance and later re-estimated by indicator amino-acid oxidation. The two methods do not always agree, and neither is a hypertrophy prescription. Protein quality scores — PDCAAS and DIAAS — rank foods by digestible indispensable amino acids; they do not rank supplements. Isolated leucine and branched-chain amino acids can raise acute MPS when other indispensable amino acids are present and the subject is not already protein-replete; they have not been shown, in adequately protein-controlled human trials, to be a reliable route to long-term muscle gain. Methionine restriction extends life in rodents. That finding has not been converted into a human longevity intervention. Glutamine is a major fuel of the gut and immune cells; high-dose glutamine in the critically ill produced harm in a large randomised trial. The recurring error is mechanistic extrapolation: from a kinase, a rodent cage, or a four-hour tracer infusion to a year of human outcome.

Every proteinogenic amino acid is an α-amino carboxylic acid. At physiological pH the molecule is a zwitterion: the carboxyl is deprotonated, the α-amino group is protonated, and the side chain decides almost everything else — size, charge, polarity, sulphur, aromaticity, and whether the carbon skeleton can be made in human tissues. Nutrition inherits that chemistry. It does not get to treat “amino acids” as a single substrate any more than organic chemistry treats “side chains” as a single functional group.

Nineteen of the twenty proteinogenic amino acids are chiral at the α-carbon; glycine is not. Human proteins are built from the L-enantiomers. D-amino acids occur in bacterial cell walls and in a few mammalian free pools; they are not a dietary protein-quality problem in ordinary food. What is a dietary problem is the side-chain inventory. Lysine and threonine have no safe transamination escape in humans. The branched-chain amino acids — leucine, isoleucine, valine — share the mitochondrial branched-chain aminotransferase and the branched-chain keto-acid dehydrogenase complex, so they compete with one another for the same first steps (Harper et al., 1984). The aromatic amino acids share transport systems with one another and with large neutral amino acids at the blood–brain barrier, which is why tryptophan availability is not just a protein-intake question (Fernstrom and Wurtman, 1971; Fernstrom, 2013).

Taurine is often sold beside amino-acid supplements and is therefore inside the scope of this article. It is not a proteinogenic amino acid. It is a β-amino sulfonic acid made from cysteine, concentrated in heart, retina, and bile-acid conjugation, and it does not enter peptide bonds. Classifying it with leucine is a retail convenience, not a metabolic one.

02 Essential, nonessential, conditionally essential

William Rose’s human depletion experiments in the 1940s and 1950s established the adult indispensable set by removing one amino acid at a time and watching nitrogen balance and clinical signs (Rose, 1957). The modern list for healthy adults is histidine, isoleucine, leucine, lysine, methionine, phenylalanine, threonine, tryptophan, and valine. Histidine was the late admission: short nitrogen-balance studies missed a need that longer depletion made visible. That history is the first warning in this article. A method can be internally consistent and still be wrong about a requirement if the observation window is too short.

“Nonessential” is a laboratory word, not a biological one. Alanine, glutamate, and aspartate sit at the centre of nitrogen traffic. The organism can make them; it cannot do without them. The useful distinction is whether the carbon skeleton must be supplied preformed. Even that distinction moves. Arginine is dispensable in healthy adults because the urea cycle can release it, and conditionally indispensable in infants and in some catabolic states because synthesis does not keep up (Wu and Morris, 1998). Cysteine becomes indispensable if methionine is short, because trans-sulphuration is the human route. Tyrosine becomes indispensable if phenylalanine hydroxylase is absent or if phenylalanine intake is too low. Glutamine demand rises in trauma, burns, and critical illness; whether that rise creates a dietary requirement is a clinical question, not a slogan, and it is taken up in Part Five.

Glycine is abundant in collagen and in one-carbon metabolism. Endogenous synthesis is large. Whether it is large enough in ageing or methionine-loaded diets is an open quantitative question, not a settled longevity claim (Meléndez-Hevia and de Paz-Lugo, 2008; McCarty et al., 2018). The article treats that claim as plausible mechanism, unverified human outcome.

03 Nitrogen, pools, and why protein is a rate

The adult body does not store protein the way it stores triglyceride. The free amino-acid pool is small relative to protein-bound amino acids. Whole-body protein turnover in healthy adults is on the order of several hundred grams per day — several times typical dietary protein intake (Waterlow, 2006; Young and Pellett, 1987). The diet therefore tops up a flux, it does not fill a tank. When intake falls, the organism reduces synthesis and, depending on energy and stress hormones, increases breakdown. Nitrogen appears in urea, ammonia, creatinine, and miscellaneous losses. Nitrogen balance is the difference between intake and those measured outputs. It is a necessary idea and a treacherous assay.

The free pools are compartmented. Plasma concentrations are not tissue concentrations. Muscle free glutamine is high; plasma glutamine is not a simple readout of muscle. The splanchnic bed sees portal concentrations that peripheral tissues never see. Branched-chain amino acids escape the liver more than most other amino acids because hepatic branched-chain aminotransferase activity is low; muscle and fat do the first transamination (Harper et al., 1984). That is why a post-prandial rise in plasma BCAA is a real physiological event and why it has been over-interpreted as a signal that BCAA supplements are uniquely anabolic.

Dietary protein is hydrolysed, not absorbed intact in nutritionally relevant amounts. Gastric pepsin opens the structure; pancreatic trypsin, chymotrypsin, elastase, and carboxypeptidases produce oligopeptides; brush-border peptidases finish the job. The enterocyte takes up a mixture of free amino acids and di- and tripeptides. The proton-coupled peptide transporter PEPT1 carries a large fraction of absorbed amino nitrogen as small peptides (Adibi, 1997; Daniel, 2004). That fact matters for scoring: a food’s ileal digestibility is not the same as the appearance of free amino acids in peripheral blood, and a free-amino-acid supplement skips a transport path that meals use.

Absorption is not completion. The enterocyte itself is a major consumer. Glutamate, glutamine, and aspartate are oxidised as fuels of the gut; little of a protein meal’s glutamate reaches the portal vein as glutamate (Reeds et al., 2000; Stoll and Burrin, 2006). Animal work in piglets, which is the best quantitative map of first-pass use, shows extensive extraction of several indispensable amino acids by the portal-drained viscera before the liver is even reached. Human tracer studies are fewer and more constrained, but they agree on the qualitative point: the periphery does not see the meal the plate described (Biolo et al., 1992; Matthews et al., 1993).

05 First-pass splanchnic metabolism

First-pass splanchnic extraction is amino-acid specific. Branched-chain amino acids are extracted less by liver than most other amino acids; phenylalanine, methionine, and the small polar amino acids are extracted more. A human meal therefore delivers a BCAA-enriched signal to muscle relative to the food’s amino-acid profile. That is physiology, not a rationale for removing the other indispensable amino acids from the diet and selling them back as capsules.

The same first-pass step is why free arginine and free glutamine do not behave like arginine or glutamine in food. Oral arginine is taken up and metabolised by gut and liver; oral citrulline bypasses much of that extraction and can raise plasma arginine more efficiently in human pharmacokinetic studies (Schwedhelm et al., 2008). Oral glutamine is a gut fuel first. Plasma increments after a glutamine drink are not proof of a systemic anabolic effect. These are human observations about appearance, not outcome trials.

06 Liver, transamination, deamination, the urea cycle, oxidation

Once inside a cell, most amino acids can donate their nitrogen by transamination to α-ketoglutarate, making glutamate, which can then be oxidatively deaminated by glutamate dehydrogenase. The carbon skeletons enter glycolysis, the citrate cycle, or ketone and glucose production. The nitrogen that is not reused becomes urea in periportal hepatocytes through the urea cycle first described by Krebs and Henseleit. Human inborn errors of that cycle are the clinical proof that it is not optional. In ordinary nutrition the cycle is a disposal route: when amino acids are supplied in excess of synthetic need, or when energy is short and protein is used as fuel, urea production rises (Jungas et al., 1992; Morris, 2002).

Oxidation is the irreversible loss. Indicator amino-acid oxidation (IAAO) uses that irreversibility as a measurement: when the test amino acid is below requirement, the indicator (often ¹³C-phenylalanine) is oxidised; when the test amino acid meets need, the indicator is spared for protein synthesis (Elango et al., 2008; Pencharz and Ball, 2003). The method is now the main competitor to nitrogen balance for indispensable-amino-acid requirements. It is not a muscle-building assay. It estimates the intake at which whole-body oxidative disposal of an indicator stops falling.

07 Sensing: mTORC1, leucine, and the limits of a kinase story

Cells sense amino acids. The most studied pathway is mTORC1. In cultured mammalian cells, leucine is a particularly strong activator; Sestrin2 is a leucine-binding inhibitor of GATOR2, and leucine relieves that inhibition so mTORC1 can move to the lysosome and become active (Wolfson et al., 2016; Saxton et al., 2016; Saxton and Sabatini, 2017). Methionine, arginine, and other amino acids have their own sensors. This is established in vitro and in animals. It is not a human hypertrophy programme.

Human muscle biopsies after protein or leucine drinks show phosphorylation of mTORC1 substrates and a rise in myofibrillar FSR (Atherton et al., 2010; Dickinson et al., 2011). Those measurements last hours. Resistance-training hypertrophy is measured in weeks and months and requires a full complement of indispensable amino acids, mechanical tension, and energy. Acute MPS can rise without a later difference in fibre area or lean mass. Reviews that treat every mTOR blot as a clinical recommendation are doing the work this article exists to refuse.

Ageing complicates the story without simplifying it. Older human muscle often shows a smaller MPS response to a low protein dose and a more intact response when the dose, or its leucine content, is raised (Cuthbertson et al., 2005; Katsanos et al., 2006; Wall et al., 2015). That is anabolic resistance as an acute tracer phenomenon. Whether it is the main cause of sarcopenia, and whether leucine supplements reverse years of loss, are separate questions. The first is strongly supported as a description of acute physiology. The second is not established.

08 Skeletal muscle: synthesis, breakdown, turnover

Muscle protein mass is the difference between MPS and muscle protein breakdown (MPB). Both run continuously. Feeding suppresses MPB and raises MPS; fasting and disuse do the reverse (Biolo et al., 1995; Phillips et al., 1997; Tipton et al., 1999). Tracer methods that report only MPS can miss a change in net balance driven by MPB. Exercise, especially resistance exercise, sensitises muscle to amino acids for a period of hours (Biolo et al., 1997; Tipton and Wolfe, 2001). That is the physiological basis of the “anabolic window.” The window in trained humans is wide, not a thirty-minute door (Schoenfeld and Aragon, 2018).

The most important methodological warning in this part is simple. A four-hour infusion after a drink is not a twelve-week training study. Mitchell and colleagues, and later reviews, have shown that acute MPS differences do not reliably rank hypertrophy outcomes (Mitchell et al., 2014; Damas et al., 2015). This article will keep repeating that sentence until the last controversy is closed.

Nitrogen balance looks like bookkeeping. Intake minus output should equal zero in a healthy adult who is neither growing nor wasting. The method built the twentieth-century protein and amino-acid requirement tables (Rose, 1957; Rand et al., 2003). It is still cited as if it were a gold standard. It is not.

Unmeasured losses — sweat, hair, skin, miscellaneous nitrogen — are estimated, not fully collected. Adaptation to a low intake can restore balance at a new, lower lean-mass set point. Short studies miss slow depletion, as they did for histidine. Positive balance in a growing child is required; zero balance in an older adult who is already sarcopenic is not a success. Young and colleagues, and later Millward, argued for years about whether nitrogen-balance estimates were too low (Young and Marchini, 1990; Millward, 1998). The argument was not pedantry. It decided official numbers that still sit in policy documents.

IAAO and 24-hour indicator-oxidation protocols were developed in part because of those defects (Pencharz and Ball, 2003; Elango et al., 2008, 2012). They tend to give higher indispensable-amino-acid estimates than classical nitrogen balance. They are still whole-body methods. They do not tell a clinician how much protein an 80-year-old needs to recover gait speed, and they do not tell a coach how much leucine to put in a shaker.

10 Indispensable amino-acid requirements

The WHO/FAO/UNU 2007 report remains the international reference for adult indispensable amino acids, expressed in milligrams per kilogram per day and as a pattern for scoring (WHO/FAO/UNU, 2007). The US/Canadian DRI for protein, 0.80 g·kg⁻¹·d⁻¹ for healthy adults, is an estimated average requirement plus a safety factor for protein as a whole, not a hypertrophy target (Institute of Medicine, 2005). EFSA later published its own dietary reference values (EFSA NDA Panel, 2012). These documents are established as policy references. They are not interchangeable with sports-nutrition position stands or geriatric consensus statements, which use different endpoints.

IAAO re-estimates for lysine, sulphur amino acids, and other indispensable amino acids have often exceeded the 2007 WHO numbers (Elango et al., 2012; Pillai and Kurpad, 2012). Pregnancy IAAO work suggests higher lysine and protein needs than non-pregnant adult values (Elango and Ball, 2016). Those studies are human, small, and method-specific. This article reports them as strongly supported method-dependent estimates, not as intake advice.

11 Scoring: PDCAAS, DIAAS, digestibility, limiting amino acids

A food can supply enough protein nitrogen and still be limited by one indispensable amino acid. The limiting amino acid is the one whose digestible supply, relative to the reference pattern, is lowest. In many cereals it is lysine; in many legumes it is methionine plus cysteine; in some diets it is lysine and the sulphur amino acids together. Complementary proteins are meals or daily patterns that cover each other’s gaps. That is a food-pattern idea. It is not a requirement to combine rice and beans in the same bite.

PDCAAS scores a food by faecal crude-protein digestibility times the limiting amino-acid score, and truncates values above 1.0 (Schaafsma, 2000; FAO/WHO, 1991). DIAAS uses ileal digestibility of individual indispensable amino acids and does not truncate, so high-quality animal proteins can score above 100% (FAO, 2013; Rutherfurd et al., 2015). Ileal digestibility is the better physiological number because colon microbes alter faecal amino-acid disappearance. Human ileal data are still thinner than pig data. Wolfe and colleagues have argued that DIAAS better reflects the value of high-quality proteins for humans (Wolfe et al., 2016). Plant proteins generally score lower, not because plants are “incomplete” in a mystical sense, but because digestibility and the limiting amino acid are often less favourable.

These scores compare foods. They do not compare leucine capsules to beef. A supplement that supplies one amino acid can raise a score on paper and still leave the other eight indispensable amino acids untouched.

12 Plant versus animal protein

Human acute MPS studies have repeatedly shown smaller myofibrillar FSR responses to some plant proteins than to matched-protein milk or whey, especially at moderate doses, with the gap narrowing when the plant dose is increased or the amino-acid profile is fortified (Tang et al., 2009; van Vliet et al., 2015; Gorissen et al., 2016; Pinckaers et al., 2021). That is strongly supported as an acute tracer finding. Long-term hypertrophy trials in vegans versus omnivores, when total protein and training are matched, are fewer. Hevia-Larraín and colleagues reported that a high-protein vegan diet could support similar lean-mass gains to an omnivorous diet in young men during resistance training (Hevia-Larraín et al., 2021). Adequacy is therefore a function of total protein, amino-acid pattern, digestibility, and energy — not a moral property of the food kingdom.

The popular claim that plant protein is inherently inadequate is false at the level of a well-planned diet. The popular claim that plant and animal proteins are interchangeable at the same gram weight for the same acute MPS response is also false at typical serving sizes. Both overstatements fail the same test: they drop the limiting amino acid and the digestibility correction.

13 Meal distribution and the leucine-threshold concept

Moore and colleagues described a saturable dose–response of myofibrillar FSR to ingested protein after resistance exercise in young men (Moore et al., 2009). Witard and others refined the curve (Witard et al., 2014). Older adults often need a larger protein dose, or more leucine in the dose, to reach a similar acute FSR (Katsanos et al., 2006; Moore et al., 2015). From these data came the “leucine threshold”: a per-meal leucine amount below which MPS is not fully switched on.

The concept is useful as a description of acute human tracer studies. It becomes a dogma when it is treated as a daily law. Mamerow and colleagues found, in a 7-day crossover in healthy adults, that even protein distribution produced higher 24-hour MPS than a skewed pattern at the same total protein (Mamerow et al., 2014). Areta and colleagues showed that 20 g of protein every three hours after exercise outperformed smaller pulses or two large boluses for myofibrillar FSR over 12 hours (Areta et al., 2013). Those are short studies. They do not prove that anyone who misses a leucine target at breakfast will lose muscle. They do argue against the idea that a single large protein meal can be assumed to do the whole day’s work.

The anabolic window after training is real as a period of heightened amino-acid sensitivity and overstated as a stopwatch (Schoenfeld and Aragon, 2018). Total daily protein, energy balance, and the training stimulus still dominate long-term trials (Morton et al., 2018).

Resistance exercise raises MPS and, for a time, MPB; feeding tilts the balance toward net gain (Biolo et al., 1997; Phillips et al., 1997). Endurance exercise oxidises amino acids, especially BCAA, as a minor but real fuel when glycogen is low (Rennie et al., 2006). Recovery protein in athletes is therefore a question about net muscle protein balance and about glycogen and energy, not about a unique amino-acid potion.

Morton and colleagues’ meta-analysis of protein supplementation during resistance training found a positive effect on fat-free mass and strength, with diminishing returns as total daily protein rose, and little additional benefit once intake was already high (Morton et al., 2018). The typical effective contrast was protein versus carbohydrate or lower protein, not leucine versus an isonitrogenous mixed protein. ISSN and related position stands summarise that literature as support for higher-than-RDA protein in athletes (Jäger et al., 2017). Those stands are secondary documents. They are not amino-acid-supplement trials.

When supplement studies fail to match total protein and energy, they cannot be read as evidence for a specific amino acid. That design flaw is common in BCAA and leucine papers and is one of the adversarial review attacks this article accepts as decisive.

15 Aging, anabolic resistance, sarcopenia

Sarcopenia is a clinical syndrome of low muscle mass, strength, and function (Cruz-Jentoft et al., 2010, 2019). Anabolic resistance is a physiological description: a smaller MPS response to a given protein or amino-acid dose in older than in younger adults (Cuthbertson et al., 2005; Wall et al., 2015). The two are related and not identical. A person can show anabolic resistance in a tracer study without meeting sarcopenia criteria. A person can be sarcopenic because of disuse, disease, and energy deficit even if a large protein dose still raises FSR.

PROT-AGE and ESPEN expert groups reviewed human data and recommended higher protein intakes for older adults than the adult RDA, especially in illness, with attention to per-meal protein and leucine-rich foods (Bauer et al., 2013; Deutz et al., 2014). Those documents are consensus, not randomised proof that a specific leucine supplement prevents disability. Human trials of leucine or essential-amino-acid mixtures in older adults show mixed effects on acute MPS and inconsistent effects on long-term lean mass and function when background diet is already adequate (Dillon et al., 2009; Verhoeven et al., 2009; Leenders et al., 2011). The honest summary is emerging for food-protein pattern in older adults; not established for isolated leucine as a sarcopenia drug.

Athlete data must not be generalised to older adults, and geriatric consensus must not be generalised to young athletes. The same 25-gram protein serving is a different physiological event in those two bodies.

16 Pregnancy, childhood, growth

Growth is positive nitrogen balance by definition. Fetal and infant indispensable-amino-acid needs include arginine and histidine in a way adult maintenance does not. Human milk and complementary foods are the ordinary vehicles. IAAO in pregnant women suggests higher lysine and protein requirements than non-pregnant adult values (Elango and Ball, 2016; Payne et al., 2018). Those studies are small human protocols. They are not prenatal supplement recipes.

Childhood protein-quality crises are still lysine and digestibility crises in cereal-based diets. That is a public-health fact with a long field history (Kurpad and Thomas, 2011). It is not evidence that healthy children in protein-sufficient households need amino-acid bottles.

17 Fasting and caloric restriction

In a fast, hepatic gluconeogenesis consumes amino-acid carbon, urea production rises, and muscle net balance goes negative (Cahill, 2006; Owen et al., 1998). The organism defends glucose and essential functions, not gym measurements. Protein-sparing during caloric restriction is improved when protein intake is kept high relative to energy and when resistance training is present (Pasiakos et al., 2013; Longland et al., 2016; Hector and Phillips, 2018). Those are human body-composition trials of dietary protein and training, not of isolated amino acids.

Caloric restriction and protein restriction are different interventions. Rodent life-extension has been reported with methionine restriction and with low-protein, high-carbohydrate diets (Orentreich et al., 1993; Miller et al., 2005; Solon-Biet et al., 2014). Human observational work linking high animal protein to IGF-1 and mortality in middle age is not a methionine-restriction trial (Levine et al., 2014). The leap from those papers to a human longevity protocol is the leap Part Five refuses.

18 Disease and catabolic states

Trauma, burns, sepsis, and cancer cachexia raise whole-body protein breakdown and change amino-acid demand (Wolfe, 2005; Biolo et al., 1997). Glutamine consumption by immune cells and gut mucosa rises. Whether extra glutamine helps is a trial question. In the REDOXS trial, Heyland and colleagues randomised critically ill adults with multiorgan failure to glutamine, antioxidants, both, or placebo; early glutamine was associated with increased mortality (Heyland et al., 2013). SIGNET did not show benefit of parenteral glutamine in a large ICU population (Andrews et al., 2011). Those human outcomes sit above a mountain of mechanistic plausibility. They are why this article will not treat glutamine as a general tonic.

Arginine is a precursor of nitric oxide and of urea-cycle intermediates. Immunonutrition cocktails that include arginine have mixed surgical and ICU results and are not reviewed here as a licence to dose arginine. Citrulline’s cleaner oral pharmacokinetics do not by themselves make it a clinical therapy (Schwedhelm et al., 2008; Cynober et al., 2013).

Leucine is an indispensable amino acid, a preferred mTORC1 ligand in cells, and a strong acute stimulus of human MPS when the other indispensable amino acids are available (Atherton et al., 2010; Churchward-Venne et al., 2012). Isolated BCAA supplements supply leucine, isoleucine, and valine and omit lysine, methionine, threonine, histidine, phenylalanine, and tryptophan. Wolfe’s review of that biochemistry is blunt: BCAA alone cannot make new muscle protein because the other indispensable amino acids are missing (Wolfe, 2017). Human trials that add BCAA on top of an already protein-sufficient diet often measure soreness, fatigue, or a few hours of FSR. They rarely measure hypertrophy against an isonitrogenous control. Meta-analyses of BCAA and exercise performance are mixed and frequently include studies that did not control total protein (Plotkin et al., 2021; Khemtong et al., 2021).

Leucine co-ingestion can raise the acute MPS response to a suboptimal protein dose in young and older adults (Churchward-Venne et al., 2014; Wall et al., 2013). That is a real human tracer finding. Long-term leucine supplementation in older men has failed to increase muscle mass or strength in randomised trials when the background diet was adequate (Verhoeven et al., 2009; Leenders et al., 2011). The red-team challenge holds: acute MPS was confused with hypertrophy; supplement studies were inadequately controlled for total protein; athletes were generalised to older adults and the reverse.

Circulating BCAA are also elevated in obesity and type 2 diabetes (Newgard et al., 2009; White and Newgard, 2019). Whether they are causal or a marker of impaired disposal is not settled in humans. They are not a reason to prescribe BCAA, and they are not, by themselves, a reason to forbid dietary protein.

20 Lysine, methionine, cysteine

Lysine is the limiting indispensable amino acid in many cereal diets. Human IAAO estimates of lysine requirement have been higher than some older nitrogen-balance values (Kurpad et al., 2003; Elango et al., 2012). Lysine fortification of cereals is a public-health intervention with a different evidence base from lysine capsules sold to protein-sufficient adults.

Methionine is indispensable, a methyl donor, and the precursor of cysteine via trans-sulphuration. Methionine restriction extends lifespan in rats and mice and improves some metabolic markers in rodents (Orentreich et al., 1993; Richie et al., 1994; Miller et al., 2005). Those are established animal findings. Human evidence is limited to short dietary studies and observational protein-pattern work. There is no randomised human demonstration that methionine restriction extends life or reduces hard clinical events. The red-team challenge on rodent-to-human longevity extrapolation is accepted. Cysteine and glutathione status can fall if sulphur amino acids are too low; the direction of risk is not only “less methionine is better.”

21 Glycine and the longevity claim

Glycine is used in collagen, glutathione, creatine, and one-carbon metabolism. Endogenous synthesis is large. McCarty and others have argued that glycine may be conditionally short when methionine is high, and that glycine supplementation might mimic some features of methionine restriction (McCarty et al., 2018). Rodent glycine supplementation has been reported to extend life in some studies (Miller et al., 2019). Human trials with longevity or validated ageing endpoints do not exist. Sleep and metabolic-marker studies are not life-extension trials. Grade: plausible mechanism, speculative human longevity claim.

22 Glutamine: healthy versus clinical

Glutamine is the most abundant free amino acid in human muscle and plasma. It fuels enterocytes and immune cells (Newsholme, 2001; Cruzat et al., 2018). In healthy athletes, glutamine supplements have not consistently reduced illness or improved performance when diet is adequate (Gleeson, 2008). In critical illness, the mechanistic story predicted benefit. REDOXS found harm with early high-dose glutamine in patients with multiorgan failure (Heyland et al., 2013). SIGNET did not find benefit (Andrews et al., 2011). ASPEN and ESPEN later narrowed or withdrew routine high-dose glutamine recommendations. The lesson is not that glutamine is unimportant. The lesson is that a plausible pathway plus a small early trial is not a licence to generalise from healthy gym users to ICU patients or the reverse.

23 Arginine versus citrulline

Arginine is a urea-cycle intermediate and the substrate of nitric oxide synthases. Oral arginine undergoes substantial first-pass metabolism. Oral citrulline raises plasma arginine more efficiently in human pharmacokinetic studies and can raise NO-related markers (Schwedhelm et al., 2008; Bahri et al., 2013). Exercise and blood-pressure trials of citrulline are mixed and often small (Figueroa et al., 2017). Neither amino acid has the outcome evidence of an antihypertensive drug or a training programme. The correct comparison is pharmacokinetic and mechanistic, not “citrulline is the better arginine.”

24 Tryptophan, histidine, taurine

Tryptophan is indispensable, the precursor of serotonin and of niacin, and a competitor with other large neutral amino acids for brain uptake (Fernstrom, 2013). Human requirement estimates exist; mood and sleep claims for isolated tryptophan or 5-hydroxytryptophan are a different literature and are not settled here as nutrition science. Histidine is indispensable; short studies missed it; haemoglobin and carnosine bind large amounts. Taurine is not proteinogenic. Human taurine trials in heart failure, metabolic disease, and performance exist and are heterogeneous (Waldron et al., 2018; Schaffer and Kim, 2018). They do not make taurine an honorary essential amino acid for healthy adults eating mixed diets.

25 What the controversies actually turn on

The controversies named in the commission reduce to a short list of errors.

BCAA and leucine supplementation. Acute MPS and cell signalling are real. Durable hypertrophy against protein-matched controls in protein-sufficient humans is not established. Wolfe’s missing-IAA argument remains the chemical veto on BCAA-only muscle building.

Methionine restriction and glycine for longevity. Rodent findings are strong enough to be interesting. Human outcome evidence is not. Observational protein-pattern papers are not methionine-restriction trials.

Glutamine. Healthy-user studies are mostly null. Large ICU trials were not a success and one was a harm signal. The populations are not interchangeable.

Arginine versus citrulline. Pharmacokinetics favour citrulline for raising plasma arginine. Outcome superiority is not established.

Amino-acid supplements for muscle gain. Protein-plus-training evidence is stronger than isolated-amino-acid evidence. Design sins include unmatched protein, short endpoints, and athlete-to-elder generalisation.

Plant-protein adequacy. Adequacy is achievable with attention to total protein, digestibility, and limiting amino acids. Acute MPS equivalence at equal grams is not guaranteed.

Anabolic window and per-meal thresholds. Both describe real acute physiology. Both become false when treated as stopwatches or as substitutes for daily protein and training.

Amino-acid sensing and ageing. Anabolic resistance is a documented acute phenomenon. It does not by itself prove that an mTOR-targeted amino-acid supplement is a sarcopenia therapy.

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27 Evidence handling

Study type is labelled in the reporting sentence. Animal and in-vitro results are never phrased as human outcomes. Acute MPS, mTOR phosphorylation, nitrogen balance, IAAO breakpoints, DIAAS scores, expert consensus, and hard clinical endpoints are treated as different objects. When a newer null trial and an older positive trial conflict, both are kept and the design reasons are named. Isolated-amino-acid trials that do not control total protein and energy are marked as inadequately controlled. Rodent longevity is labelled as rodent longevity.

Project 06 was queried read-only. Its current integration layer is rich in glutamine-and-cancer biochemistry and thin on human amino-acid nutrition trials; those 06 hits were used as orientation, not as the evidence base. 07_Peptide_News is a journalism/discovery layer and is not cited as scientific evidence. Full-text retrieval preferred PMC open access. Paywalled papers were used at metadata and abstract level when a verified identifier existed and the claim did not require a hidden table.

28 Limitations

This is a scientific article, not a systematic review with a registered protocol. Coverage is deep on muscle, requirements, protein quality, and the named controversies, and thinner on paediatric field nutrition and inborn errors of metabolism. Human ileal DIAAS data remain incomplete relative to pig data. Several official requirement numbers are still nitrogen-balance descendants. The literature was searched on 20 August 2026; later corrections and retractions after that date are not in the file.

Figures are original schematics. They are not measured mass-balances and not dosing charts. No third-party published figure has been reproduced.

29 Glossary

DIAAS. Digestible indispensable amino-acid score; ileal digestibility of individual IAA versus a reference pattern; not truncated at 1.0.

IAAO. Indicator amino-acid oxidation; a breakpoint method for estimating an indispensable-amino-acid requirement.

MPS / MPB. Muscle protein synthesis / breakdown; usually tracer-measured over hours.

PDCAAS. Protein digestibility-corrected amino-acid score; faecal digestibility; truncated at 1.0.

Splanchnic bed. Gut plus liver; the first-pass filter between a meal and the periphery.