Proteins are polymers of amino acids linked via α-peptide bonds. They can be represented as primary, secondary, tertiary, and even quaternary structures, but from a nutritional viewpoint only the primary (amino acid) sequence is of interest. Similarly, although there are many compounds in the body that can be chemically defined as amino acids, we are only concerned with the 20 canonical amino acids encoded in DNA, plus 5 others-ornithine, citrulline, γ-aminobutyrate, β-alanine, and taurine-that play quantitatively important roles in the body. We consume proteins, which are digested in the gastrointestinal tract, absorbed as small peptides (di- and tripeptides) and free amino acids, and then used for the resynthesis of proteins in our cells. Additionally, some amino acids are also used for the synthesis of specific (nonprotein) products, such as nitric oxide, polyamines, creatine, glutathione, nucleotides, glucosamine, hormones, neurotransmitters, and other factors. Again, such functions are not quantitatively important for most amino acids, and the bulk of amino acid metabolism is directly related to protein turnover (synthesis and degradation). For an individual in nitrogen balance, an amount of protein equal to that of the daily protein (nitrogen) intake is degraded each day with the nitrogen being excreted as urea and ammonia (with limited amounts of creatinine and uric acid). The carbon skeletons of the amino acids degraded to urea and ammonia are recovered through gluconeogenesis or ketone synthesis, or oxidized to carbon dioxide. Of the 20 amino acids present in proteins, 9 are considered nutritionally indispensable (essential) in adult humans because the body is not able to synthesize their carbon skeletons. These 9 amino acids are leucine, valine, isoleucine, histidine, lysine, methionine, threonine, tryptophan, and phenylalanine. In addition, 2 others are made from their indispensable precursors: cysteine from methionine, and tyrosine from phenylalanine. Although arginine is needed in neonates, it appears that adults, with the possible exceptions of pregnancy in females and spermatogenesis in males, can synthesize sufficient arginine to maintain a nitrogen balance. The others, glutamate, glutamine, aspartate, asparagine, serine, glycine, proline, and alanine, can all be synthesized from glucose and a suitable nitrogen source. Under some conditions, glutamine, glutamate, glycine, proline, and arginine may be considered as conditionally indispensable, meaning that the body is not capable of synthesizing them in sufficient quantities for a specific physiologic or pathologic condition (1). Thus, any discussion of dietary protein must consider not only quantity but also quality (ratio of indispensable amino acids).

Glutamine should be reclassified as a conditionally essential amino acid in the catabolic state because the body's glutamine expenditures exceed synthesis and low glutamine levels in plasma are associated with poor clinical outcome. After severe stress, several amino acids are mobilized from muscle tissue to supply energy and substrate to the host. Glutamine is one of the most important amino acids that provide this function. Glutamine acts as the preferred respiratory fuel for lymphocytes, hepatocytes and intestinal mucosal cells and is metabolized in the gut to citrulline, ammonium and other amino acids. Low concentrations of glutamine in plasma reflect reduced stores in muscle and this reduced availability of glutamine in the catabolic state seems to correlate with increased morbidity and mortality. Adding glutamine to the nutrition of clinical patients, enterally or parenterally, may reduce morbidity. Several excellent clinical trials have been performed to prove efficacy and feasibility of the use of glutamine supplementation in parenteral and enteral nutrition. The increased intake of glutamine has resulted in lower septic morbidity in certain critically ill patient populations. This review will focus on the efficacy and the importance of glutamine supplementation in diverse catabolic states.

The intestinal barrier integrity is essential for the absorption of nutrients and health in humans and animals. Dysfunction of the mucosal barrier is associated with increased gut permeability and development of multiple gastrointestinal diseases. Recent studies highlighted a critical role for glutamine, which had been traditionally considered as a nutritionally non-essential amino acid, in activating the mammalian target of rapamycin cell signaling in enterocytes. In addition, glutamine has been reported to enhance intestinal and whole-body growth, to promote enterocyte proliferation and survival, and to regulate intestinal barrier function in injury, infection, weaning stress, and other catabolic conditions. Mechanistically, these effects were mediated by maintaining the intracellular redox status and regulating expression of genes associated with various signaling pathways. Furthermore, glutamine stimulates growth of the small intestinal mucosa in young animals and also enhances ion transport by the gut in neonates and adults. Growing evidence supports the notion that glutamine is a nutritionally essential amino acid for neonates and a conditionally essential amino acid for adults. Thus, as a functional amino acid with multiple key physiological roles, glutamine holds great promise in protecting the gut from atrophy and injury under various stress conditions in mammals and other animals.

The intestinal barrier integrity is essential for the absorption of nutrients and health in humans and animals. Dysfunction of the mucosal barrier is associated with increased gut permeability and development of multiple gastrointestinal diseases. Recent studies highlighted a critical role for glutamine, which had been traditionally considered as a nutritionally non-essential amino acid, in activating the mammalian target of rapamycin cell signaling in enterocytes. In addition, glutamine has been reported to enhance intestinal and whole-body growth, to promote enterocyte proliferation and survival, and to regulate intestinal barrier function in injury, infection, weaning stress, and other catabolic conditions. Mechanistically, these effects were mediated by maintaining the intracellular redox status and regulating expression of genes associated with various signaling pathways. Furthermore, glutamine stimulates growth of the small intestinal mucosa in young animals and also enhances ion transport by the gut in neonates and adults. Growing evidence supports the notion that glutamine is a nutritionally essential amino acid for neonates and a conditionally essential amino acid for adults. Thus, as a functional amino acid with multiple key physiological roles, glutamine holds great promise in protecting the gut from atrophy and injury under various stress conditions in mammals and other animals.

Purpose Of Review: Glutamine is the most abundant amino acid in plasma and plays a key role in maintaining the integrity of intestinal barrier.

Recent Findings: Experimental studies showed that glutamine is able to modulate intestinal permeability and tight junction protein expression in several conditions. Recent articles underlined its putative beneficial role in gastrointestinal disorders such as irritable bowel syndrome.

Summary: Glutamine is a major nutrient to maintain intestinal barrier function in animals and humans. Depletion of glutamine results in villus atrophy, decreased expression of tight junction proteins and increased intestinal permeability. Moreover, glutamine supplementation can improve gut barrier function in several experimental conditions of injury and in some clinical situations. Furthermore, preventive effects of glutamine in experimental models of intestinal injuries have been recently reported. Despite promising data in experimental models, further studies are needed to evaluate glutamine supplementation in clinical practice.

Glutamine should be reclassified as a conditionally essential amino acid in the catabolic state because the body's glutamine expenditures exceed synthesis and low glutamine levels in plasma are associated with poor clinical outcome. After severe stress, several amino acids are mobilized from muscle tissue to supply energy and substrate to the host. Glutamine is one of the most important amino acids that provide this function. Glutamine acts as the preferred respiratory fuel for lymphocytes, hepatocytes and intestinal mucosal cells and is metabolized in the gut to citrulline, ammonium and other amino acids. Low concentrations of glutamine in plasma reflect reduced stores in muscle and this reduced availability of glutamine in the catabolic state seems to correlate with increased morbidity and mortality. Adding glutamine to the nutrition of clinical patients, enterally or parenterally, may reduce morbidity. Several excellent clinical trials have been performed to prove efficacy and feasibility of the use of glutamine supplementation in parenteral and enteral nutrition. The increased intake of glutamine has resulted in lower septic morbidity in certain critically ill patient populations. This review will focus on the efficacy and the importance of glutamine supplementation in diverse catabolic states.

Glutamine and glutamate with proline, histidine, arginine and ornithine, comprise 25% of the dietary amino acid intake and constitute the "glutamate family" of amino acids, which are disposed of through conversion to glutamate. Although glutamine has been classified as a nonessential amino acid, in major trauma, major surgery, sepsis, bone marrow transplantation, intense chemotherapy and radiotherapy, when its consumption exceeds its synthesis, it becomes a conditionally essential amino acid. In mammals the physiological levels of glutamine is 650 micromol/l and it is one of the most important substrate for ammoniagenesis in the gut and in the kidney due to its important role in the regulation of acid-base homeostasis. In cells, glutamine is a key link between carbon metabolism of carbohydrates and proteins and plays an important role in the growth of fibroblasts, lymphocytes and enterocytes. It improves nitrogen balance and preserves the concentration of glutamine in skeletal muscle. Deamidation of glutamine via glutaminase produces glutamate a precursor of gamma-amino butyric acid, a neurotransmission inhibitor. L-Glutamic acid is a ubiquitous amino acid present in many foods either in free form or in peptides and proteins. Animal protein may contain from 11 to 22% and plants protein as much as 40% glutamate by weight. The sodium salt of glutamic acid is added to several foods to enhance flavor. L-Glutamate is the most abundant free amino acid in brain and it is the major excitatory neurotransmitter of the vertebrate central nervous system. Most free L-glutamic acid in brain is derived from local synthesis from L-glutamine and Kreb's cycle intermediates. It clearly plays an important role in neuronal differentiation, migration and survival in the developing brain via facilitated Ca++ transport. Glutamate also plays a critical role in synaptic maintenance and plasticity. It contributes to learning and memory through use-dependent changes in synaptic efficacy and plays a role in the formation and function of the cytoskeleton. Glutamine via glutamate is converted to alpha-ketoglutarate, an integral component of the citric acid cycle. It is a component of the antioxidant glutathione and of the polyglutamated folic acid. The cyclization of glutamate produces proline, an amino acid important for synthesis of collagen and connective tissue. Our aim here is to review on some amino acids with high functional priority such as glutamine and to define their effective activity in human health and pathologies.

Glutamine (Gln) is an important energy source and has been used as a supplementary energy substrate. Furthermore, Gln is an essential component for numerous metabolic functions, including acid-base homeostasis, gluconeogenesis, nitrogen transport and synthesis of proteins and nucleic acids. Therefore, glutamine plays a significant role in cell homeostasis and organ metabolism. This article aims to review the mechanisms of glutamine action during severe illnesses. In critically ill patients, the increase in mortality was associated with a decreased plasma Gln concentration. During catabolic stress, Gln consumption rate exceeds the supply, and both plasma and skeletal muscle pools of free Gln are severely reduced. The dose and route of Gln administration clearly influence its effectiveness: high-dose parenteral appears to be more beneficial than low-dose enteral administration. Experimental studies reported that Gln may protect cells, tissues, and whole organisms from stress and injury through the following mechanisms: attenuation of NF (nuclear factor)-kB activation, a balance between pro- and anti-inflammatory cytokines, reduction in neutrophil accumulation, improvement in intestinal integrity and immune cell function, and enhanced of heat shock protein expression. In conclusion, high-doses of parenteral Gln (>0.50 g/kg/day) demonstrate a greater potential to benefit in critically ill patients, although Gln pathophysiological mechanisms requires elucidation.

Nonessential amino acids are synthesized de novo and therefore not diet dependent. In contrast, essential amino acids must be obtained through nutrition since they cannot be synthesized internally. Several nonessential amino acids may become essential under conditions of stress and catabolic states when the capacity of endogenous amino acid synthesis is exceeded. Arginine and glutamine are 2 such conditionally essential amino acids and are the focus of this review. Low arginine bioavailability plays a pivotal role in the pathogenesis of a growing number of varied diseases, including sickle cell disease, thalassemia, malaria, acute asthma, cystic fibrosis, pulmonary hypertension, cardiovascular disease, certain cancers, and trauma, among others. Catabolism of arginine by arginase enzymes is the most common cause of an acquired arginine deficiency syndrome, frequently contributing to endothelial dysfunction and/or T-cell dysfunction, depending on the clinical scenario and disease state. Glutamine, an arginine precursor, is one of the most abundant amino acids in the body and, like arginine, becomes deficient in several conditions of stress, including critical illness, trauma, infection, cancer, and gastrointestinal disorders. At-risk populations are discussed together with therapeutic options that target these specific acquired amino acid deficiencies.

The intestinal barrier integrity is essential for the absorption of nutrients and health in humans and animals. Dysfunction of the mucosal barrier is associated with increased gut permeability and development of multiple gastrointestinal diseases. Recent studies highlighted a critical role for glutamine, which had been traditionally considered as a nutritionally non-essential amino acid, in activating the mammalian target of rapamycin cell signaling in enterocytes. In addition, glutamine has been reported to enhance intestinal and whole-body growth, to promote enterocyte proliferation and survival, and to regulate intestinal barrier function in injury, infection, weaning stress, and other catabolic conditions. Mechanistically, these effects were mediated by maintaining the intracellular redox status and regulating expression of genes associated with various signaling pathways. Furthermore, glutamine stimulates growth of the small intestinal mucosa in young animals and also enhances ion transport by the gut in neonates and adults. Growing evidence supports the notion that glutamine is a nutritionally essential amino acid for neonates and a conditionally essential amino acid for adults. Thus, as a functional amino acid with multiple key physiological roles, glutamine holds great promise in protecting the gut from atrophy and injury under various stress conditions in mammals and other animals.

Purpose Of Review: Glutamine is the most abundant amino acid in plasma and plays a key role in maintaining the integrity of intestinal barrier.

Recent Findings: Experimental studies showed that glutamine is able to modulate intestinal permeability and tight junction protein expression in several conditions. Recent articles underlined its putative beneficial role in gastrointestinal disorders such as irritable bowel syndrome.

Summary: Glutamine is a major nutrient to maintain intestinal barrier function in animals and humans. Depletion of glutamine results in villus atrophy, decreased expression of tight junction proteins and increased intestinal permeability. Moreover, glutamine supplementation can improve gut barrier function in several experimental conditions of injury and in some clinical situations. Furthermore, preventive effects of glutamine in experimental models of intestinal injuries have been recently reported. Despite promising data in experimental models, further studies are needed to evaluate glutamine supplementation in clinical practice.

Glutamine should be reclassified as a conditionally essential amino acid in the catabolic state because the body's glutamine expenditures exceed synthesis and low glutamine levels in plasma are associated with poor clinical outcome. After severe stress, several amino acids are mobilized from muscle tissue to supply energy and substrate to the host. Glutamine is one of the most important amino acids that provide this function. Glutamine acts as the preferred respiratory fuel for lymphocytes, hepatocytes and intestinal mucosal cells and is metabolized in the gut to citrulline, ammonium and other amino acids. Low concentrations of glutamine in plasma reflect reduced stores in muscle and this reduced availability of glutamine in the catabolic state seems to correlate with increased morbidity and mortality. Adding glutamine to the nutrition of clinical patients, enterally or parenterally, may reduce morbidity. Several excellent clinical trials have been performed to prove efficacy and feasibility of the use of glutamine supplementation in parenteral and enteral nutrition. The increased intake of glutamine has resulted in lower septic morbidity in certain critically ill patient populations. This review will focus on the efficacy and the importance of glutamine supplementation in diverse catabolic states.

Critical illness is characterized by glutamine depletion owing to increased metabolic demand. Glutamine is essential to maintain intestinal integrity and function, sustain immunologic response, and maintain antioxidative balance. Insufficient endogenous availability of glutamine may impair outcome in critically ill patients. Consequently, glutamine has been considered to be a conditionally essential amino acid and a necessary component to complete any parenteral nutrition regimen. Recently, this scientifically sound recommendation has been questioned, primarily based on controversial findings from a large multicentre study published in 2013 that evoked considerable uncertainty among clinicians. The present review was conceived to clarify the most important questions surrounding glutamine supplementation in critical care. This was achieved by addressing the role of glutamine in the pathophysiology of critical illness, summarizing recent clinical studies in patients receiving parenteral nutrition with intravenous glutamine, and describing practical concepts for providing parenteral glutamine in critical care.

Glutamine is designated a non-essential amino acid: however, evidence is accumulating that glutamine becomes essential when catabolic conditions prevail.It has been established that glutamine is an important fuel for lymphocytes and macrophages, even when resting. Plasma and muscle glutamine concentrations are decreased after trauma such as burns, major surgery, and in sepsis. The effectiveness of the immune system is decreased after trauma: this may be due, in part, to the decrease in plasma glutamine concentrations.Most studies on sepsis in humans have shown plasma glutamine concentrations to bedecreased: this may be due to an increased rate of utilization of glutamine by lymphocytes and macrophages during proliferation or phagocytosis. In contrast, several studies on rats showincreased plasma glutamine levels in sepsis. A species difference in the way in which glutamine is metabolised could be the main reason for the conflicting results. Other contributory factors could be diurnal variation and timing of sample collection.A substantial amount of dietary glutamine is taken up by intestinal cells. When the supply of glutamine via the diet is decreased, glutamine is taken up from the circulation by the intestine. In total parenteral nutrition (TPN) sepsis can sometimes occur because the gut is "rested", leading to villous atrophy and increased gut mucosal barrier permeability. There is now a move towards the use of enteral nutrition in preference to TPN. Provision of exogenous glutamine has had beneficial effects in humans and animals, particularly in improving intestinal function. The safety and efficacy of glutamine administration to humans is discussed in detail.

Glutamine is the most abundant and versatile amino acid in the body. In health and disease, the rate of glutamine consumption by immune cells is similar or greater than glucose. For instance, in vitro and in vivo studies have determined that glutamine is an essential nutrient for lymphocyte proliferation and cytokine production, macrophage phagocytic plus secretory activities, and neutrophil bacterial killing. Glutamine release to the circulation and availability is mainly controlled by key metabolic organs, such as the gut, liver, and skeletal muscles. During catabolic/hypercatabolic situations glutamine can become essential for metabolic function, but its availability may be compromised due to the impairment of homeostasis in the inter-tissue metabolism of amino acids. For this reason, glutamine is currently part of clinical nutrition supplementation protocols and/or recommended for immune suppressed individuals. However, in a wide range of catabolic/hypercatabolic situations (e.g., ill/critically ill, post-trauma, sepsis, exhausted athletes), it is currently difficult to determine whether glutamine supplementation (oral/enteral or parenteral) should be recommended based on the amino acid plasma/bloodstream concentration (also known as glutaminemia). Although the beneficial immune-based effects of glutamine supplementation are already established, many questions and evidence for positive in vivo outcomes still remain to be presented. Therefore, this paper provides an integrated review of how glutamine metabolism in key organs is important to cells of the immune system. We also discuss glutamine metabolism and action, and important issues related to the effects of glutamine supplementation in catabolic situations.

Glutamine and glutamate with proline, histidine, arginine and ornithine, comprise 25% of the dietary amino acid intake and constitute the "glutamate family" of amino acids, which are disposed of through conversion to glutamate. Although glutamine has been classified as a nonessential amino acid, in major trauma, major surgery, sepsis, bone marrow transplantation, intense chemotherapy and radiotherapy, when its consumption exceeds its synthesis, it becomes a conditionally essential amino acid. In mammals the physiological levels of glutamine is 650 micromol/l and it is one of the most important substrate for ammoniagenesis in the gut and in the kidney due to its important role in the regulation of acid-base homeostasis. In cells, glutamine is a key link between carbon metabolism of carbohydrates and proteins and plays an important role in the growth of fibroblasts, lymphocytes and enterocytes. It improves nitrogen balance and preserves the concentration of glutamine in skeletal muscle. Deamidation of glutamine via glutaminase produces glutamate a precursor of gamma-amino butyric acid, a neurotransmission inhibitor. L-Glutamic acid is a ubiquitous amino acid present in many foods either in free form or in peptides and proteins. Animal protein may contain from 11 to 22% and plants protein as much as 40% glutamate by weight. The sodium salt of glutamic acid is added to several foods to enhance flavor. L-Glutamate is the most abundant free amino acid in brain and it is the major excitatory neurotransmitter of the vertebrate central nervous system. Most free L-glutamic acid in brain is derived from local synthesis from L-glutamine and Kreb's cycle intermediates. It clearly plays an important role in neuronal differentiation, migration and survival in the developing brain via facilitated Ca++ transport. Glutamate also plays a critical role in synaptic maintenance and plasticity. It contributes to learning and memory through use-dependent changes in synaptic efficacy and plays a role in the formation and function of the cytoskeleton. Glutamine via glutamate is converted to alpha-ketoglutarate, an integral component of the citric acid cycle. It is a component of the antioxidant glutathione and of the polyglutamated folic acid. The cyclization of glutamate produces proline, an amino acid important for synthesis of collagen and connective tissue. Our aim here is to review on some amino acids with high functional priority such as glutamine and to define their effective activity in human health and pathologies.

Nonessential amino acids are synthesized de novo and therefore not diet dependent. In contrast, essential amino acids must be obtained through nutrition since they cannot be synthesized internally. Several nonessential amino acids may become essential under conditions of stress and catabolic states when the capacity of endogenous amino acid synthesis is exceeded. Arginine and glutamine are 2 such conditionally essential amino acids and are the focus of this review. Low arginine bioavailability plays a pivotal role in the pathogenesis of a growing number of varied diseases, including sickle cell disease, thalassemia, malaria, acute asthma, cystic fibrosis, pulmonary hypertension, cardiovascular disease, certain cancers, and trauma, among others. Catabolism of arginine by arginase enzymes is the most common cause of an acquired arginine deficiency syndrome, frequently contributing to endothelial dysfunction and/or T-cell dysfunction, depending on the clinical scenario and disease state. Glutamine, an arginine precursor, is one of the most abundant amino acids in the body and, like arginine, becomes deficient in several conditions of stress, including critical illness, trauma, infection, cancer, and gastrointestinal disorders. At-risk populations are discussed together with therapeutic options that target these specific acquired amino acid deficiencies.

Proteins are polymers of amino acids linked via α-peptide bonds. They can be represented as primary, secondary, tertiary, and even quaternary structures, but from a nutritional viewpoint only the primary (amino acid) sequence is of interest. Similarly, although there are many compounds in the body that can be chemically defined as amino acids, we are only concerned with the 20 canonical amino acids encoded in DNA, plus 5 others-ornithine, citrulline, γ-aminobutyrate, β-alanine, and taurine-that play quantitatively important roles in the body. We consume proteins, which are digested in the gastrointestinal tract, absorbed as small peptides (di- and tripeptides) and free amino acids, and then used for the resynthesis of proteins in our cells. Additionally, some amino acids are also used for the synthesis of specific (nonprotein) products, such as nitric oxide, polyamines, creatine, glutathione, nucleotides, glucosamine, hormones, neurotransmitters, and other factors. Again, such functions are not quantitatively important for most amino acids, and the bulk of amino acid metabolism is directly related to protein turnover (synthesis and degradation). For an individual in nitrogen balance, an amount of protein equal to that of the daily protein (nitrogen) intake is degraded each day with the nitrogen being excreted as urea and ammonia (with limited amounts of creatinine and uric acid). The carbon skeletons of the amino acids degraded to urea and ammonia are recovered through gluconeogenesis or ketone synthesis, or oxidized to carbon dioxide. Of the 20 amino acids present in proteins, 9 are considered nutritionally indispensable (essential) in adult humans because the body is not able to synthesize their carbon skeletons. These 9 amino acids are leucine, valine, isoleucine, histidine, lysine, methionine, threonine, tryptophan, and phenylalanine. In addition, 2 others are made from their indispensable precursors: cysteine from methionine, and tyrosine from phenylalanine. Although arginine is needed in neonates, it appears that adults, with the possible exceptions of pregnancy in females and spermatogenesis in males, can synthesize sufficient arginine to maintain a nitrogen balance. The others, glutamate, glutamine, aspartate, asparagine, serine, glycine, proline, and alanine, can all be synthesized from glucose and a suitable nitrogen source. Under some conditions, glutamine, glutamate, glycine, proline, and arginine may be considered as conditionally indispensable, meaning that the body is not capable of synthesizing them in sufficient quantities for a specific physiologic or pathologic condition (1). Thus, any discussion of dietary protein must consider not only quantity but also quality (ratio of indispensable amino acids).

Amino acids11 are the central units in protein metabolism. They are incorporated into various proteins and converted to metabolically essential compounds (ie, nucleic acids, creatine, and porphyrins). Of the ≈20 amino acids in human proteins, 12 are manufactured by the body and are known as nonessential amino acids. The remaining 8 (isoleucine, leucine, lysine, methionine, phenylalanine, threonine, tryptophan, and valine) must be obtained from the diet and are thus termed essential amino acids. Proper protein nutriture is based on proper balance and sufficient intake of essential amino acids and intake of an adequate amount of nitrogen for the body to produce the nonessential amino acids.12 The nutritional quality of food proteins varies and depends on essential amino acid composition. Foods that contain essential amino acids at levels that facilitate tissue growth and repair are known as complete protein foods. Such foods are also classified as having high biological value, ie, a large proportion of protein is absorbed and retained. Biological value refers to an index in which all protein sources are compared with egg whites, which provide the most complete protein and have the highest biological value of 100. In general, foods with high protein quality or high biological value are from animal sources, such as eggs, milk, meat, poultry, and fish.
Conversely, a low concentration of 1 or more essential amino acids in a food lowers its nutritional quality. Although plant proteins form a large part of the human diet, most are deficient in 1 or more essential amino acids and are therefore regarded as incomplete proteins. Their protein quality can be upgraded, however, by combining them with others that are higher in protein quality or that contain whatever essential amino acids are lacking or deficient (protein complementarity).9,10,13 For example, combining corn (limited in lysine) with beans (limited in methionine) results in a high-quality protein food combination. Thus, the requirement for adequate essential amino acids can be met in a vegetarian diet by mixing foods of complementary amino acid composition.12–14 Only a few dietary sources of pure protein do not contain fat or carbohydrates, eg, egg white (albumin) and powdered casein from milk. Most high-protein foods contain fat (eg, meat, fish, and poultry) and/or carbohydrates (eg, milk, fruit, vegetables, legumes, nuts, breads, and cereals). Lean animal protein sources and vegetable proteins can be incorporated easily into a healthy diet plan.

Glutamine is synthesized primarily in skeletal muscle, lungs, and adipose tissue. Plasma glutamine plays an important role as a carrier of nitrogen, carbon, and energy between organs and is used for hepatic urea synthesis, for renal ammoniagenesis, for gluconeogenesis in both liver and kidney, and as a major respiratory fuel for many cells. The catabolism of glutamine is initiated by either of two isoforms of the mitochondrial glutaminase. Liver-type glutaminase is expressed only in periportal hepatocytes of the postnatal liver, where it effectively couples ammonia production with urea synthesis. Kidney-type glutaminase is abundant in kidney, brain, intestine, fetal liver, lymphocytes, and transformed cells, where the resulting ammonia is released without further metabolism. The two isoenzymes have different structural and kinetic properties that contribute to their function and short-term regulation. Although there is a high degree of identity in amino acid sequences, the two glutaminases are the products of different but related genes. The two isoenzymes are also subject to long-term regulation. Hepatic glutaminase is increased during starvation, diabetes, and feeding a high-protein diet, whereas kidney-type glutaminase is increased only in kidney in response to metabolic acidosis. The adaptations in hepatic glutaminase are mediated by changes in the rate of transcription, whereas kidney-type glutaminase is regulated at a posttranscriptional level.

Glutamine (Gln) is an important energy source and has been used as a supplementary energy substrate. Furthermore, Gln is an essential component for numerous metabolic functions, including acid-base homeostasis, gluconeogenesis, nitrogen transport and synthesis of proteins and nucleic acids. Therefore, glutamine plays a significant role in cell homeostasis and organ metabolism. This article aims to review the mechanisms of glutamine action during severe illnesses. In critically ill patients, the increase in mortality was associated with a decreased plasma Gln concentration. During catabolic stress, Gln consumption rate exceeds the supply, and both plasma and skeletal muscle pools of free Gln are severely reduced. The dose and route of Gln administration clearly influence its effectiveness: high-dose parenteral appears to be more beneficial than low-dose enteral administration. Experimental studies reported that Gln may protect cells, tissues, and whole organisms from stress and injury through the following mechanisms: attenuation of NF (nuclear factor)-kB activation, a balance between pro- and anti-inflammatory cytokines, reduction in neutrophil accumulation, improvement in intestinal integrity and immune cell function, and enhanced of heat shock protein expression. In conclusion, high-doses of parenteral Gln (>0.50 g/kg/day) demonstrate a greater potential to benefit in critically ill patients, although Gln pathophysiological mechanisms requires elucidation.

Intravenous glutamine supplementation is standard care when parenteral nutrition is given for critical illness. There are data of a reduced mortality when glutamine supplementation is given. In addition, standard commercial products for parenteral nutrition do not contain any glutamine due to glutamine instability in aqueous solutions. For the majority of critical ill patients who are fed enterally, the available evidence is insufficient to recommend glutamine supplementation. Standard formulation of enteral nutrition contains some glutamine: 2-4 g/L. However, this dose is insufficient to normalize glutamine plasma concentration.Plasma concentration of glutamine is low in many patients with critical illness and a low level is an independent risk factor for mortality. A low plasma glutamine concentration is the best indicator of glutamine depletion. Data are emerging about how the endogenous production of glutamine is regulated. We know that skeletal muscle is the major producer of glutamine and that a part of the profound depletion of skeletal muscle seen in critical illness is a reflection of the need to produce glutamine.Glutamine is utilized in rapidly dividing cells in the splanchnic area. Quantitatively most glutamine is oxidized, but the availability of glutamine in surplus is important for the de novo synthesis of nucleotides and necessary for cell division and protein synthesis. More knowledge about the regulation of the endogenous production of glutamine is needed to outline better guidelines for glutamine supplementation in the future.

Glutamine should be reclassified as a conditionally essential amino acid in the catabolic state because the body's glutamine expenditures exceed synthesis and low glutamine levels in plasma are associated with poor clinical outcome. After severe stress, several amino acids are mobilized from muscle tissue to supply energy and substrate to the host. Glutamine is one of the most important amino acids that provide this function. Glutamine acts as the preferred respiratory fuel for lymphocytes, hepatocytes and intestinal mucosal cells and is metabolized in the gut to citrulline, ammonium and other amino acids. Low concentrations of glutamine in plasma reflect reduced stores in muscle and this reduced availability of glutamine in the catabolic state seems to correlate with increased morbidity and mortality. Adding glutamine to the nutrition of clinical patients, enterally or parenterally, may reduce morbidity. Several excellent clinical trials have been performed to prove efficacy and feasibility of the use of glutamine supplementation in parenteral and enteral nutrition. The increased intake of glutamine has resulted in lower septic morbidity in certain critically ill patient populations. This review will focus on the efficacy and the importance of glutamine supplementation in diverse catabolic states.

Glutamine. Glutamine levels are also reduced during critical illness. Exogenous supplementation can improve gut mucosal atrophy and permeability, possibly leading to reduced bacterial translocation. Other potential benefits are enhanced immune cell function, decreased pro-inflammatory cytokine production, and higher levels of glutathione and antioxidative capacity [452, 453]. However, the clinical significance of these findings is not clearly established.
Although a previous meta-analysis showed mortality reduction , four other meta-analyses did not [458–462]. Other small studies not included in those meta-analyses had similar results [463, 464]. Three recent well-designed studies also failed to show a mortality benefit in the primary analyses [227, 465, 466], but again, none focused specifically on septic patients. Two small studies on septic patients showed no benefit in mortality rates [467, 468] but a significant reduction in infectious complications and a faster recovery of organ dysfunction . Some previous individual studies and meta-analyses showed positive secondary outcomes, such as reduction in infectious morbidity [461, 462, 465] and organ dysfunction . Beneficial effects were found mostly in trials using parenteral rather than enteral glutamine. However, recent and well-sized studies could not demonstrate a reduction of infectious complications or organ dysfunction [465, 466], even with parenteral glutamine. An ongoing trial (REDOXS) of 1,200 patients will test both enteral and parenteral glutamine and antioxidant supplementation in critically ill, mechanically ventilated patients . Although no clear benefit could be demonstrated in clinical trials with supplemental glutamine, there is no sign of harm.

Glutamine levels are also reduced during critical illness. Exogenous supplementation can improve gut mucosal atrophy and permeability, possibly leading to reduced bacterial translocation. Other potential benefits are enhanced immune cell function, decreased pro-inflammatory cytokine production, and higher levels of glutathione and antioxidative capacity (452, 453). However, the clinical significance of these findings is not clearly established.
Although a previous meta-analysis showed mortality reduction (428), four other meta-analyses did not (458–462). Other small studies not included in those meta-analyses had similar results (463, 464). Three recent well-designed studies also failed to show a mortality benefit in the primary analyses (227, 465, 466), but again, none focused specifically on septic patients. Two small studies on septic patients showed no benefit in mortality rates (467, 468) but a significant reduction in infectious complications (467) and a faster recovery of organ dysfunction (468). Some previous individual studies and meta-analyses showed positive secondary outcomes, such as reduction in infectious morbidity (461, 462, 465) and organ dysfunction (462). Beneficial effects were found mostly in trials using parenteral rather than enteral glutamine. However, recent and well-sized studies could not demonstrate a reduction of infectious complications (227) or organ dysfunction (465, 466), even with parenteral glutamine. An ongoing trial (REDOXS) of 1,200 patients will test both enteral and parenteral glutamine and antioxidant supplementation in critically ill, mechanically ventilated patients (469). Although no clear benefit could be demonstrated in clinical trials with supplemental glutamine, there is no sign of harm.

Amino acids (AA) were traditionally classified as nutritionally essential or nonessential for animals and humans based on nitrogen balance or growth. A key element of this classification is that all nonessential AA (NEAA) were assumed to be synthesized adequately in the body as substrates to meet the needs for protein synthesis. Unfortunately, regulatory roles for AA in nutrition and metabolism have long been ignored. Such conceptual limitations were not recognized until recent seminal findings that dietary glutamine is necessary for intestinal mucosal integrity and dietary arginine is required for maximum neonatal growth and embryonic survival. Some of the traditionally classified NEAA (e.g. glutamine, glutamate, and arginine) play important roles in regulating gene expression, cell signaling, antioxidative responses, and immunity. Additionally, glutamate, glutamine, and aspartate are major metabolic fuels for the small intestine and they, along with glycine, regulate neurological function. Among essential AA (EAA), much emphasis has been placed on leucine (which activates mammalian target of rapamycin to stimulate protein synthesis and inhibit proteolysis) and tryptophan (which modulates neurological and immunological functions through multiple metabolites, including serotonin and melatonin). A growing body of literature leads to a new concept of functional AA, which are defined as those AA that regulate key metabolic pathways to improve health, survival, growth, development, lactation, and reproduction of organisms. Both NEAA and EAA should be considered in the classic "ideal protein" concept or formulation of balanced diets to maximize protein accretion and optimize health in animals and humans.

Based on growth or nitrogen balance, amino acids (AA) had traditionally been classified as nutritionally essential (indispensable) or non-essential (dispensable) for animals and humans. Nutritionally essential AA (EAA) are defined as either those AA whose carbon skeletons cannot be synthesized de novo in animal cells or those that normally are insufficiently synthesized de novo by the animal organism relative to its needs for maintenance, growth, development, and health and which must be provided in the diet to meet requirements. In contrast, nutritionally non-essential AA (NEAA) are those AA which can be synthesized de novo in adequate amounts by the animal organism to meet requirements for maintenance, growth, development, and health and, therefore, need not be provided in the diet. Although EAA and NEAA had been described for over a century, there are no compelling data to substantiate the assumption that NEAA are synthesized sufficiently in animals and humans to meet the needs for maximal growth and optimal health. NEAA play important roles in regulating gene expression, cell signaling pathways, digestion and absorption of dietary nutrients, DNA and protein synthesis, proteolysis, metabolism of glucose and lipids, endocrine status, men and women fertility, acid-base balance, antioxidative responses, detoxification of xenobiotics and endogenous metabolites, neurotransmission, and immunity. Emerging evidence indicates dietary essentiality of "nutritionally non-essential amino acids" for animals and humans to achieve their full genetic potential for growth, development, reproduction, lactation, and resistance to metabolic and infectious diseases. This concept represents a new paradigm shift in protein nutrition to guide the feeding of mammals (including livestock), poultry, and fish.

As the average human lifespan increases, so does the recognition that advancing age is associated with changes in nutrient intake and requirements as a consequence of biological, social, and pathological factors. Studies show that whereas protein requirements may not differ significantly between younger and older adults, the adaptive mechanisms and responses to nutritional or pathological stressors may differ and alter the balance between requirement and toxicity of specific amino acids (AAs). As an individual gets older, cardiovascular disease and cancer become the leading causes of morbidity and mortality. Advancing age is also associated with changes in appetite, food intake, and physical activity, all of which can influence protein and AA metabolism. The sulfur amino acids (SAAs) methionine and cysteine recently attracted attention because of their pivotal roles in methyl group metabolism and maintenance of the cellular redox state. Methionine, an indispensable AA, is important for methylation reactions and as a precursor for cysteine, which is the rate-limiting AA for glutathione (GSH) synthesis. On one hand, high intake levels or blood concentrations of methionine are associated with adverse consequences such as hyperhomocysteinemia and endothelial dysfunction, which are risk factors for cardiovascular disease. On the other hand, methionine deficiency is reported to lower the threshold of chemical-induced toxicity and play a role in carcinogenesis. Therefore, it is evident that understanding the biological significance of the interrelationship between SAAs, GSH, and methyl group metabolism is key to determining optimal dietary intakes of SAAs in older individuals.

Purpose Of Review: Recently, the concept of dietary dispensable amino acids has been increasingly challenged, as more indirect and direct (experimental) evidence has pointed to the need for them in the diet during specific life stages or disease states. Here, we discuss the classification of amino acids, methods to assess the needs for dispensable amino acids with experimental evidence from our recent studies, and highlight the role of specific dispensable amino acids in metabolism and health.

Recent Findings: There exist differences among the dispensable amino acids to act as effective nitrogen sources in humans. Glycine, a dispensable amino acid is conditionally indispensable in later stages of human pregnancy.

Summary: The so-called 'dispensable' amino acids are quantitatively nearly 75% of the daily protein needs in humans. In certain life-stages and diseases, there is a dietary demand for the dispensable amino acids. Future well-designed studies are required to identify the dietary demand for these amino acids, which will certainly be useful for dietary management in specific diseases and to maintain health across all life-stages.

Nonessential amino acids are synthesized de novo and therefore not diet dependent. In contrast, essential amino acids must be obtained through nutrition since they cannot be synthesized internally. Several nonessential amino acids may become essential under conditions of stress and catabolic states when the capacity of endogenous amino acid synthesis is exceeded. Arginine and glutamine are 2 such conditionally essential amino acids and are the focus of this review. Low arginine bioavailability plays a pivotal role in the pathogenesis of a growing number of varied diseases, including sickle cell disease, thalassemia, malaria, acute asthma, cystic fibrosis, pulmonary hypertension, cardiovascular disease, certain cancers, and trauma, among others. Catabolism of arginine by arginase enzymes is the most common cause of an acquired arginine deficiency syndrome, frequently contributing to endothelial dysfunction and/or T-cell dysfunction, depending on the clinical scenario and disease state. Glutamine, an arginine precursor, is one of the most abundant amino acids in the body and, like arginine, becomes deficient in several conditions of stress, including critical illness, trauma, infection, cancer, and gastrointestinal disorders. At-risk populations are discussed together with therapeutic options that target these specific acquired amino acid deficiencies.

Amino acids11 are the central units in protein metabolism. They are incorporated into various proteins and converted to metabolically essential compounds (ie, nucleic acids, creatine, and porphyrins). Of the ≈20 amino acids in human proteins, 12 are manufactured by the body and are known as nonessential amino acids. The remaining 8 (isoleucine, leucine, lysine, methionine, phenylalanine, threonine, tryptophan, and valine) must be obtained from the diet and are thus termed essential amino acids. Proper protein nutriture is based on proper balance and sufficient intake of essential amino acids and intake of an adequate amount of nitrogen for the body to produce the nonessential amino acids.12 The nutritional quality of food proteins varies and depends on essential amino acid composition. Foods that contain essential amino acids at levels that facilitate tissue growth and repair are known as complete protein foods. Such foods are also classified as having high biological value, ie, a large proportion of protein is absorbed and retained. Biological value refers to an index in which all protein sources are compared with egg whites, which provide the most complete protein and have the highest biological value of 100. In general, foods with high protein quality or high biological value are from animal sources, such as eggs, milk, meat, poultry, and fish.
Conversely, a low concentration of 1 or more essential amino acids in a food lowers its nutritional quality. Although plant proteins form a large part of the human diet, most are deficient in 1 or more essential amino acids and are therefore regarded as incomplete proteins. Their protein quality can be upgraded, however, by combining them with others that are higher in protein quality or that contain whatever essential amino acids are lacking or deficient (protein complementarity).9,10,13 For example, combining corn (limited in lysine) with beans (limited in methionine) results in a high-quality protein food combination. Thus, the requirement for adequate essential amino acids can be met in a vegetarian diet by mixing foods of complementary amino acid composition.12–14 Only a few dietary sources of pure protein do not contain fat or carbohydrates, eg, egg white (albumin) and powdered casein from milk. Most high-protein foods contain fat (eg, meat, fish, and poultry) and/or carbohydrates (eg, milk, fruit, vegetables, legumes, nuts, breads, and cereals). Lean animal protein sources and vegetable proteins can be incorporated easily into a healthy diet plan.

Conversely, a low concentration of 1 or more essential amino acids in a food lowers its nutritional quality. Although plant proteins form a large part of the human diet, most are deficient in 1 or more essential amino acids and are therefore regarded as incomplete proteins. Their protein quality can be upgraded, however, by combining them with others that are higher in protein quality or that contain whatever essential amino acids are lacking or deficient (protein complementarity).9,10,13 For example, combining corn (limited in lysine) with beans (limited in methionine) results in a high-quality protein food combination. Thus, the requirement for adequate essential amino acids can be met in a vegetarian diet by mixing foods of complementary amino acid composition.12–14 Only a few dietary sources of pure protein do not contain fat or carbohydrates, eg, egg white (albumin) and powdered casein from milk. Most high-protein foods contain fat (eg, meat, fish, and poultry) and/or carbohydrates (eg, milk, fruit, vegetables, legumes, nuts, breads, and cereals). Lean animal protein sources and vegetable proteins can be incorporated easily into a healthy diet plan.
An average of 102 g of protein per person per day is available in the US food supply.15 Actual protein consumption ranges from 88 to 92 g for men and from 63 to 66 g for women.16 Animal products provide ≈75% of the essential amino acids in the food supply, followed by dairy products, cereal products, eggs, legumes, fruits, and vegetables.16 The recommended daily allowance (RDA) for protein of high biological value for adults, based on body weight, is ≈0.8 g/kg17 or 0.36 g/lb. There are many conditions in which extra protein is needed, including childhood/adolescence (ie, periods of growth), pregnancy, lactation, intense strength and endurance training and other forms of physical activity, some disease states, and possibly in the elderly.18 In the general population, however, protein intake above the required amount is inefficiently used by the body and imposes the additional burdens of metabolizing and excreting excess waste products (eg, urea and ammonia) by the liver and kidney.19–22

Nonessential amino acids are synthesized de novo and therefore not diet dependent. In contrast, essential amino acids must be obtained through nutrition since they cannot be synthesized internally. Several nonessential amino acids may become essential under conditions of stress and catabolic states when the capacity of endogenous amino acid synthesis is exceeded. Arginine and glutamine are 2 such conditionally essential amino acids and are the focus of this review. Low arginine bioavailability plays a pivotal role in the pathogenesis of a growing number of varied diseases, including sickle cell disease, thalassemia, malaria, acute asthma, cystic fibrosis, pulmonary hypertension, cardiovascular disease, certain cancers, and trauma, among others. Catabolism of arginine by arginase enzymes is the most common cause of an acquired arginine deficiency syndrome, frequently contributing to endothelial dysfunction and/or T-cell dysfunction, depending on the clinical scenario and disease state. Glutamine, an arginine precursor, is one of the most abundant amino acids in the body and, like arginine, becomes deficient in several conditions of stress, including critical illness, trauma, infection, cancer, and gastrointestinal disorders. At-risk populations are discussed together with therapeutic options that target these specific acquired amino acid deficiencies.

Estimates of protein and amino acid requirements in this paper are proposed for healthy elderly people. The estimate of protein requirement was based on nitrogen (N) balance, as well as functional indicators such as immune function or muscle strength. Data suggest that the protein requirement for nitrogen equilibrium in the elderly, is greater than 0.8 gm/kg body weight/day. There do not appear to be any adverse consequences with protein intakes that are about 1 gm/kg body weight/day. The tentative recommendation in this paper is higher than the current mean recommended intake of protein (FAO/WHO/UNU, 1985). However, because of methodological difficulties, the data does not allow for a confident prediction of what the exact level of protein intake should be. Further studies are needed to come to a firm conclusion on the exact protein requirement. Indispensable amino acid requirements based on nitrogen balance data, in the elderly, are fragmentary and conflicting. These requirements can alternatively be based on obligatory nitrogen loss, for which data is available in the elderly. The overlap of the obligatory nitrogen loss between the young and the elderly, suggest that the amino acid requirement based on this technique is similar in young and elderly individuals. Tracer based techniques measuring amino acid balance at different amino acid intakes, also support the view that there are no differences in the amino acid requirements between young and elderly people. In general, these amino acid requirement studies have been performed in healthy USA subjects, and data is needed to know if these estimates can be extended to populations from other, less-developed countries.

The aims of this introductory article are to survey and critically evaluate the concepts and approaches that have been used to assess amino acid adequacy and to hypothesize about possible future directions of research. The issue in question is extensive, consequently this article will be limited to: 1) definitions of amino acid requirements; 2) available techniques to assess amino acid requirements; 3) actual recommendations for healthy adults; 4) factors influencing requirements; and 5) requirements in acute and chronic wasting diseases. Recommendations for amino acid intakes for healthy adults were proposed by the FAO/WHO expert committee in 2001. They have not yet been published. The major factors affecting amino acid requirements are the stage of development, reproductive state, environmental factors, digestibility of dietary proteins, genotype of the individual, and pathological conditions. Remarkably, there are no conclusive data relative to changes in requirements induced by infection, injury, trauma, and renal or liver failure. Future research using modern methods to evaluate requirements must thus receive a high priority. Wasting diseases are associated with deficiencies and imbalances of particular amino acids causing specific changes in requirements. Consequently, a new approach has been used to categorize amino acids as conditionally indispensable according to their functional and physiological properties. Kinetic measurements of plasma amino acids might help to estimate qualitative requirements. Measurement of tissue intracellular free amino acid deficiencies or excesses is another method to estimate qualitative requirements. Based on these measurements tentative values for conditionally indispensable amino acids during disease are given in the article.

Amino acids are integral for human health, influencing an array of physiological processes from gene expression to vasodilation to the immune response. In accordance with this expansive range of unique functions, the tissues of the body engage in a complex interplay of amino acid exchange and metabolism to respond to the organism's dynamic needs for a range of nitrogenous products. Interorgan amino acid metabolism is required for numerous metabolic pathways, including the synthesis of functional amino acids like arginine, glutamate, glutamine, and glycine. This physiological process requires the cooperative handling of amino acids by organs (e.g., the small intestine, skeletal muscle, kidneys, and liver), as well as the complete catabolism of nutritionally essential amino acids such as the BCAAs, with their α-ketoacids shuttled from muscle to liver. These exchanges are made possible by several mechanisms, including organ location, as well as the functional zonation of enzymes and the cell-specific expression of amino acid transporters. The cooperative handling of amino acids between the various organs does not appear to be under the control of any centralized regulation, but is instead influenced by factors such as fluctuations in nutrient availability, hormones, changes associated with development, and altered environmental factors. While the normal function of these pathways is associated with health and homeostasis, affected by physical activity, diet and body composition, dysregulation is observed in numerous disease states, including cardiovascular disease and cancer cachexia, presenting potential avenues for the manipulation of amino acid consumption as part of the therapeutic approach to these conditions in individuals.

The metabolic roles for L-leucine, an essential branched-chain amino acid (BCAA), go far beyond serving exclusively as a building block for de novo protein synthesis. Growing evidence shows that leucine regulates protein and lipid metabolism in animals. Specifically, leucine activates the mammalian target of rapamycin (mTOR) signaling pathway, including the 70 kDa ribosomal protein S6 kinase 1 (S6K1) and eukaryotic initiation factor (eIF) 4E-binding protein 1 (4EBP1) to stimulate protein synthesis in skeletal muscle and adipose tissue and to promote mitochondrial biogenesis, resulting in enhanced cellular respiration and energy partitioning. Activation of cellular energy metabolism favors fatty acid oxidation to CO2 and water in adipocytes, lean tissue gain in young animals, and alleviation of muscle protein loss in aging adults, lactating mammals, and food-deprived subjects. As a functional amino acid, leucine holds great promise to enhance the growth, efficiency of food utilization, and health of animals and humans.

Purpose Of Review: To highlight recent studies that have examined the cell-signalling mechanisms responsible for the amino acid (primarily leucine and the essential amino acids) stimulation of human skeletal muscle protein synthesis.

Recent Findings: Ingestion of a leucine-enriched essential amino acid nutrient solution rapidly and potently activates the mammalian target of rapamycin signalling pathway and protein synthesis in human skeletal muscle. Further, mTOR signalling and muscle protein synthesis are enhanced when leucine-enriched nutrients are ingested following resistance exercise. The addition of leucine to regular meals may improve the ability of feeding to stimulate protein synthesis in old human muscle.

Summary: Leucine and essential amino acids appear to stimulate human muscle protein synthesis primarily by activating the mammalian target of rapamycin signalling pathway. How human muscle cells sense an increase in leucine and/or essential amino acids to activate mammalian target of rapamycin signalling is currently unknown. Recent work, however, suggests that the kinases hVps34 and MAP43K may be involved. Leucine-enriched essential amino acid ingestion, in combination with resistance exercise in some cases, may be a useful intervention to promote mTOR signalling and protein synthesis in an effort to counteract a variety of muscle wasting conditions (e.g. sarcopenia, cachexia, AIDS, inactivity/bed rest, sepsis, kidney failure, and trauma).

High-performance physical activity and postexercise recovery lead to significant changes in amino acid and protein metabolism in skeletal muscle. Central to these changes is an increase in the metabolism of the BCAA leucine. During exercise, muscle protein synthesis decreases together with a net increase in protein degradation and stimulation of BCAA oxidation. The decrease in protein synthesis is associated with inhibition of translation initiation factors 4E and 4G and ribosomal protein S6 under regulatory controls of intracellular insulin signaling and leucine concentrations. BCAA oxidation increases through activation of the branched-chain alpha-keto acid dehydrogenase (BCKDH). BCKDH activity increases with exercise, reducing plasma and intracellular leucine concentrations. After exercise, recovery of muscle protein synthesis requires dietary protein or BCAA to increase tissue levels of leucine in order to release the inhibition of the initiation factor 4 complex through activation of the protein kinase mammalian target of rapamycin (mTOR). Leucine's effect on mTOR is synergistic with insulin via the phosphoinositol 3-kinase signaling pathway. Together, insulin and leucine allow skeletal muscle to coordinate protein synthesis with physiological state and dietary intake.

Leucine is an essential nutrient with potent abilities to stimulate both muscle protein synthesis as well as increased oxidative metabolism supported by mitochondrial biogenesis. Few studies have simultaneously investigated anabolic and catabolic responses following leucine treatment with the exception of master regulator of cellular energetics, AMPK. The unique ability of leucine to stimulate both favorable anabolic and catabolic processes in highly metabolically active tissues suggests leucine consumption/supplementation may provide benefits beyond hypertrophic gains. This review highlights original investigations reporting leucine’s ability to stimulate both anabolic and catabolic processes in muscle. Additionally, this report discusses potential explanations for the simultaneous activation of two seemingly opposing processes, as well as the interplay between them. The role of cellular energetics is of undeniable importance in sustaining increased protein synthesis following leucine administration; however, the dependence of leucine-induced mitochondrial biogenesis on heightened energy expenditure from elevated protein synthesis remains to be defined experimentally.

Amino acids are potent modulators of protein turnover and skeletal muscle cells are highly sensitive to changes in amino acid availability. During amino acid abundance increased activity of mTORC1 drives protein synthesis and growth. In skeletal muscle, it has been clearly demonstrated that of all the amino acids, leucine is the most potent stimulator of mTORC1 and protein synthesis in vitro and in vivo. As such, leucine has received considerable attention as a potential pharmaconutrient for the treatment of numerous muscle wasting conditions. However, despite a multitude of studies showing enhanced acute protein synthesis with leucine or leucine-rich supplements in healthy individuals, additional leucine intake does not necessarily enhance protein synthesis during muscle wasting conditions. In addition, long-term, placebo controlled, iso-caloric studies in humans consistently show no beneficial effect of leucine supplementation on skeletal muscle mass or function. This review, critically evaluates the therapeutic potential of leucine to attenuate the skeletal muscle wasting associated with ageing, cancer and immobilization/bed rest. It also highlights the impact of inflammation on amino acid sensing, mTORC1 activation and stimulation of protein synthesis and challenges the underlying hypothesis that the acute activation of mTORC1 and stimulation of protein synthesis by leucine increases in muscle mass over time. We conclude that leucine, as a standalone nutritional intervention, is not effective in the prevention of muscle wasting. Future work should focus on identifying and utilizing other nutrients or treatments that sensitize skeletal muscle to leucine, thereby enhancing its therapeutic potential for muscle wasting conditions.

Leucine has been shown to stimulate adipose tissue protein synthesis in vivo as well as leptin secretion, protein synthesis, hyper-plastic growth, and tissue morphogenesis in in vitro experiments using freshly isolated adipocytes. Recently, others have proposed that leucine oxidation in the mitochondria may be required to activate the mammalian target of rapamycin (mTOR), the cytosolic Ser/Thr protein kinase that appears to mediate some of these effects. The first irreversible and rate-limiting step in leucine oxidation is catalyzed by the branched-chain alpha-keto acid dehydrogenase (BCKD) complex. The activity of this complex is regulated acutely by phosphorylation of the E1alpha-subunit at Ser293 (S293), which inactivates the complex. Because the alpha-keto acid of leucine regulates the activity of BCKD kinase, it has been suggested as a potential target for leucine regulation of mTOR. To study the regulation of BCKD phosphorylation and its potential link to mTOR activation, a phosphopeptide-specific antibody recognizing this site was developed and characterized. Phospho-S293 (pS293) immunoreactivity in liver corresponded closely to diet-induced changes in BCKD activity state. Immunoreactivity was also increased in TREMK-4 cells after the induction of BCKD kinase by a drug-inducible promoter. BCKD S293 phosphorylations in adipose tissue and gastrocnemius (which is mostly inactive in vivo) were similar. This suggests that BCKD complex in epididymal adipose tissue from food-deprived rats is mostly inactive (unable to oxidize leucine), as is the case in muscle. To begin to test the leucine oxidation hypothesis of mTOR activation, the dose-dependent effects of orally administered leucine on acute activation of S6K1 (an mTOR substrate) and BCKD were compared using the pS293 antibodies. Increasing doses of leucine directly correlated with increases in plasma leucine concentration. Phosphorylation of S6K1 (Thr389, the phosphorylation site leading to activation) in adipose tissue was maximal at a dose of leucine that increased plasma leucine approximately threefold. Changes in BCKD phosphorylation state required higher plasma leucine concentrations. The results seem more consistent with a role for BCKD and BCKD kinase in the activation of leucine metabolism/oxidation than in the activation of the leucine signal to mTOR.

The preservation or restoration of muscle mass is of prime importance for healthy aging. However, aging has been repeatedly shown to be associated with resistance of muscle to the anabolic effects of feeding. Leucine supplementation has been proposed as a possible strategy because of its regulatory role on protein homeostasis. Indeed, it acts independently of growth factors and leads to enhanced cap-dependent mRNA translation initiation and increased protein synthesis. Leucine acts as a signaling molecule directly at the muscle level via the activation of mammalian/mechanistic target of rapamycin complex 1 (mTORC1). However, in aged muscle, mTORC1 activation seems to be impaired, with decreased sensitivity and responsiveness of muscle protein synthesis to amino acids, whereas the phosphorylation state of several components of this signaling pathway appears to be higher in the basal state. This may stem from specific age-related impairment of muscle signaling and from decreased nutrient and growth factor delivery to the muscle. Whether aging per se affects mTORC1 signaling remains to be established, because aging is frequently associated with inadequate protein intake, decreased insulin sensitivity, inactivity, inflammatory processes, etc. Whatever its origin, this anabolic resistance to feeding can be mitigated by quantitative and qualitative manipulation of protein supply, such as leucine supplementation; however, there remains the question of possible adverse effects of long-term, high-dose leucine supplementation in terms of insulin resistance and tumorigenesis.

Mammalian target of rapamycin (mTOR) signaling is one of the main signaling pathways controlling protein synthesis. Leucine treatment upregulates mTOR signaling, which enhances protein synthesis; however, the mechanisms are not well understood. Herein, treatment of C2C12 myoblast cells with leucine enhanced the phosphorylation of mTOR and ribosomal protein S6 kinase. Leucine treatment also decreased the adenosine monophosphate/ATP ratio in myoblasts by 36.4 +/- 9.1% (P < 0.05) and reduced the phosphorylation of adenosine monophosphate-activated protein kinase (AMPK) alpha subunit at Thr172 (28.6 +/- 4.9% reduction, P < 0.05) and inhibited AMPK activity (43.6 +/- 3.5% reduction, P < 0.05). In addition, leucine increased the phosphorylation of mTOR at Ser2448 by 63.5 +/- 10.0% (P < 0.05) and protein synthesis by 30.6 +/- 6.1% (P < 0.05). Applying 5-aminoimidazole-4-carbox-amide 1-beta-d-ribonucleoside, an activator of AMPK, abolished the stimulation of mTOR signaling by leucine, showing that AMPK negatively controls mTOR signaling. To further show the role of AMPK in mTOR signaling, myoblasts expressing a dominant negative AMPKalpha subunit were employed. Negative myoblasts had very low AMPK activity. The activation of mTOR induced by leucine in these cells was abated, showing that AMPK contributed to mTOR activation. In conclusion, leucine stimulates mTOR signaling in part through AMPK inhibition. This study implicates AMPK as an important target for nutritional management to enhance mTOR signaling and protein synthesis in muscle cells, thereby increasing muscle growth.

Macronutrients, such as protein or amino acid, not only supply calories but some components may also play as signaling molecules to affect feeding behavior, energy balance, and fuel efficiency. Leucine, a branched-chain amino acid is a good example. After structural roles are satisfied, the ability of leucine to function as signal and oxidative substrate is based on a sufficient intracellular concentration. Therefore, leucine level must be sufficiently high to play the signaling and metabolic roles. Leucine is not only a substrate for protein synthesis of skeletal muscle, but also plays more roles beyond that. Leucine activates signaling factor of mammalian target of rapamycin (mTOR) to promote protein synthesis in skeletal muscle and in adipose tissue. It is also a major regulator of the mTOR sensitive response of food intake to high protein diet. Meanwhile, leucine regulates blood glucose level by promoting gluconeogenesis and aids in the retention of lean mass in a hypocaloric state. It is beneficial to animal nutrition and clinical application and extrapolation to humans.

The metabolic roles for L-leucine, an essential branched-chain amino acid (BCAA), go far beyond serving exclusively as a building block for de novo protein synthesis. Growing evidence shows that leucine regulates protein and lipid metabolism in animals. Specifically, leucine activates the mammalian target of rapamycin (mTOR) signaling pathway, including the 70 kDa ribosomal protein S6 kinase 1 (S6K1) and eukaryotic initiation factor (eIF) 4E-binding protein 1 (4EBP1) to stimulate protein synthesis in skeletal muscle and adipose tissue and to promote mitochondrial biogenesis, resulting in enhanced cellular respiration and energy partitioning. Activation of cellular energy metabolism favors fatty acid oxidation to CO2 and water in adipocytes, lean tissue gain in young animals, and alleviation of muscle protein loss in aging adults, lactating mammals, and food-deprived subjects. As a functional amino acid, leucine holds great promise to enhance the growth, efficiency of food utilization, and health of animals and humans.

Branched-chain amino acids promote both protein and mRNA synthesis through mechanistic target of rapamycin (mTOR) signaling. A previous report demonstrated that chronic branched-chain amino acid supplementation increased mitochondrial biogenesis in the skeletal muscle of middle-aged mice through activation of mTOR signaling. In this study, we hypothesized that the acute oral administration of L-leucine alone has the ability to alter the gene expression related to fiber type and metabolism in skeletal muscle of young rats through the activation of mTOR signaling. Although the gene expression of representative glycolytic enzymes (Hk2 and Eno3) was not altered, L-leucine administration (135 mg/100 g body weight) upregulated the expression of slow-fiber-related genes (Myh7, Myl3, and Tnni1) and a mitochondrial biogenesis-related gene (Ppargc1a) in the soleus and extensor digitorum longus muscles compared with the control. In addition, L-leucine treatment also upregulated the slow-fiber genes and mitochondrial gene expression in cultured C2C12 myotubes, whereas rapamycin inhibited the effects of L-leucine. However, L-alanine, L-phenylalanine, and L-valine treatment did not alter the expression of the fiber type- and metabolism-related genes as observed in L-leucine. Our results suggest that L-leucine may have the ability to alter skeletal muscle fiber type toward slow fiber and oxidative metabolism by upregulation of gene expression through mTOR signaling.

The classical small molecule neurotransmitters are essential for cell-cell signaling in the nervous system for regulation of behaviors and physiological functions. Metabolomics approaches are ideal for quantitative analyses of neurotransmitter profiles but have not yet been achieved for the repertoire of 14 classical neurotransmitters. Therefore, this study developed targeted metabolomics analyses by full scan gas chromatography/time-of-flight mass spectrometry (GC-TOF) and hydrophilic interaction chromatography-QTRAP mass spectrometry (HILIC-MS/MS) operated in positive ionization mode for identification and quantitation of 14 neurotransmitters consisting of acetylcholine, adenosine, anandamide, aspartate, dopamine, epinephrine, GABA, glutamate, glycine, histamine, melatonin, norepinephrine, serine, and serotonin. GC-TOF represents a new metabolomics method for neurotransmitter analyses. Sensitive measurements of 11 neurotransmitters were achieved by GC-TOF, and three neurotransmitters were analyzed by LC-MS/MS (acetylcholine, anandamide, and melatonin). The limits of detection (LOD) and limits of quantitation (LOQ) were assessed for linearity for GC-TOF and LC-MS/MS protocols. In neurotransmitter-containing dense core secretory vesicles of adrenal medulla, known as chromaffin granules (CG), metabolomics measured the concentrations of 9 neurotransmitters consisting of the catecholamines dopamine, norepinephrine, and epinephrine, combined with glutamate, serotonin, adenosine, aspartate, glycine, and serine. The CG neurotransmitters were constitutively secreted from sympathoadrenal chromaffin cells in culture. Nicotine- and KCl-stimulated release of the catecholamines and adenosine. Lithium, a drug used for the treatment of bipolar disorder, decreased the constitutive secretion of dopamine and norepinephrine and decreased nicotine-stimulated secretion of epinephrine. Lithium had no effect on other secreted neurotransmitters. Overall, the newly developed GC-TOF with LC-MS/MS metabolomics methods for analyses of 14 neurotransmitters will benefit investigations of neurotransmitter regulation in biological systems and in human disease conditions related to drug treatments.

Amino acids are involved in various metabolic pathways and some of them also act as neurotransmitters. Since biosynthesis of L-glutamate and γ-aminobutyric acid (GABA) requires 2-oxoglutarate while 3-phosphoglycerate is the precursor of L-glycine and D-serine, evolutionary selection of these amino acid neurotransmitters might have been driven by their capacity to provide important information about the glycolytic pathway and Krebs cycle. Synthesis and recycling of amino acid neurotransmitters as well as composition and function of their receptors are often compromised in inherited metabolic diseases. For instance, increased plasma L-phenylalanine concentrations impair cerebral biosynthesis of protein and bioamines in phenylketonuria, while elevated cerebral L-phenylalanine directly acts via ionotropic glutamate receptors. In succinic semialdehyde dehydrogenase deficiency, the neurotransmitter GABA and neuromodulatory γ-hydroxybutyric acid are elevated. Chronic hyperGABAergic state results in progressive downregulation of GABA and GABA receptors and impaired mitophagy. In glycine encephalopathy, the neurological phenotype is precipitated by L-glycine acting both via cortical NMDA receptors and glycine receptors in spinal cord and brain stem neurons. Serine deficiency syndromes are biochemically characterized by decreased biosynthesis of L-serine, an important neurotrophic factor, and the neurotransmitters D-serine and L-glycine. Supplementation with L-serine and L-glycine has a positive effect on seizure frequency and spasticity, while neurocognitive development can only be improved if treatment starts in utero or immediately postnatally. With novel techniques, the study of synaptic dysfunction in inherited metabolic diseases has become an emerging research field. More and better therapies are needed for these difficult-to-treat diseases.

The metabolism of the amino acid L-tryptophan is a highly regulated physiological process leading to the generation of several neuroactive compounds within the central nervous system. These include the aminergic neurotransmitter serotonin (5-hydroxytryptamine, 5-HT), products of the kynurenine pathway of tryptophan metabolism (including 3-hydroxykynurenine, 3-hydroxyanthranilic acid, quinolinic acid and kynurenic acid), the neurohormone melatonin, several neuroactive kynuramine metabolites of melatonin, and the trace amine tryptamine. The integral role of central serotonergic systems in the modulation of physiology and behaviour has been well documented since the first description of serotonergic neurons in the brain some 40 years ago. However, while the significance of the peripheral kynurenine pathway of tryptophan metabolism has also been recognised for several decades, it has only recently been appreciated that the synthesis of kynurenines within the central nervous system has important consequences for physiology and behaviour. Altered kynurenine metabolism has been implicated in the pathophysiology of conditions such as acquired immunodeficiency syndrome (AIDS)-related dementia, Huntington's disease and Alzheimer's disease. In this review we discuss the molecular mechanisms involved in regulating the metabolism of tryptophan and consider the medical implications associated with dysregulation of both serotonergic and kynurenine pathways of tryptophan metabolism.

The ancient and ubiquitous monoamine signalling molecules serotonin, dopamine, norepinephrine, and epinephrine are involved in multiple physiological functions. The aromatic amino acid hydroxylases tyrosine hydroxylase (TH), tryptophan hydroxylase 1 (TPH1), and tryptophan hydroxylase 2 (TPH2) catalyse the rate-limiting steps in the biosynthesis of these monoamines. Genetic variants of TH, TPH1, and TPH2 genes are associated with neuropsychiatric disorders. The interest in these enzymes as therapeutic targets is increasing as new roles of these monoamines have been discovered, not only in brain function and disease, but also in development, cardiovascular function, energy and bone homeostasis, gastrointestinal motility, hemostasis, and liver function. Areas covered: Physiological roles of TH, TPH1, and TPH2. Enzyme structures, catalytic and regulatory mechanisms, animal models, and associated diseases. Interactions with inhibitors, pharmacological chaperones, and regulatory proteins relevant for drug development. Expert opinion: Established inhibitors of these enzymes mainly target their amino acid substrate binding site, while tetrahydrobiopterin analogues, iron chelators, and allosteric ligands are less studied. New insights into monoamine biology and 3D-structural information and new computational/experimental tools have triggered the development of a new generation of more selective inhibitors and pharmacological chaperones. The enzyme complexes with their regulatory 14-3-3 proteins are also emerging as therapeutic targets.

There is evidence that changes in the concentrations of the monoamine neurotransmitters within the brain are associated with changes in mental processes, with disorders of control of movement and with certain neuropsychiatric diseases. These neurotransmitters are synthesized in the brain from aromatic amino acid precursors that have to be obtained from the circulating blood. In this study some factors which alter the rates of entry of four amino acids (the important neurotransmitter precursors L-tyrosine and L-tryptophan, as well as L-phenylalanine and L-histidine) into the brain have been studied and the findings considered in relation to conditions in which the quantities of one or more of the monoamine neurotransmitters formed within the cerebral cells may be either too large or too small. Thus too little neurotransmitter will be formed if competition between amino acids for the carriers transporting them into the cerebral cells causes the exclusion of a large proportion of any of the aromatic amino acid precursors from the brain. ,or example, L-tryptophan is partially excluded from the brain if a raised level of any one of several other amino acids is maintained in the circulation. Of these, L-phenylalanine inhibits the transport of L-tryptophan into the brain most effectively, while aromatic amino acids in general exclude L-tryptophan more effectively than do other neutral amino acids. Over-production of one or more of the monoamine neurotransmitters is likely to occur when there is too much of one of the aromatic amino acid precursors in the brain cells as a result of abnormally high uptake from the blood, or as a result of their release by an excessive breakdown of the protein within these cells. Underproduction of neurotransmitters may occur in certain disease states, such as some aminoacidurias or Parkinsonism. We have listed some conditions associated with altered mental states or motor disability in which over- or under-production of monoamine neurotransmitters may occur and have tried to relate the findings in human disease with our experimental results.

Amino acids (AAs) and their metabolites play an important role in neurological health and function. They are not only the building blocks of protein but are also neurotransmitters. In the brain, glutamate and aspartate are the major excitatory neurotransmitters, whereas γ-aminobutyrate (GABA, a metabolite of glutamate) and glycine are the major inhibitory neurotransmitters. Nitric oxide (NO, a metabolite of arginine), HS (a metabolite of cysteine), serotonin (a metabolite of tryptophan) and histamine (a metabolite of histidine), as well as dopamine and norepinephrine (metabolites of tyrosine) are neurotransmitters to modulate synaptic plasticity, neuronal activity, learning, motor control, motivational behavior, emotion, and executive function. Concentrations of glutamine (a precursor of glutamate and aspartate), branched-chain AAs (precursors of glutamate, glutamine and aspartate), L-serine (a precursor of glycine and D-serine), methionine and phenylalanine in plasma are capable of affecting neurotransmission through the syntheses of glutamate, aspartate, and glycine, as well as the competitive transport of tryptophan and tyrosine across from the blood-brain barrier. Adequate consumption of AAs is crucial to maintain their concentrations and the production of neurotransmitters in the central nervous system. Thus, the content and balance of AAs in diets have a profound impact on food intake by animals. Knowledge of AA transport and metabolism in the brain is beneficial for improving the health and well-being of humans and animals.

The ancient and ubiquitous monoamine signalling molecules serotonin, dopamine, norepinephrine, and epinephrine are involved in multiple physiological functions. The aromatic amino acid hydroxylases tyrosine hydroxylase (TH), tryptophan hydroxylase 1 (TPH1), and tryptophan hydroxylase 2 (TPH2) catalyse the rate-limiting steps in the biosynthesis of these monoamines. Genetic variants of TH, TPH1, and TPH2 genes are associated with neuropsychiatric disorders. The interest in these enzymes as therapeutic targets is increasing as new roles of these monoamines have been discovered, not only in brain function and disease, but also in development, cardiovascular function, energy and bone homeostasis, gastrointestinal motility, hemostasis, and liver function. Areas covered: Physiological roles of TH, TPH1, and TPH2. Enzyme structures, catalytic and regulatory mechanisms, animal models, and associated diseases. Interactions with inhibitors, pharmacological chaperones, and regulatory proteins relevant for drug development. Expert opinion: Established inhibitors of these enzymes mainly target their amino acid substrate binding site, while tetrahydrobiopterin analogues, iron chelators, and allosteric ligands are less studied. New insights into monoamine biology and 3D-structural information and new computational/experimental tools have triggered the development of a new generation of more selective inhibitors and pharmacological chaperones. The enzyme complexes with their regulatory 14-3-3 proteins are also emerging as therapeutic targets.

Tryptophan is an indispensable amino acid that should to be supplied by dietary protein. Apart from its incorporation into body proteins, tryptophan is the precursor for serotonin, an important neuromediator, and for kynurenine, an intermediary metabolite of a complex metabolic pathway ending with niacin, CO(2), and kynurenic and xanthurenic acids. Tryptophan metabolism within different tissues is associated with numerous physiological functions. The liver regulates tryptophan homeostasis through degrading tryptophan in excess. Tryptophan degradation into kynurenine by immune cells plays a crucial role in the regulation of immune response during infections, inflammations and pregnancy. Serotonin is synthesized from tryptophan in the gut and also in the brain, where tryptophan availability is known to influence the sensitivity to mood disorders. In the present review, we discuss the major functions of tryptophan and its role in the regulation of growth, mood, behavior and immune responses with regard to the low availability of this amino acid and the competition between tissues and metabolic pathways for tryptophan utilization.

Biosynthesis and metabolism of serotonin and catecholamines involve at least eight individual enzymes that are mainly expressed in tissues derived from the neuroectoderm, e.g., the central nervous system (CNS), pineal gland, adrenal medulla, enterochromaffin tissue, sympathetic nerves, and ganglia. Some of the enzymes appear to have additional biological functions and are also expressed in the heart and various other internal organs. The biosynthetic enzymes are tyrosine hydroxylase (TH), tryptophan hydroxylases type 1 and 2 (TPH1, TPH2), aromatic amino acid decarboxylase (AADC), dopamine beta-hydroxylase (DbetaH), and phenylethanolamine N-methyltransferase (PNMT), and the specific catabolic enzymes are monoamine oxidase A (MAO-A) and catechol O-methyltransferase (COMT). For the TH, DDC, DBH, and MAOA genes, many single nucleotide polymorphisms (SNPs) with unknown function, and small but increasing numbers of cases with autosomal recessive mutations have been recognized. For the remaining genes (TPH1, TPH2, PNMT, and COMT) several different genetic markers have been suggested to be associated with regulation of mood, pain perception, and aggression, as well as psychiatric disturbances such as schizophrenia, depression, suicidality, and attention deficit/hyperactivity disorder. The genetic markers may either have a functional role of their own, or be closely linked to other unknown functional variants. In the future, molecular testing may become important for the diagnosis of such conditions. Here we present an overview on mutations and polymorphisms in the group of genes encoding monoamine neurotransmitter metabolizing enzymes. At the same time we propose a unified nomenclature for the nucleic acid aberrations in these genes. New variations or details on mutations will be updated in the Pediatric Neurotransmitter Disorder Data Base (PNDDB) database (www.bioPKU.org).

Amino acids (AAs) and their metabolites play an important role in neurological health and function. They are not only the building blocks of protein but are also neurotransmitters. In the brain, glutamate and aspartate are the major excitatory neurotransmitters, whereas γ-aminobutyrate (GABA, a metabolite of glutamate) and glycine are the major inhibitory neurotransmitters. Nitric oxide (NO, a metabolite of arginine), HS (a metabolite of cysteine), serotonin (a metabolite of tryptophan) and histamine (a metabolite of histidine), as well as dopamine and norepinephrine (metabolites of tyrosine) are neurotransmitters to modulate synaptic plasticity, neuronal activity, learning, motor control, motivational behavior, emotion, and executive function. Concentrations of glutamine (a precursor of glutamate and aspartate), branched-chain AAs (precursors of glutamate, glutamine and aspartate), L-serine (a precursor of glycine and D-serine), methionine and phenylalanine in plasma are capable of affecting neurotransmission through the syntheses of glutamate, aspartate, and glycine, as well as the competitive transport of tryptophan and tyrosine across from the blood-brain barrier. Adequate consumption of AAs is crucial to maintain their concentrations and the production of neurotransmitters in the central nervous system. Thus, the content and balance of AAs in diets have a profound impact on food intake by animals. Knowledge of AA transport and metabolism in the brain is beneficial for improving the health and well-being of humans and animals.

Epinephrine (E) and sympathetic nerve stimulation were described by Thomas Renton Elliott in 1905 for the first time. Dopamine (DA), norepinephrine (NE), E, and serotonin (5-HT) belong to the classic biogenic amines (or monoamines). Parkinson's disease (PD) is among the diseases in which it has been established that catecholamines may account for the neurodegeneration of central and peripheral catecholamine neural systems. PD is a chronic and progressive neurological disorder characterized by resting tremor, rigidity, and bradykinesia, affecting 2% of individuals above the age of 65 years. This disorder is a result of degeneration of DA-producing neurons of the substantia nigra and a significant loss of noradrenergic neurons in the locus coeruleus. In PD and other related neurodegerative diseases, catecholamines play the role of endogenous neurotoxins. Catechol-O-methyltransferase (COMT) and/or monoamine oxidase (MAO) catalyze the metabolism of monoamines. However, the monoamine transporters for DA, NE, and 5-HT namely DAT, NET, and SERT, respectively regulate the monoamine concentration. The metabolism of catecholamines and 5-HT involves common factors. Monoamine transporters represent targets for many pharmacological agents that affect brain function, including psychostimulators and antidepressants. In PD, polymorphisms of the COMT, MAO, DAT, NET, and 5- HTT genes may change the levels of biogenic amines and their metabolic products. The currently available therapies for PD improve the symptoms but do not halt the progression of the disease. The most effective treatment for PD patients is therapy with L-dopa. Combined therapy for PD involves a DA agonist and decarboxylase, MAOs and COMT inhibitors, and is the current optimal form of PD treatment maintaining monoamine balance.

Alterations in noradrenergic and serotonergic function in the central nervous system (CNS) have been implicated in the pathophysiology of depression and the mechanism of action of antidepressant drugs. Based on changes in norepinephrine and serotonin metabolism in the CNS, it has been postulated that subgroups of patients with differential responses to norepinephrine and serotonin reuptake inhibitors may exist. Alpha-methylparatyrosine (AMPT), which causes rapid depletion of brain catecholamines, has been used as a noradrenergic probe to test the hypothesis that changes in neurotransmission through the catecholamine system may underlie the therapeutic response to norepinephrine reuptake inhibitors. Brain serotonin is dependent on plasma levels of the essential amino acid tryptophan. Rapid tryptophan depletion, in the form of a tryptophan-free amino acid drink, has been used as a serotonergic probe to identify therapeutically responsive subsets of patients. Using these probes, we have recently examined the behavioral effects of reduced concentrations of brain monoamines on depressed patients treated with a variety of serotonin selective reuptake inhibitors (SSRIs) or the relatively norepinephrine-selective antidepressant desipramine, during 3 different states: drug-free and depressed; in remission on antidepressant drugs; and drug-free in remission. The results of a series of investigations confirm the importance of monoamines in the mediation of depressed mood, but also suggest that other brain neural systems may have more of a primary role than previously thought in the pathophysiology of depression. Noradrenergic and serotonergic probes may be used in time to identify subsets of depressed patients to determine which patients might respond differentially to the new selective norepinephrine reuptake inhibitors or SSRIs.

Depression is a common and serious disorder, characterized by symptoms like anhedonia, lack of energy, sad mood, low appetite, and sleep disturbances. This disease is very complex and not totally elucidated, in which diverse molecular and biological mechanisms are involved, such as neuroinflammation. There is a high need for the development of new therapies and gaining new insights into this disease is urgent. One important player in depression is the amino acid tryptophan. This amino acid can be metabolized in two important pathways in the context of depression: the serotonin and kynurenine pathways. These metabolic pathways of tryptophan are crucial in several processes that are linked with depression. Indeed, the maintenance of the balance of serotonin and kynurenine pathways is critical for the human physiological homeostasis. Thus, this narrative review aims to explore tryptophan metabolism (particularly in the serotonin and kynurenine pathways) in depression, starting with a global overview about these topics and ending with the focus on these pathways in neuroinflammation, stress, microbiota, and brain-derived neurotrophic factor regulation in this disease. Taken together, this information aims to clarify the metabolism of tryptophan in depression, particularly the serotonin and kynurenine pathways.

Neurotransmitter metabolism plays a critical role in the pathophysiology of major depressive disorder (MDD). However, whether the neurotransmitter metabolism in adolescent MDD is differentiated from adult MDD is still elusive. In the current study, plasma concentrations of monoamine and amino acid neurotransmitters as well as their metabolites, including tryptophan (TRP), kynurenine (KYN), kynurenic acid (KYNA), serotonin (5-HT), 5-hydroxyindoleacetic acid (5-HIAA), dopamine (DA), 3,4-dihydroxyphenylacetic acid (DOPAC), homovanillic acid (HVA), norepinephrine (NE), vanillylmandelic acid (VMA), 3-methoxy-4-hydroxyphenylglycol (MHPG), glutamine (GLN), glutamate (GLU) and gamma-aminobutyric acid (GABA), were measured and compared in two cohorts of subjects (adult cohort: 31 first-episode MDD vs. 35 healthy controls; adolescent cohort: 33 first-episode MDD vs. 30 healthy controls). To assess the effects of antidepressant treatment, we also analyzed the concentrations of these indexes pre- and post-treatment in adult and adolescent cohorts. At baseline, the deficits of neurotransmitter metabolism in adult MDD were manifested in all the neurotransmitter systems. In contrast, for adolescent MDD, the dysregulation of neurotransmission was mainly indicated in the catecholaminergic systems. After antidepressant treatment, adult MDD showed increased TRP, KYN, KYNA and GLU levels, together with decreased levels of 5-HIAA and DOPAC. Adolescent MDD illustrated an increased level of 5-HT and decreased levels of TRP and GABA. The improvements of Hamilton total scores correlated with the changes in plasma TRP and the turnover of KYN/TRP after treatment in all MDD patients. However, these correlations were only manifested in the adult MDD rather than in adolescent MDD patients. The findings highlight the shared and distinguished neurotransmitter pathways in MDD and emphasize the different antidepressant responses between adults and adolescents. Potentially, the neurotransmitters above could serve as diagnostic biomarkers and provide a novel pharmacological treatment strategy for MDD.

Protein is the only dietary macronutrient required for life. As such, it is reasonable to consider dietary protein as the centerpiece of a healthy eating pattern. To do so requires consideration of what type of protein should be eaten. Account should be taken of the quality of the protein, the density of the protein in the protein food source, and the non-protein components of protein food source. The quality of protein can be quantified based on the amount and profile of essential amino acids (EAAs), as well as the true ileal digestibility of the EAAs in the protein. The density of protein in a food source can be quantified on the basis of the amount of total calories ingested to achieve intake of the daily requirement of all EAAs. Non-protein components of protein food sources can be considered in terms of the amount and nature of fat, carbohydrate and fiber, as well as the content of micronutrients. Potential beneficial effects of high-quality protein food sources should be balanced against any possible adverse effects. When all of these factors are considered we conclude that animal-based protein foods (e.g., eggs, dairy, meat, fish, poultry) occupy an important place in a healthy eating pattern.

Amino acids11 are the central units in protein metabolism. They are incorporated into various proteins and converted to metabolically essential compounds (ie, nucleic acids, creatine, and porphyrins). Of the ≈20 amino acids in human proteins, 12 are manufactured by the body and are known as nonessential amino acids. The remaining 8 (isoleucine, leucine, lysine, methionine, phenylalanine, threonine, tryptophan, and valine) must be obtained from the diet and are thus termed essential amino acids. Proper protein nutriture is based on proper balance and sufficient intake of essential amino acids and intake of an adequate amount of nitrogen for the body to produce the nonessential amino acids.12 The nutritional quality of food proteins varies and depends on essential amino acid composition. Foods that contain essential amino acids at levels that facilitate tissue growth and repair are known as complete protein foods. Such foods are also classified as having high biological value, ie, a large proportion of protein is absorbed and retained. Biological value refers to an index in which all protein sources are compared with egg whites, which provide the most complete protein and have the highest biological value of 100. In general, foods with high protein quality or high biological value are from animal sources, such as eggs, milk, meat, poultry, and fish.
Conversely, a low concentration of 1 or more essential amino acids in a food lowers its nutritional quality. Although plant proteins form a large part of the human diet, most are deficient in 1 or more essential amino acids and are therefore regarded as incomplete proteins. Their protein quality can be upgraded, however, by combining them with others that are higher in protein quality or that contain whatever essential amino acids are lacking or deficient (protein complementarity).9,10,13 For example, combining corn (limited in lysine) with beans (limited in methionine) results in a high-quality protein food combination. Thus, the requirement for adequate essential amino acids can be met in a vegetarian diet by mixing foods of complementary amino acid composition.12–14 Only a few dietary sources of pure protein do not contain fat or carbohydrates, eg, egg white (albumin) and powdered casein from milk. Most high-protein foods contain fat (eg, meat, fish, and poultry) and/or carbohydrates (eg, milk, fruit, vegetables, legumes, nuts, breads, and cereals). Lean animal protein sources and vegetable proteins can be incorporated easily into a healthy diet plan.

The postprandial rise in essential amino acid (EAA) concentrations modulates the increase in muscle protein synthesis rates after protein ingestion. The EAA content and AA composition of the dietary protein source contribute to the differential muscle protein synthetic response to the ingestion of different proteins. Lower EAA contents and specific lack of sufficient leucine, lysine, and/or methionine may be responsible for the lower anabolic capacity of plant-based compared with animal-based proteins. We compared EAA contents and AA composition of a large selection of plant-based protein sources with animal-based proteins and human skeletal muscle protein. AA composition of oat, lupin, wheat, hemp, microalgae, soy, brown rice, pea, corn, potato, milk, whey, caseinate, casein, egg, and human skeletal muscle protein were assessed using UPLC-MS/MS. EAA contents of plant-based protein isolates such as oat (21%), lupin (21%), and wheat (22%) were lower than animal-based proteins (whey 43%, milk 39%, casein 34%, and egg 32%) and muscle protein (38%). AA profiles largely differed among plant-based proteins with leucine contents ranging from 5.1% for hemp to 13.5% for corn protein, compared to 9.0% for milk, 7.0% for egg, and 7.6% for muscle protein. Methionine and lysine were typically lower in plant-based proteins (1.0 ± 0.3 and 3.6 ± 0.6%) compared with animal-based proteins (2.5 ± 0.1 and 7.0 ± 0.6%) and muscle protein (2.0 and 7.8%, respectively). In conclusion, there are large differences in EAA contents and AA composition between various plant-based protein isolates. Combinations of various plant-based protein isolates or blends of animal and plant-based proteins can provide protein characteristics that closely reflect the typical characteristics of animal-based proteins.

The quality and nutritional value of dietary proteins are determined by the quantity, digestibility and bioavailability of essential amino acids (EAA), which play a critical role in human growth, longevity and metabolic health. Plant-source protein is often deficient in one or more EAAs (e.g., branched-chain amino acids, lysine, methionine and/or tryptophan) and, in its natural form, is less digestible than animal-source protein. Nevertheless, dietary intake of plant-source protein has been promoted because of its potential health benefits, lower cost of production and lower environmental impact compared to animal-source protein. Implementation of dietary strategies that improve both human and planetary health are of critical importance and subject to growing interest from researchers and consumers. Therefore, in this review we analyse current plant protein intake patterns and discuss possible countermeasures that can enhance plant protein nutrition, examples include: (1) combining different plant proteins with complementary EAA profiles; (2) identification and commercial cultivation of new and novel high-quality plant proteins; (3) industrial and domestic processing methods; and (4) genome-editing techniques.

The sources or types of protein in the diet have long been overlooked regarding their link to cardiometabolic health. The picture is complicated by the fact that animal and plant proteins are consumed along with other nutrients and substances which make up the "protein package" so plant and animal protein come with clear nutrient clusters. This review aimed at deciphering the relation between plant and animal protein and cardiometabolic health by examining different nutritional levels (such as amino acids, protein type, protein foods, protein patterns, and associated overall dietary and nutrient patterns) and varying levels of scientific evidence [basic science, randomized controlled trials (RCTs), observational data]. Plant protein in Western countries is a robust marker of nutrient adequacy of the diet, whereas the contribution of animal protein is highly heterogeneous. Yet recent data from large cohorts have confirmed that total and animal proteins are associated with the risk of cardiovascular disease and diabetes, even when fully adjusting for lifestyle and dietary or nutritional factors. Here again, there is marked variability depending on the type of animal protein. Protein from processed red meat and total red meat on the one hand, and from legumes, nuts, and seeds on the other, are often reported at the extremes of the risk range. RCTs using purified proteins have contributed little to the topic to date, inasmuch as the findings cannot readily be extrapolated to current or near-future diets, but RCTs studying whole protein foods have shown a beneficial effect of pulses. Despite the fact that many of the benefits of plant protein reported in observational or interventional studies may stem from the protein package that they convey and the nutrients that they displace, there are also important indications that protein per se may affect cardiometabolic health via the many amino acids that are present in typically contrasting levels in plant compared with animal proteins.

While animal products are rich in protein, the adequacy of dietary protein intake from vegetarian/vegan diets has long been controversial. In this review, we examine the protein and amino acid intakes from vegetarian diets followed by adults in western countries and gather information in terms of adequacy for protein and amino acids requirements, using indirect and direct data to estimate nutritional status. We point out that protein-rich foods, such as traditional legumes, nuts and seeds, are sufficient to achieve full protein adequacy in adults consuming vegetarian/vegan diets, while the question of any amino acid deficiency has been substantially overstated. Our review addresses the adequacy in changes to protein patterns in people newly transitioning to vegetarian diets. We also specifically address this in older adults, where the issues linked to the protein adequacy of vegetarian diets are more complex. This contrasts with the situation in children where there are no specific concerns regarding protein adequacy because of their very high energy requirements compared to those of protein. Given the growing shifts in recommendations from nutrition health professionals for people to transition to more plant-based, whole-food diets, additional scientific evidence-based communications confirming the protein adequacy of vegetarian and vegan diets is warranted.

Plant-sourced proteins offer environmental and health benefits, and research increasingly includes them in study formulas. However, plant-based proteins have less of an anabolic effect than animal proteins due to their lower digestibility, lower essential amino acid content (especially leucine), and deficiency in other essential amino acids, such as sulfur amino acids or lysine. Thus, plant amino acids are directed toward oxidation rather than used for muscle protein synthesis. In this review, we evaluate the ability of plant- versus animal-based proteins to help maintain skeletal muscle mass in healthy and especially older people and examine different nutritional strategies for improving the anabolic properties of plant-based proteins. Among these strategies, increasing protein intake has led to a positive acute postprandial muscle protein synthesis response and even positive long-term improvement in lean mass. Increasing the quality of protein intake by improving amino acid composition could also compensate for the lower anabolic potential of plant-based proteins. We evaluated and discussed four nutritional strategies for improving the amino acid composition of plant-based proteins: fortifying plant-based proteins with specific essential amino acids, selective breeding, blending several plant protein sources, and blending plant with animal-based protein sources. These nutritional approaches need to be profoundly examined in older individuals in order to optimize protein intake for this population who require a high-quality food protein intake to mitigate age-related muscle loss.

This review aimed to compare alternative protein sources in terms of nutritional composition and health benefits with the purpose of disseminating up-to-date knowledge and contribute for diversification of the food marked and consumers decision-making. Plant-based is the most well-established category of alternative proteins, but there is still room for diversification. Less conventional species such as chia seeds are prominent sources of ω-3 (∼60% total lipids), while hempseed and quinoa are notable sources of ω-6 (up to 58% and 61%, respectively). Edible insects and microalgae are alternative foods rich in protein (up to 70%), fibers (∼30%), as well as peptides and polysaccharides with antimicrobial, antioxidant, anti-hypertensive, antidiabetic, antidepressant, antitumor, and immunomodulatory activities. Additionally, lipid contents in insect larvae can be as high as 50%, on a dry weight basis, containing fatty acids with anti-inflammatory and antitumor properties. In contrast, edible fungi have low lipid contents (∼2%), but are rich in carbohydrates (up to 79%) and have balanced amino acid profiles. The results suggest that food formulations combining different alternative protein sources can meet dietary requirements. Further studies on flavoring and texturing processes will help to create meat and dairy analogs, thus helping to broaden acceptance and applicability of alternative protein sources.

The development of novel protein sources to compensate for the expected future shortage of traditional animal proteins due to their high carbon footprint is a major contemporary challenge in the agri-food industry currently. Therefore, both industry and consumers are placing a greater emphasis on plant proteins as a sustainable source of protein to meet the growing nutritional demand of ever increasing population. In addition to being key alternatives, many plant-based foods have biological properties that make them potentially functional or health-promoting foods, particularly physiologically active peptides and proteins accounting for most of these properties. This review discusses the importance of plant-based protein as a viable and sustainable alternative to animal proteins. The current advances in plant protein isolation and production and characterization of bioactive hydrolysates and peptides from plant proteins are described comprehensively. Furthermore, the recent research on bioactivities and bioavailability of plant protein-derived bioactive peptides is reviewed briefly. The limitations of using bioactive peptides, regulatory criteria, and the possible future applications of plant protein-derived bioactive peptides are highlighted. This review may help understand plant proteins and their bioactive peptides and provide valuable suggestions for future research and applications in the food industry.

Quality of the dietary protein in foods rather than amount of dietary protein may be of greater importance from a human health and wellness standpoint. Various systems are in place to determine the value of dietary protein. Protein digestibility-corrected amino acid score (PDCAAS) and digestible indispensable amino acid score (DIAAS) are the two major protein standards used to determine the completeness of proteins by their unique concentration and digestibility of indispensable amino acids. The purpose of this review was to provide a comprehensive comparison of the amino acid concentration of high protein foods and provide the current status of the use and practicality of the PDCAAS and DIAAS system. This review builds upon previous research analyzing the total nutrient density of protein-rich foods and expands scientific research investigating the quality of proteins. In summary, the average sum of indispensable amino acids for meat and fish products is much more consistent than that of non-meat and plant-based food products. However, some non-meat products have relatively similar amounts of indispensable amino acids on a similar serving size basis. The overwhelming aspect of determining protein quality is that greater research is needed to determine protein digestibility of food products.

The postprandial rise in essential amino acid (EAA) concentrations modulates the increase in muscle protein synthesis rates after protein ingestion. The EAA content and AA composition of the dietary protein source contribute to the differential muscle protein synthetic response to the ingestion of different proteins. Lower EAA contents and specific lack of sufficient leucine, lysine, and/or methionine may be responsible for the lower anabolic capacity of plant-based compared with animal-based proteins. We compared EAA contents and AA composition of a large selection of plant-based protein sources with animal-based proteins and human skeletal muscle protein. AA composition of oat, lupin, wheat, hemp, microalgae, soy, brown rice, pea, corn, potato, milk, whey, caseinate, casein, egg, and human skeletal muscle protein were assessed using UPLC-MS/MS. EAA contents of plant-based protein isolates such as oat (21%), lupin (21%), and wheat (22%) were lower than animal-based proteins (whey 43%, milk 39%, casein 34%, and egg 32%) and muscle protein (38%). AA profiles largely differed among plant-based proteins with leucine contents ranging from 5.1% for hemp to 13.5% for corn protein, compared to 9.0% for milk, 7.0% for egg, and 7.6% for muscle protein. Methionine and lysine were typically lower in plant-based proteins (1.0 ± 0.3 and 3.6 ± 0.6%) compared with animal-based proteins (2.5 ± 0.1 and 7.0 ± 0.6%) and muscle protein (2.0 and 7.8%, respectively). In conclusion, there are large differences in EAA contents and AA composition between various plant-based protein isolates. Combinations of various plant-based protein isolates or blends of animal and plant-based proteins can provide protein characteristics that closely reflect the typical characteristics of animal-based proteins.

Conversely, a low concentration of 1 or more essential amino acids in a food lowers its nutritional quality. Although plant proteins form a large part of the human diet, most are deficient in 1 or more essential amino acids and are therefore regarded as incomplete proteins. Their protein quality can be upgraded, however, by combining them with others that are higher in protein quality or that contain whatever essential amino acids are lacking or deficient (protein complementarity).9,10,13 For example, combining corn (limited in lysine) with beans (limited in methionine) results in a high-quality protein food combination. Thus, the requirement for adequate essential amino acids can be met in a vegetarian diet by mixing foods of complementary amino acid composition.12–14 Only a few dietary sources of pure protein do not contain fat or carbohydrates, eg, egg white (albumin) and powdered casein from milk. Most high-protein foods contain fat (eg, meat, fish, and poultry) and/or carbohydrates (eg, milk, fruit, vegetables, legumes, nuts, breads, and cereals). Lean animal protein sources and vegetable proteins can be incorporated easily into a healthy diet plan.
An average of 102 g of protein per person per day is available in the US food supply.15 Actual protein consumption ranges from 88 to 92 g for men and from 63 to 66 g for women.16 Animal products provide ≈75% of the essential amino acids in the food supply, followed by dairy products, cereal products, eggs, legumes, fruits, and vegetables.16 The recommended daily allowance (RDA) for protein of high biological value for adults, based on body weight, is ≈0.8 g/kg17 or 0.36 g/lb. There are many conditions in which extra protein is needed, including childhood/adolescence (ie, periods of growth), pregnancy, lactation, intense strength and endurance training and other forms of physical activity, some disease states, and possibly in the elderly.18 In the general population, however, protein intake above the required amount is inefficiently used by the body and imposes the additional burdens of metabolizing and excreting excess waste products (eg, urea and ammonia) by the liver and kidney.19–22

Plant-sourced proteins offer environmental and health benefits, and research increasingly includes them in study formulas. However, plant-based proteins have less of an anabolic effect than animal proteins due to their lower digestibility, lower essential amino acid content (especially leucine), and deficiency in other essential amino acids, such as sulfur amino acids or lysine. Thus, plant amino acids are directed toward oxidation rather than used for muscle protein synthesis. In this review, we evaluate the ability of plant- versus animal-based proteins to help maintain skeletal muscle mass in healthy and especially older people and examine different nutritional strategies for improving the anabolic properties of plant-based proteins. Among these strategies, increasing protein intake has led to a positive acute postprandial muscle protein synthesis response and even positive long-term improvement in lean mass. Increasing the quality of protein intake by improving amino acid composition could also compensate for the lower anabolic potential of plant-based proteins. We evaluated and discussed four nutritional strategies for improving the amino acid composition of plant-based proteins: fortifying plant-based proteins with specific essential amino acids, selective breeding, blending several plant protein sources, and blending plant with animal-based protein sources. These nutritional approaches need to be profoundly examined in older individuals in order to optimize protein intake for this population who require a high-quality food protein intake to mitigate age-related muscle loss.

Protein intake that exceeds the recommended daily allowance is widely accepted for both endurance and power athletes. However, considering the variety of proteins that are available much less is known concerning the benefits of consuming one protein versus another. The purpose of this paper is to identify and analyze key factors in order to make responsible recommendations to both the general and athletic populations. Evaluation of a protein is fundamental in determining its appropriateness in the human diet. Proteins that are of inferior content and digestibility are important to recognize and restrict or limit in the diet. Similarly, such knowledge will provide an ability to identify proteins that provide the greatest benefit and should be consumed. The various techniques utilized to rate protein will be discussed. Traditionally, sources of dietary protein are seen as either being of animal or vegetable origin. Animal sources provide a complete source of protein (i.e. containing all essential amino acids), whereas vegetable sources generally lack one or more of the essential amino acids. Animal sources of dietary protein, despite providing a complete protein and numerous vitamins and minerals, have some health professionals concerned about the amount of saturated fat common in these foods compared to vegetable sources. The advent of processing techniques has shifted some of this attention and ignited the sports supplement marketplace with derivative products such as whey, casein and soy. Individually, these products vary in quality and applicability to certain populations. The benefits that these particular proteins possess are discussed. In addition, the impact that elevated protein consumption has on health and safety issues (i.e. bone health, renal function) are also reviewed. Key PointsHigher protein needs are seen in athletic populations.Animal proteins is an important source of protein, however potential health concerns do exist from a diet of protein consumed from primarily animal sources.With a proper combination of sources, vegetable proteins may provide similar benefits as protein from animal sources.Casein protein supplementation may provide the greatest benefit for increases in protein synthesis for a prolonged duration.

Purpose Of Review: The current review provides an update on the recent research developments regarding amino acid bioavailability in conditions of both good health and gut disorders.

Recent Findings: Determination of amino acid bioavailability is complex and invasive. Minimally invasive methods using stable isotopes have been developed for humans. Data were collected in different models - humans, pigs and rats with various procedures - leading to interstudy variability. They mainly focused on either plant protein or the effect of food processing on animal protein. Plant protein in their original food matrix (legumes, grains, nuts) are generally less digestible (about 80%) than animal protein (meat, egg, milk; about 93%). Food processing has a limited impact on animal protein but its effect might be higher on plant protein. Few studies have documented the effect of gut disorders on protein digestibility, except in gastric bypass where paradoxical effects were reported. Data are needed to identify the amplitude of protein malabsorption in diseases such as inflammatory bowel disease or environmental enteric dysfunction.

Summary: The past 5 years have seen a renewed interest in amino acid bioavailability in view of assessing protein quality to support current shifts in protein sourcing. Methodological developments have been performed and several studies have reported values in various models. The question of protein digestibility in gut disorders remains poorly addressed.

Plant-sourced proteins offer environmental and health benefits, and research increasingly includes them in study formulas. However, plant-based proteins have less of an anabolic effect than animal proteins due to their lower digestibility, lower essential amino acid content (especially leucine), and deficiency in other essential amino acids, such as sulfur amino acids or lysine. Thus, plant amino acids are directed toward oxidation rather than used for muscle protein synthesis. In this review, we evaluate the ability of plant- versus animal-based proteins to help maintain skeletal muscle mass in healthy and especially older people and examine different nutritional strategies for improving the anabolic properties of plant-based proteins. Among these strategies, increasing protein intake has led to a positive acute postprandial muscle protein synthesis response and even positive long-term improvement in lean mass. Increasing the quality of protein intake by improving amino acid composition could also compensate for the lower anabolic potential of plant-based proteins. We evaluated and discussed four nutritional strategies for improving the amino acid composition of plant-based proteins: fortifying plant-based proteins with specific essential amino acids, selective breeding, blending several plant protein sources, and blending plant with animal-based protein sources. These nutritional approaches need to be profoundly examined in older individuals in order to optimize protein intake for this population who require a high-quality food protein intake to mitigate age-related muscle loss.

Dietary proteins are indispensable to human nutrition. In addition to their tissue-building function, they affect body composition and regulate various metabolic pathways, as well as satiety and immune system activity. Protein use can be examined from a quantitative or qualitative viewpoint. In this scoping review, we compare animal- and plant-based protein sources in terms of their effects on human health and the environment. We conclude that the consumption of vegetable protein sources is associated with better health outcomes overall (namely, on the cardiovascular system) than animal-based product use. The healthier outcomes of vegetable protein sources dovetail with their lower environmental impact, which must be considered when designing an optimal diet. Indeed, the health of the planet cannot be disjointed from the health of the human being. Future research will clarify the mechanisms of action underlying the health effects of plant-based protein sources when compared with animal sources, fostering better agronomic practices and influencing public health in a direction that will benefit both the planet and its inhabitants.

The quality and nutritional value of dietary proteins are determined by the quantity, digestibility and bioavailability of essential amino acids (EAA), which play a critical role in human growth, longevity and metabolic health. Plant-source protein is often deficient in one or more EAAs (e.g., branched-chain amino acids, lysine, methionine and/or tryptophan) and, in its natural form, is less digestible than animal-source protein. Nevertheless, dietary intake of plant-source protein has been promoted because of its potential health benefits, lower cost of production and lower environmental impact compared to animal-source protein. Implementation of dietary strategies that improve both human and planetary health are of critical importance and subject to growing interest from researchers and consumers. Therefore, in this review we analyse current plant protein intake patterns and discuss possible countermeasures that can enhance plant protein nutrition, examples include: (1) combining different plant proteins with complementary EAA profiles; (2) identification and commercial cultivation of new and novel high-quality plant proteins; (3) industrial and domestic processing methods; and (4) genome-editing techniques.

Background: The Dietary Guidelines for Americans (DGA) recommends consuming a variety of "Protein Foods" based on "ounce-equivalent" (oz-eq) portions. No study has assessed the same oz-eq portions of animal- vs. plant-based protein foods on essential amino acid (EAA) bioavailability for protein anabolism in young and older adults.

Objectives: We assessed the effects of consuming two oz-eq portions of pork, eggs, black beans, and almonds on postprandial EAA bioavailability in young and older adults.

Methods: We conducted two investigator-blinded, randomized crossover trials in young ( = 30; mean age ±

Sd: 26.0 ± 4.9 y) and older adults ( = 25; mean age ±

Sd: 64.2 ± 6.6 y). Participants completed four testing sessions where they consumed a standardized meal with two oz-eq of either unprocessed lean pork, whole eggs, black beans, or sliced almonds. Blood samples were taken at baseline and 30, 60, 120, 180, 240, and 300 min postprandially. Plasma EAA bioavailability was based on postprandial integrated positive areas under the curve.

Results: Participant age did not affect EAA bioavailability among the four protein foods tested. Two oz-eq portions of pork (7.36 g EAA) and eggs (5.38 g EAA) resulted in greater EAA bioavailability than black beans (3.02 g EAA) and almonds (1.85 g EAA) in young and older adults, separately or combined ( < 0.0001 for all). Pork resulted in greater EAA bioavailability than eggs in young adults ( < 0.0001), older adults ( = 0.0007), and combined ( < 0.0001). There were no differences in EAA bioavailability between black beans and almonds.

Conclusions: The same "oz-eq" portions of animal- and plant-based protein foods do not provide equivalent EAA content and postprandial bioavailability for protein anabolism in young and older adults.

The sources or types of protein in the diet have long been overlooked regarding their link to cardiometabolic health. The picture is complicated by the fact that animal and plant proteins are consumed along with other nutrients and substances which make up the "protein package" so plant and animal protein come with clear nutrient clusters. This review aimed at deciphering the relation between plant and animal protein and cardiometabolic health by examining different nutritional levels (such as amino acids, protein type, protein foods, protein patterns, and associated overall dietary and nutrient patterns) and varying levels of scientific evidence [basic science, randomized controlled trials (RCTs), observational data]. Plant protein in Western countries is a robust marker of nutrient adequacy of the diet, whereas the contribution of animal protein is highly heterogeneous. Yet recent data from large cohorts have confirmed that total and animal proteins are associated with the risk of cardiovascular disease and diabetes, even when fully adjusting for lifestyle and dietary or nutritional factors. Here again, there is marked variability depending on the type of animal protein. Protein from processed red meat and total red meat on the one hand, and from legumes, nuts, and seeds on the other, are often reported at the extremes of the risk range. RCTs using purified proteins have contributed little to the topic to date, inasmuch as the findings cannot readily be extrapolated to current or near-future diets, but RCTs studying whole protein foods have shown a beneficial effect of pulses. Despite the fact that many of the benefits of plant protein reported in observational or interventional studies may stem from the protein package that they convey and the nutrients that they displace, there are also important indications that protein per se may affect cardiometabolic health via the many amino acids that are present in typically contrasting levels in plant compared with animal proteins.

Dietary proteins are indispensable to human nutrition. In addition to their tissue-building function, they affect body composition and regulate various metabolic pathways, as well as satiety and immune system activity. Protein use can be examined from a quantitative or qualitative viewpoint. In this scoping review, we compare animal- and plant-based protein sources in terms of their effects on human health and the environment. We conclude that the consumption of vegetable protein sources is associated with better health outcomes overall (namely, on the cardiovascular system) than animal-based product use. The healthier outcomes of vegetable protein sources dovetail with their lower environmental impact, which must be considered when designing an optimal diet. Indeed, the health of the planet cannot be disjointed from the health of the human being. Future research will clarify the mechanisms of action underlying the health effects of plant-based protein sources when compared with animal sources, fostering better agronomic practices and influencing public health in a direction that will benefit both the planet and its inhabitants.

Importance: Although emphasis has recently been placed on the importance of high-protein diets to overall health, a comprehensive analysis of long-term cause-specific mortality in association with the intake of plant protein and animal protein has not been reported. Objective: To examine the associations between overall mortality and cause-specific mortality and plant protein intake. Design, Setting, and Participants: This prospective cohort study analyzed data from 416 104 men and women in the US National Institutes of Health-AARP Diet and Health Study from 1995 to 2011. Data were analyzed from October 2018 through April 2020. Exposures: Validated baseline food frequency questionnaire dietary information, including intake of plant protein and animal protein. Main Outcomes and Measures: Hazard ratios and 16-year absolute risk differences for overall mortality and cause-specific mortality. Results: The final analytic cohort included 237 036 men (57%) and 179 068 women. Their overall median (SD) ages were 62.2 (5.4) years for men and 62.0 (5.4) years for women. Based on 6 009 748 person-years of observation, 77 614 deaths (18.7%; 49 297 men and 28 317 women) were analyzed. Adjusting for several important clinical and other risk factors, greater dietary plant protein intake was associated with reduced overall mortality in both sexes (hazard ratio per 1 SD was 0.95 [95% CI, 0.94-0.97] for men and 0.95 [95% CI, 0.93-0.96] for women; adjusted absolute risk difference per 1 SD was -0.36% [95% CI, -0.48% to -0.25%] for men and -0.33% [95% CI, -0.48% to -0.21%] for women; hazard ratio per 10 g/1000 kcal was 0.88 [95% CI, 0.84-0.91] for men and 0.86 [95% CI, 0.82-0.90] for women; adjusted absolute risk difference per 10 g/1000 kcal was -0.95% [95% CI, -1.3% to -0.68%] for men and -0.86% [95% CI, -1.3% to -0.55%] for women; all P < .001). The association between plant protein intake and overall mortality was similar across the subgroups of smoking status, diabetes, fruit consumption, vitamin supplement use, and self-reported health status. Replacement of 3% energy from animal protein with plant protein was inversely associated with overall mortality (risk decreased 10% in both men and women) and cardiovascular disease mortality (11% lower risk in men and 12% lower risk in women). In particular, the lower overall mortality was attributable primarily to substitution of plant protein for egg protein (24% lower risk in men and 21% lower risk in women) and red meat protein (13% lower risk in men and 15% lower risk in women). Conclusions and Relevance: In this large prospective cohort, higher plant protein intake was associated with small reductions in risk of overall and cardiovascular disease mortality. Our findings provide evidence that dietary modification in choice of protein sources may influence health and longevity.

Importance: Defining what represents a macronutritionally balanced diet remains an open question and a high priority in nutrition research. Although the amount of protein may have specific effects, from a broader dietary perspective, the choice of protein sources will inevitably influence other components of diet and may be a critical determinant for the health outcome.

Objective: To examine the associations of animal and plant protein intake with the risk for mortality. DESIGN, SETTING,

And Participants: This prospective cohort study of US health care professionals included 131 342 participants from the Nurses' Health Study (1980 to end of follow-up on June 1, 2012) and Health Professionals Follow-up Study (1986 to end of follow-up on January 31, 2012). Animal and plant protein intake was assessed by regularly updated validated food frequency questionnaires. Data were analyzed from June 20, 2014, to January 18, 2016.

Main Outcomes And Measures: Hazard ratios (HRs) for all-cause and cause-specific mortality.

Results: Of the 131 342 participants, 85 013 were women (64.7%) and 46 329 were men (35.3%) (mean [SD] age, 49 years). The median protein intake, as assessed by percentage of energy, was 14% for animal protein (5th-95th percentile, 9%-22%) and 4% for plant protein (5th-95th percentile, 2%-6%). After adjusting for major lifestyle and dietary risk factors, animal protein intake was not associated with all-cause mortality (HR, 1.02 per 10% energy increment; 95% CI, 0.98-1.05; P for trend = .33) but was associated with higher cardiovascular mortality (HR, 1.08 per 10% energy increment; 95% CI, 1.01-1.16; P for trend = .04). Plant protein was associated with lower all-cause mortality (HR, 0.90 per 3% energy increment; 95% CI, 0.86-0.95; P for trend < .001) and cardiovascular mortality (HR, 0.88 per 3% energy increment; 95% CI, 0.80-0.97; P for trend = .007). These associations were confined to participants with at least 1 unhealthy lifestyle factor based on smoking, heavy alcohol intake, overweight or obesity, and physical inactivity, but not evident among those without any of these risk factors. Replacing animal protein of various origins with plant protein was associated with lower mortality. In particular, the HRs for all-cause mortality were 0.66 (95% CI, 0.59-0.75) when 3% of energy from plant protein was substituted for an equivalent amount of protein from processed red meat, 0.88 (95% CI, 0.84-0.92) from unprocessed red meat, and 0.81 (95% CI, 0.75-0.88) from egg.

Conclusions And Relevance: High animal protein intake was positively associated with cardiovascular mortality and high plant protein intake was inversely associated with all-cause and cardiovascular mortality, especially among individuals with at least 1 lifestyle risk factor. Substitution of plant protein for animal protein, especially that from processed red meat, was associated with lower mortality, suggesting the importance of protein source.

Objective: To examine and quantify the potential dose-response relation between intake of total, animal, and plant protein and the risk of mortality from all causes, cardiovascular disease, and cancer.

Design: Systematic review and meta-analysis of prospective cohort studies.

Data Sources: PubMed, Scopus, and ISI Web of Science until December 2019, and references of retrieved relevant articles.

Study Selection: Prospective cohort studies that reported the risk estimates for all cause, cardiovascular, and cancer mortality in adults aged 18 or older.

Data Synthesis: Random effects models were used to calculate pooled effect sizes and 95% confidence intervals for the highest versus lowest categories of protein intake and to incorporate variation between studies. Linear and non-linear dose-response analyses were done to evaluate the dose-response relations between protein intake and mortality.

Results: 32 prospective cohort studies were included in the systematic review and 31 in the meta-analysis. During the follow-up period of 3.5 to 32 years, 113 039 deaths (16 429‬ from cardiovascular disease and 22 303‬ from cancer) occurred among 715 128 participants. Intake of total protein was associated with a lower risk of all cause mortality (pooled effect size 0.94, 95% confidence interval 0.89 to 0.99, I2=58.4%, P<0.001). Intake of plant protein was significantly associated with a lower risk of all cause mortality (pooled effect size 0.92, 95% confidence interval 0.87 to 0.97, I2=57.5%, P=0.003) and cardiovascular disease mortality (pooled hazard ratio 0.88, 95% confidence interval 0.80 to 0.96, I2=63.7%, P=0.001), but not with cancer mortality. Intake of total and animal protein was not significantly associated with risk of cardiovascular disease and cancer mortality. A dose-response analysis showed a significant inverse dose-response association between intake of plant protein and all cause mortality (P=0.05 for non-linearity). An additional 3% energy from plant proteins a day was associated with a 5% lower risk of death from all causes.

Conclusions: Higher intake of total protein was associated with a lower risk of all cause mortality, and intake of plant protein was associated with a lower risk of all cause and cardiovascular disease mortality. Replacement of foods high in animal protein with plant protein sources could be associated with longevity.

Dietary guidance and Canada's 2019 Food Guide encourage increased consumption of plant-based foods as a source of dietary protein. However, there is an absence of recent data on protein and nutrient intakes and quality of Canadian dietary patterns that might occur with increased plant protein intakes. This study compared food sources and nutrient intakes of Canadian adults within groups of increasing plant protein-containing diets. The CCHS 2015 Public-Use Microdata File of single 24-hour dietary recalls of males and females ≥19 years ( = 6498) or ≥70 years ( = 1482) were examined. Respondents were allocated into 4 groups defined by their protein intake percentage coming from plant-based foods (i.e., group 1: 0-24.9%, group 2: 25-49.9%, group 3: 50-74.9%, group 4: 75-100%). Protein intake in adults averaged 63.3% animal and 36.7% plant protein. Where plant protein contributed >50% protein, higher intakes of carbohydrate, dietary fibre, folate, dietary folate equivalents, iron and magnesium ( < 0.001) but lower intakes of total and saturated fat, protein, vitamin D, vitamin B12, riboflavin and niacin ( < 0.0001) were reported. In contrast, group 1 had higher total and saturated fat, protein, vitamin B12, thiamin, niacin, and zinc, but lower carbohydrate, dietary fibre, and magnesium. Balancing plant- with animal-based protein foods leads to healthier dietary patterns with more favourable nutritional properties when compared with diets based on either high animal or high plant protein content. Combinations of animal- and plant-based proteins improve nutrient quality of Canadian diets. The source of protein influences diet quality.

Health authorities increasingly recommend a more plant-based diet, rich in fruits, vegetables, pulses, whole grains and nuts, low in red meat and moderate in dairy, eggs, poultry and fish which will be beneficial for both health and the environment. A systematic review of observational and intervention studies published between 2000 and January 2020 was conducted to assess nutrient intake and status in adult populations consuming plant-based diets (mainly vegetarian and vegan) with that of meat-eaters. Mean intake of nutrients were calculated and benchmarked to dietary reference values. For micronutrient status, mean concentrations of biomarkers were calculated and compared across diet groups. A total of 141 studies were included, mostly from Europe, South/East Asia, and North America. Protein intake was lower in people following plant-based diets compared to meat-eaters, but well within recommended intake levels. While fiber, polyunsaturated fatty acids (PUFA), folate, vitamin C, E and magnesium intake was higher, eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) intake was lower in vegetarians and vegans as compared to meat-eaters. Intake and status of vitamin B12, vitamin D, iron, zinc, iodine, calcium and bone turnover markers were generally lower in plant-based dietary patterns compared to meat-eaters. Vegans had the lowest vitamin B12, calcium and iodine intake, and also lower iodine status and lower bone mineral density. Meat-eaters were at risk of inadequate intakes of fiber, PUFA, α-linolenic acid (ALA), folate, vitamin D, E, calcium and magnesium. There were nutrient inadequacies across all dietary patterns, including vegan, vegetarian and meat-based diets. As plant-based diets are generally better for health and the environment, public health strategies should facilitate the transition to a balanced diet with more diverse nutrient-dense plant foods through consumer education, food fortification and possibly supplementation.

BACKGROUND &

Aims: Overall diet quality is a key predictor of disease risk and mortality. Diets higher in animal protein have been associated with increased disease risk and all-cause mortality. However, the source of protein consumed will inevitably influence the intake of other macronutrients and micronutrients which can also play a role in the onset of disease. The aim of the present study was to assess the relationship between animal and plant protein intake and overall diet quality in young adult females and males.

Methods: Dietary intake was assessed via 3-day food log (n = 150; 53% females) and data were analyzed using the Nutrition Data Systems for Research (NDSR).

Results: Females and males consuming <70% of their protein from animal sources had higher scores on a modified Healthy Eating Index (HEI) compared those consuming >70% of their protein from animal sources. Males scored lower than females on the modified HEI regardless of protein source intake variation.

Conclusions: Our findings suggest that overall diet quality differs with varying protein source consumption and eating <70% of protein from animal sources might lead to a better score on the HEI. Future research investigating protein source and disease risk should examine overall dietary quality as a potential effect modifier.

Background: Promoting plant-based proteins is at the forefront of many initiatives in public health nutrition.

Objectives: The aim of this study was to characterize the sociodemographic drivers of plant-based protein diet consumption, and to study these in relation to diet quality and cost.

Methods: The Seattle Obesity Study series (SOS I and II) yielded the study sample (n = 1636). Sociodemographic data were obtained by survey self-report. Diet quality and cost came from the Fred Hutchinson Cancer Research Center Food-Frequency Questionnaire linked to retail food prices. The Healthy Eating Index 2010 (HEI-2010) and mean adequacy ratio (MAR) served as measures of diet quality. Linear regressions with robust standard errors examined associations.

Results: Total proteins contributed 16.8% of daily dietary energy. The breakdown by animal and plant proteins was 10.9% and 5.9%, respectively. The sociodemographic factors associated with plant-protein consumption were a positive attitude towards healthy eating and higher education but not income. Plant-protein diets were characterized by severalfold increases in nuts and seeds, soy and legumes, but much less meat, poultry, dairy, solid fats, and added sugars. Higher quartiles of plant-based diets were associated with significantly higher HEI-2010 (β: 13.0 from quartile 1 to quartile 4; 95%

Ci: 11.8, 14.3) and higher MAR (β: 6.0; 95%

Ci: 3.5, 8.5) with minimal impact on diet costs (β: 0.35; 95%

Ci: 0.04, 0.67). In contrast, higher quartiles of animal-protein diets were associated with higher diet costs (β: 1.07; 95%

Ci: 0.77, 1.36) but lower HEI-2010 (β: -3.2; 95%

Ci: -4.5, -1.9). Each additional 3% of energy from plant proteins was associated with an 8.4-unit increase in HEI-2010 (95%

Ci: 7.6, 9.1) and with a 4.1-unit increase in MAR (95%

Ci: 2.7, 5.5) with a minimal increase in diet cost (β: 0.28; 95%

Ci: 0.06, 0.50).

Conclusion: Plant-based protein diets may be a cost-effective way to improve diet quality at all levels of income. Future research needs to evaluate the quality of plant-based protein in relation to amino acids and health.