Received: 12 March 2021 Revised: 2 July 2021 Accepted: 2 August 2021

DOI: 10.1111/mcn.13264

REVIEW ARTICLE

Animal source foods, rich in essential amino acids, are

important for linear growth and development of young
children in low- and middle-income countries

Panam Parikh1 | Richard Semba2 | Mark Manary3 | Sumathi Swaminathan4 |

Emorn Udomkesmalee5 | Rolf Bos1 | Bee Koon Poh6 | Nipa Rojroongwasinkul5 |
Jan Geurts1 | Rini Sekartini7 | Tran Thuy Nga8

1
FrieslandCampina, Amersfoort, The
Netherlands Abstract
2
Wilmer Eye Institute, Johns Hopkins Growth faltering under 5 years of age is unacceptably high worldwide, and even
University School of Medicine, Baltimore,
more children, while not stunted, fail to reach their growth potential. The time
Maryland, USA
3
Department of Paediatrics, Washington between conception and 2 years of age is critical for development. The period from 6
University School of Medicine, St. Louis, to 23 months, when complementary foods are introduced, coincides with a time
Missouri, USA
4
when growth faltering and delayed neurocognitive developments are most common.
St John's Research Institute, St John's
National Academy of Health Sciences, Fortunately, this is also the period when diet exercises its greatest influence. Growing
Bangalore, Karnataka, India
up in an adverse environment, with a deficient diet, as typically seen in low- and
5
Institute of Nutrition, Mahidol University,
Nakhon Pathom, Thailand
middle-income countries (LMICs), hampers growth and development of children and
6
Nutritional Sciences Programme & Centre for prevents them from realising their full developmental and economic future potential.
Community Health, Faculty of Health Sufficient nutrient availability and utilisation are paramount to a child's growth and
Sciences, University Kebangsaan Malaysia,
Kuala Lumpur, Malaysia development trajectory, especially in the period after breastfeeding. This review
7
Faculty of Medicine, Department of highlights the importance of essential amino acids (EAAs) in early life for linear
Pediatrics, University of Indonesia and Cipto
growth and, likely, neurocognitive development. The paper further discusses
Mangunkusumo Hospital, Jakarta, Indonesia
8
Department of Occupational and School signalling through mammalian target of rapamycin complex 1 (mTORC1) as one of
Nutrition, National Institute of Nutrition (NIN), the main amino acid (AA)-sensing hubs and the master regulator of both growth and
Hanoi, Vietnam
neurocognitive development. Children in LMICs, despite consuming sufficient total
Correspondence protein, do not meet their EAA requirements due to poor diet diversity and
Jan Geurts, FrieslandCampina, Amersfoort,
The Netherlands. low-quality dietary protein. AA deficiencies in early life can cause reductions in linear
Email: [email protected] growth and cognition. Ensuring AA adequacy in diets, particularly through inclusion
of nutrient-dense animal source foods from 6 to 23 months, is strongly encouraged
in LMICs in order to compensate for less than optimal growth during complementary
feeding.

KEYWORDS
animal source protein, arginine, cognition, growth faltering, leucine, mTORC1, tryptophan

This is an open access article under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License, which permits use and distribution in any
medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made.
© 2021 FrieslandCampina. Maternal & Child Nutrition published by John Wiley & Sons Ltd.

Matern Child Nutr. 2021;e13264. wileyonlinelibrary.com/journal/mcn 1 of 12

https://doi.org/10.1111/mcn.13264
2 of 12 PARIKH ET AL.

1 | I N T RO DU CT I O N
Key messages
Physical growth is globally recognised as the best indicator of
well-being in children as well as an accurate reflection for health
• Many children in LMICs, who experience growth falter-
inequalities faced by populations (de Onis, 2017). The unacceptably
ing, have inadequate levels of essential amino acids
high burden of stunting or linear growth faltering is a stark sign
partly attributable to poor protein quality of their diets.
that infants and young children across the globe are not growing well,
Inclusion of animal source foods is encouraged to
both physically and mentally (UNICEF, 2019). In 2018, at a global
improve the quality of predominantly cereal/vegetal-
level, an estimated 149 million children under 5 were stunted,
based diets.
having a height-for-age z-score (HAZ) below 2 standard deviations
• Protein cannot be regarded as a single, homogeneous
(UNICEF, 2019).
nutrient.
Stunting is pervasively associated with and likely, in part, a cause
• Mechanistically, inadequate intake of EAAs is likely to
for increased mortality, morbidity, impaired cognitive and motor
negatively influence linear growth and neurocognition via
development, poor school performance, poor intellectual
the mTORC1 pathway.
achievement, reduced economic productivity and diminished earnings
• Further in-depth research into AA intakes and concentra-
(Engle et al., 2011; Hoddinott et al., 2013). As linear growth and
tions in infants and young children presenting with vary-
neurocognitive development share some of the underlying factors
ing physiological states across a wide range of
(e.g., suboptimal nutrition, repeated infections, inadequate access to
geographical regions can provide valuable insights for
care and lack of stimulation), it seems plausible that biological
designing appropriate nutritional strategies.
mechanisms exist that simultaneously lead to linear growth faltering
and deficits in neurodevelopment in response to continued exposure
to one or more of these factors (Leroy & Frongillo, 2019; Prado
et al., 2019; Prado & Dewey, 2014).
Nutrient availability and/or utilisation at the cellular level plays
a critical role in driving a child's trajectory of linear growth with both motor and attentional functioning have been reported in
(de Onis, 2017; MAL-ED Network Investigators, 2017) and literature (Cusick & Georgieff, 2012; Prado & Dewey, 2014;
neurocognitive development (Prado et al., 2019; Prado & Sudfeld et al., 2015). Until recently, the window of possible recov-
Dewey, 2014). For the first 6 months of life, the World Health ery from stunting or linear growth faltering was believed to be up
Organization (WHO, 2001) recommends exclusive breastfeeding to to 24 months of age. Learnings from the COHORTS study, from
support optimal growth and development. For infants and young rural Gambia (Prentice et al., 2013) and from the Young Lives
children aged 6–23 months, it is recommended to continue study in Ethiopia, Peru, India and Vietnam (Fink & Rockers, 2014;
breastfeeding and complement it with foods that are diverse and Lundeen et al., 2014; Schott et al., 2013), however, suggest that
sufficiently energy and nutrient dense to promote optimal growth possibilities for catch-up growth may extend beyond 24 months,
(Bhutta, Das, et al., 2013; Horta & Victora, 2013; WHO, 2003). offering additional opportunities for interventions that may yield
This is because, after 6 months, breastmilk alone is insufficient to life cycle and intergenerational effects (Prentice et al., 2013;
meet a child's nutrient needs (UNICEF, 2016). The high nutritional Suryawan et al., 2021).
demand coupled with limited quality and quantity of complemen- A recent systematic review and meta-analysis reported a small,
tary foods during the first 2 years of life are key drivers of sub- but significant, positive effect of post-natal macronutrient and
optimal growth, coinciding with the time of peak stunting micronutrient supplementation on linear growth and neuro-
prevalence in developing countries (Dewey & Adu-Afarwuah, 2008; development scores (language, motor and socioemotional) in chil-
Shrimpton et al., 2001). A comprehensive exploration of the diets dren under 5 years in low- and middle-income countries (LMICs)
of 76,641 children ages 6–23 months in 42 countries from five (Prado et al., 2019). Modest effects on neurodevelopment, but
geographic regions reported diminished diet diversity and low con- not linear growth, have been reported with interventions with
sumption of nutrient-rich foods. It was found that, on average, chil- multiple micronutrients, whereas single micronutrient supplementa-
dren consumed only 2.81 out of 7 food groups in the 24 h prior tion has been shown to have a small impact on linear growth
to the survey and only 39% of the children consumed dairy but not neurodevelopment (Bhutta, Salam, & Das, 2013;
(Choudhury et al., 2019). Among the five regions, Sub-Saharan Dulal et al., 2018; Prado et al., 2019; Ramakrishnan et al., 2009;
Africa had the lowest diet diversity, followed by South and South- Stammers et al., 2015). Overall, there is very limited evidence
East Asia; the greatest diet diversity was seen in Latin American from intervention studies on the impact of macronutrient supple-
and the Caribbean, with on average four out of seven food groups mentation, and more specifically protein or amino acid
consumed. The negative effects of these early life nutritional defi- (AA) supplementation, on linear growth and/or neurodevelopment
ciencies on linear growth as well as neuronal development, synap- in children at community level. Although no consistent benefit of
tic pruning and connectivity within regions of the brain associated additional protein on linear growth has been reported, it is
PARIKH ET AL. 3 of 12

important to note that these studies did not quantify protein Therefore, assessing adequacy of protein intakes should take into
intakes, protein quality or any biomarkers of protein status account the content, pattern and bioavailability of the EAAs.
(Arsenault & Brown, 2017). The persistent global burden of linear Another factor often overlooked is the physiological state of the
growth faltering and delayed development in children under 5 years population. Infants and young children move between a healthy
in LMICs suggests a need to (re-)evaluate some fundamental die- maintenance state, an acute routine infectious state and a rapid
tary nutrients (Semba, Shardell, Sakr Ashour, et al., 2016) that may catch-up growth phase after a period of infection or food insecu-
be lacking or inadequately represented in the dietary patterns of rity, the latter two states being characterised by twofold to four-
this vulnerable population. fold increased AA requirements (Reeds et al., 1994; Shivakumar
In this review, we present evidence on the critical importance of et al., 2020). The relevance of these factors was reinforced in the
protein, more specifically essential amino acids (EAAs), for linear analysis of national level data from 180 countries by Ghosh and
growth and neurocognitive development in children under 5 years colleagues. After correcting for EAA composition, digestibility,
(0–59 months) of age in LMICs and suggest areas for future nutrition energy deficit and infections, the authors reported up to 50% prev-
research. alence of protein inadequacy with lysine as the primary limiting AA
(Ghosh et al., 2012).
In LMICs where the diets of infants and young children are
2 | METHODS largely dominated by staple foods like rice, wheat, maize (corn),
millet, sorghum, roots and tubers (Dewey, 2013; FAO, 2019;
An exhaustive search for eligible studies was performed in Scopus, Lee, 2014), there is a high likelihood of inadequate intake of EAAs
PubMed and Google Scholar. Searches were carried out without and utilisable dietary protein to support overall growth. To illus-
restrictions to date of publication, with main search terms including trate, Table 1 lists the dry weight percentage of protein and quan-
‘infant, newborn, child’, ‘diet, dietary protein, protein quality, amino tity of digestible AAs per gram of protein, based on Digestible
acids’, ‘protein status, amino acid status’, ‘linear growth, stunting, Indispensable Amino Acid Score (DIAAS) analyses, in 21 of the
height’ and ‘child development, cognitive development, neuro- most consumed protein sources around the world along with the
cognition’. Proper Boolean operators ‘AND’ and ‘OR’ were daily protein and AA requirements for a 12-month-old child
included to ensure comprehensiveness. This was supplemented weighing 9.5 kg for different physiological states including environ-
with electronic searching of reference lists and ‘related articles’ on mental enteric dysfunction (EED). EED is a subclinical disorder of
PubMed. Studies were eligible if their primary focus was on pro- the gut and an important underlying cause of growth faltering,
tein nutriture in linear growth and neurocognition in infants and characterised by reduced villus height, increased crypt depth and
young children (0–59 months) from LMIC. We excluded articles on lymphocyte infiltration, resulting in impaired absorption and
protein in pregnancy or later in childhood, protein in medical con- increased small intestinal permeability (Mutasa et al., 2021). Assum-
ditions or disorders, all other forms of malnutrition and non-LMIC ing the child is consuming the minimum required amount of pro-
populations. tein with approximately 80% coming from grain, cereal, tuber or
root, and the remaining from legumes, nuts or seeds, it can be rea-
sonably expected that the intakes of AAs will be inadequate to
3 | RESULTS meet the requirements of the different physiological states. As an
example, consider a few common diets, none with animal source
3.1 | EAA deficiency is common among children in foods: an East African diet of 80% cassava and 20% common bean
developing countries will not adequately meet most of the daily EAA requirements. In
contrast, a West African diet of 80% maize and 20% cowpea and
Historically, it has been assumed that children in developing a South Asian diet of 80% rice and 20% lentils will meet the AA
countries receive adequate dietary protein (Semba, 2016). This was requirements for both a healthy child and child with EED but not
largely based on the reference of protein as a homogenous nutri- for catch-up growth. Modest amounts of protein from animal
ent needed in the diet in a certain amount, not taking into account source foods can address these dietary limitations as these are the
that proteins are structurally diverse macromolecules made up of best sources of EAAs and are known to have high digestibility as
various amounts of AAs that are largely not always interconvertible well as biological value. It should be noted that the FAO/WHO
(Young, 2000). A steady supply of AAs is essential to ensure all estimates of EAA requirements for infants are based on the
body proteins can be assembled as well as execute their vital func- assumption that human milk intake from a healthy well-nourished
tions for optimal growth, development and health (Millward, 2003). mother provides optimal protein intake for an infant (WHO &
Nine AAs (histidine, isoleucine, leucine, lysine, methionine, phenylal- FAO, 2007). For children 12–59 months of age, estimates are
anine, threonine, tryptophan and valine) cannot be synthesised in based on a factorial computation (Pillai & Kurpad, 2012; WHO &
the body and need to be acquired exclusively from dietary sources FAO, 2007) and reflect the physiological needs obtained under
(WHO & FAO, 2007). The nutritional value of the dietary protein, ideal conditions (Uauy, 2013). These estimates do not consider the
in effect, relates to the provision of these EAAs to the body. added requirements of catch-up growth (Pillai & Kurpad, 2012), or
4 of 12 PARIKH ET AL.

T A B L E 1 Per cent of protein and quantity of digestible amino acids per gram of protein of the most consumed protein sources around the
world along with the daily protein and AA requirements

Prot His Ile Leu Lys Thr Val SAA AAA Trp
(g) (mg) (mg) (mg) (mg) (mg) (mg) (mg) (mg) (mg)
Requirements (based FAO requirement for 8.2 142.5 256.5 513.0 427.5 218.5 342.0 209.0 380.0 60.8
on a 12-month-old, 1–2 years old
weight of 9.5 kg) (Shivakumar
et al., 2020)
Adapted to account for 9.4 163.9 295.0 590.0 491.6 251.3 393.3 240.4 437.0 69.9
15% loss due to EEDa
Catch-up growthb 26.79 627.0 902.5 1881.0 1738.5 978.5 1235.0 836.0 1681.5 275.5
(Owino et al., 2016;
Semba, Shardell,
Trehan, et al., 2016;
Shivakumar
et al., 2020)

Digestible AA content (mg/g protein)

Prot His Ile Leu Lys Thr Val SAA AAA Trp
(%) (mg) (mg) (mg) (mg) (mg) (mg) (mg) (mg) (mg)
Cereals and Maize (20316) 5.7 25.6 30.8 112.8 21.4 28.6 43.1 33.3 78.5 5.5
grains Rice (20061) 5.4 24.8 30.8 66.4 32.0 28.9 51.5 38.6 87.5 10.8
Wheat (20072) 11.6 21.5 33.4 63.7 23.6 26.1 39.7 38.6 73.0 11.5
Sorghum (20067) 8.8 18.8 35.5 123.5 21.1 27.4 45.4 23.0 71.0 10.2
Millet (20031) 9.8 18.8 31.6 100.3 14.4 21.4 34.1 30.6 73.0 10.0
Tubers or roots Cassava (11134) 2.1 14.6 14.9 23.2 29.8 16.9 22.6 26.4 41.9 12.4
Sweet potatoes 2.9 17.1 31.2 53.8 37.7 45.8 48.2 26.8 89.8 16.4
(11510)
Yams (11602) 4.7 21.3 28.1 36.8 38.5 19.9 24.5 35.3 44.6 6.4
Potato (11413) 6.1 20.9 38.6 56.1 53.3 34.9 45.4 21.4 70.8 13.3
Legumes, nuts or Cowpea (16062) 18.3 25.1 31.3 59.0 54.8 28.2 35.3 18.7 69.8 8.5
seeds Pigeon pea (16101) 12.6 25.3 16.6 42.8 46.3 18.7 21.6 15.0 61.3 5.7
Peanuts (16087) 19.9 22.7 29.2 55.7 21.9 24.3 34.0 18.6 83.2 7.0
Chickpeas (16056) 15.6 21.3 35.1 56.9 40.4 27.1 32.1 17.4 60.0 7.4
Lentils (16069) 19.7 28.2 27.9 54.3 55.4 25.8 32.4 15.6 83.9 6.6
Soybeans (16111) 38.1 22.6 41.6 69.2 57.7 35.3 42.4 23.5 79.1 11.4
Common bean (16027) 17.4 17.5 30.9 55.1 57.0 31.1 32.4 19.2 55.9 8.8
Roasted sesame 14.6 25.6 37.4 67.4 26.3 34.5 48.6 47.0 85.4 17.9
(12024)
Animal source Chicken (05126) 28.0 28.5 46.9 66.7 81.5 39.7 44.6 37.2 78.3 10.8
foods Egg (01129) 11.4 20.1 46.3 75.2 63.9 46.1 53.0 47.4 94.4 10.8
Fish (15261) 18.3 19.9 43.1 72.6 83.8 43.5 43.5 36.8 70.3 9.5
Powdered whole milk 23.4 34.4 52.6 93.1 72.2 41.5 59.6 32.2 92.7 13.1
(01090)

Note: Protein percentages were obtained from the USDA food composition database (https://fdc.nal.usda.gov); AAs are presented as DIAAS corrected
values.
Abbreviations: AA, amino acid; AAA, aromatic AA; His, histidine; EED, environmental enteric dysfunction; Ile, isoleucine; Leu, leucine; Lys, lysine; Prot,
protein; SAA, sulfur AA; Thr, threonine; Trp, tryptophan; Val, valine.
a
Cumulative needs based on age and malabsorption due to gut permeability and EED.
b
Catch-up growth for severe wasting based on the preferred weight gain of 10 g/kg/day.

the high infectious disease burden common among children in et al., 2015; Uauy, 2013; Uauy et al., 2015). There is therefore a
developing countries (Uauy, 2013). Even a modest energy deficit, need to re-evaluate the EAA requirements for infants and young
as often found in LMICs, may increase protein needs (Pillai children in developing countries. In LMICs, less than one in five
PARIKH ET AL. 5 of 12

children aged 6–23 months get animal source foods in their diets Perturbations in AA levels in stunted compared with healthy
(Aguayo, 2017), whereas most children consume only one animal children are corroborated by studies reporting plasma AA levels
source food serving or less per day (White et al., 2017). Children (Kosek et al., 2016; Tessema et al., 2018) or metabolic phenotypes
consuming food with inadequate amounts of animal source protein (Kumar et al., 2018; Moreau et al., 2019; Ordiz et al., 2019;
are reported to have greater incidences of stunting (Arsenault & Semba, Shardell, Sakr Ashour, et al., 2016). Semba, Shardell, Sakr
Brown, 2017; Grasgruber et al., 2016; Headey et al., 2018; Ashour, et al. (2016) reported 10%–20% lower concentrations of
Moradi, 2010). This is also confirmed in an analysis of 74,548 chil- all nine EAAs in stunted Malawian children compared with
dren aged 6–23 months from 39 Demographic and Health Surveys, nonstunted children. Additionally, stunted children exhibited signifi-
which shows that children who did not consume any animal source cantly lower concentrations of conditionally EAAs: arginine, glycine
foods (eggs, meat and dairy) had 1.44 higher odds of being stunted and glutamine (Semba, Shardell, Sakr Ashour, et al., 2016). In
compared with those who reported consuming animal source foods 9-month-old children in Bangladesh, poor linear growth was associ-
on the day prior to the survey (Krasevec et al., 2017). Interestingly, ated with low plasma tryptophan, valine, threonine and total EAAs
among the various animal source foods, evidence indicates a stron- (Moreau et al., 2019). At 24 months, stunted Bangladeshi children
ger favourable role for dairy protein in promoting linear growth in had lower levels of tryptophan, lysine, threonine, arginine, total
children from LMICs and developed countries (Allen, 2013; EAAs, tryptophan/neutral AA ratio and two non-EAAs (hydroxypro-
Michaelsen, 2013; Thomas et al., 2020). For nutritional interven- line and α-aminobutyric acid) compared with healthy children
tions to be effective, multiple factors, including total energy con- (Kumar et al., 2018). Studies from Peru, Tanzania and Ethiopia
tent and the micronutrient and macronutrient composition, need to further support the relationship between stunting and low concen-
be considered. Optimally, combinations of plant-based and animal trations of tryptophan (Kosek et al., 2016; Tessema et al., 2018)
source foods could be developed to provide effective and and lysine (Tessema et al., 2018). A direct correlation between
sustainable nutritional support that is both culturally acceptable length (height) velocity and several AAs (glycine, proline, serine,
and affordable. isoleucine and threonine, Ordiz et al., 2019; lysine, leucine, arginine
and α-aminobutyric acid, Moreau et al., 2019; and valine, Moreau
et al., 2019; Ordiz et al., 2019) has also been suggested. When
3.2 | AA signatures of linear growth (faltering) and compared with an age-matched, nonstunted German population,
neurocognition Malawian infants with linear growth velocity z-score < 0 had lower
concentrations of lysine, proline, tryptophan, tyrosine and valine
Although the staples and dietary practices may differ across (Ordiz et al., 2019).
geographic locations, recent insights from the Peru, Bangladesh There is limited understanding on the AA signatures associated
and Tanzania sites of the Malnutrition and Enteric Disease (MAL-ED) with neurocognition (Moreau et al., 2019). A recent study in
birth cohort unveil a consistent age-related metabolic signature Bangladeshi infants showed an association for threonine with
(in urine and plasma) for a developing infant, suggesting a common improved neurocognitive outcomes measured as full-scale intelligence
metabolic maturation process (Giallourou et al., 2020). A decline in quotient (IQ), whereas kynurenine and the kynurenine:tryptophan
plasma tryptophan and glutamine with age, and an increase in ratio were associated with poor IQ outcomes (Moreau et al., 2019),
the urinary excretion of gut bacterial–host cometabolites of the indicative of an influence of infection and inflammation.
AAs tryptophan (3-indoxyl sulfate), tyrosine (4-cresol sulfate and The low levels of EAAs in children have been attributed to
4-hydroxyphenylacetate) and phenylalanine (phenylacetylglutamine), poor protein quality of the diets (Giallourou et al., 2020; Semba,
was reported (Giallourou et al., 2020). Evidence suggests that these Shardell, Sakr Ashour, et al., 2016), reduced capacity of the
signatures diverge based on the infants' growth trajectories. gut microbiome to produce EAAs (Kumar et al., 2018) and/or
In growth-constrained children, the aforementioned urinary functional modulation of the gut microbiome towards increased
metabolites are excreted in greater amounts than in their healthy proteolytic activity (Giallourou et al., 2020; Mayneris-Perxachs
peers (Mayneris-Perxachs et al., 2016; Mayneris-Perxachs & et al., 2016; Mayneris-Perxachs & Swann, 2019). Such low concen-
Swann, 2019), suggesting a metabolic immaturity, which can trations of EAAs can have potential adverse consequences for child
be seen from as early as 3 months of age until at least the growth and development, because these processes are regulated
second year of life (Giallourou et al., 2020). In addition, the higher by the AA-sensing mammalian target of rapamycin complex
excretion of N-methyl-2-pyridone-5-carboxamide (2-PY) and 1 (mTORC1) pathway.
N-methyl nicotinic acid, downstream metabolites of kynurenine,
by stunted children reflects a greater oxidation of tryptophan
to kynurenine (Mayneris-Perxachs et al., 2016). Elevated 3.3 | AAs are key drivers for mTORC1, the master
kynurenine and the kynurenine:tryptophan ratio are markers for regulator of growth and development
increased indoleamine 2,3-dioxygenase 1 (IDO1) enzyme activity in
response to infection and inflammation (Mayneris-Perxachs The mammalian (or mechanistic) target of rapamycin (mTOR) is a mas-
et al., 2016). ter growth regulator (Laplante & Sabatini, 2012) that functions as a
6 of 12 PARIKH ET AL.

signal integrator combining regulatory inputs from nutrients, growth mTORC1 plays an important role in the most rapid phase of child-
factors, energy levels and stress signals (Efeyan et al., 2012). The hood growth and development (Figure 2). The elongation of tubular
mTOR regulator forms two multiprotein complexes, mTORC1 and bones occurs at the growth plate through endochondral ossification, a
mTORC2, which are composed of discrete protein binding partners to process in which cartilage is replaced by bone (Mackie et al., 2011).
regulate cell growth, motility and metabolism. These complexes are The rate of chondrogenesis determines the height of children (Baron
sensitive to distinct stimuli, as mTORC1 is sensitive to nutrients et al., 2015) and is critically controlled by mTORC1 (Chen &
whereas mTORC2 is regulated via phosphoinositide 3-kinase (PI3K) Long, 2014; Phornphutkul et al., 2008). mTORC1 stimulates
and growth factor signalling. EAAs provoke a conformation of chondrocyte growth, synthesis of extracellular matrix and transition of
mTORC1 that allows for linear growth; without these AAs, the switch chondrocytes to a hypertrophic state (Kim et al., 2009), whereas direct
is off, and growth does not occur. When activated, mTORC1 pro- mTORC1 inhibition with rapamycin reduces growth of long bones
motes anabolic processes such as protein, lipid and nucleotide synthe- (Phornphutkul et al., 2009). Furthermore, mTORC1 regulates
sis and inhibits catabolic processes such as autophagy (Aylett osteoblast differentiation, proliferation and bone formation (Chen
et al., 2016; Laplante & Sabatini, 2012). The mTORC1 pathway is et al., 2014; Chen & Long, 2015) and plays a role in skeletal muscle
exquisitely sensitive to AA availability (Figure 1) (Jewell et al., 2013; growth (Goodman et al., 2015; Semba, Trehan, Gonzalez-Freire,
Laplante & Sabatini, 2012). In their absence, other signals, such as et al., 2016). In addition, mTORC1 promotes myelination in both the
growth factors and energy status, cannot overcome the lack of AAs to central and peripheral nervous systems (Lebrun-Julien et al., 2014;
activate mTORC1 (Bar-Peled & Sabatini, 2014; Jewell et al., 2013). Norrmén et al., 2014; Wahl et al., 2014), regulates neuronal
Under conditions of AA deficiency, mTORC1 is inactive, lipid and pro- development (Lipton & Sahin, 2014) and is crucial in defining neuronal
tein synthesis are suppressed and complexes involved in autophagy polarity, axon guidance, dendrite arborisation and gliogenesis
are upregulated (Laplante & Sabatini, 2012; Semba, Trehan, Gonzalez-  & Gonsebatt, 2016; Graber et al., 2013; Switon
(Garza-Lombo
Freire, et al., 2016). The other major regulatory mechanism for AA et al., 2017; Takei & Nawa, 2014). The activation of mTORC1 is
sensing is the general control nonderepressible 2 (GCN2) pathway, essential for synaptic plasticity that underlies processes involved in
activated by the lack of AAs (Lehman et al., 2015; Ye et al., 2015). learning and memory (Switon et al., 2017). mTORC1 has also been
GCN2 activation leads to attenuated translation of mRNAs (Bar-Peled shown to play a role in several other brain functions, such as regula-
& Sabatini, 2014), initiation of autophagy and growth arrest (Lehman tion of food uptake and circadian entrainment (Lipton & Sahin, 2014).
et al., 2015; Ye et al., 2015). The GCN2 pathway can inactivate and Somewhat paradoxically, the specific AAs—the most effective
lead to sustained suppression of mTORC1 (Ye et al., 2015). stimuli—required for the activation of mTORC1 are least understood

FIGURE 1 Amino acid sensing by mammalian target of rapamycin complex 1 (mTORC1)

PARIKH ET AL. 7 of 12

F I G U R E 2 Biological processes regulated by

mammalian target of rapamycin complex
1 (mTORC1)

(Jewell et al., 2013). Limited available evidence suggests that the 3.4 | Other nutrients essential for healthy growth
withdrawal of the EAAs leucine and arginine is as efficient as total AA and development
removal in downregulating mTORC1 signalling (Avruch et al., 2009).
Additionally, glutamine is required for extracellular leucine to activate Recent studies implicate an association of a broader range of nutri-
mTOR (Nicklin et al., 2009), and glutamine metabolism has recently tional metabolites, than only AAs, with linear growth and neuro-
been shown to control mTORC1 (Jewell et al., 2013). Dietary lysine cognition, suggesting the involvement of multiple metabolic
increases mTORC1 signalling in skeletal muscle and suppresses pathways. Studies from Malawi (Semba, Shardell, Sakr Ashour,
autophagy (Sato et al., 2015). Tryptophan activates mTORC1 and the et al., 2016) and Bangladesh (Moreau et al., 2019) show a significant
expression of tight junction proteins that maintain gut barrier association of phosphatidylcholines, sphingomyelins and hydroxy-
function (Wang et al., 2015). Leucine activates mTORC1 in neurons sphingomyelins with growth outcomes. Phosphatidylcholines, the
after influx through system L amino acid transporter (LAT). Uptake of most abundant phospholipid in mammalian cell membrane, constitute
arginine by cationic amino acid transporters CAT1 and CAT3 has also the dominant phospholipids circulating in plasma and are critical for
been reported to activate mTORC1 in neurons (Huang et al., 2007). In cell membrane structure and linear growth of bones (Fagone &
the central nervous system, neurotransmitters (such as glutamate Jackowski, 2013; Li et al., 2014; Watkins et al., 2003). Although the
and serotonin), neuromodulators and hormones have been mechanism by which sphingomyelins contribute to stunting is not well
reported to activate mTORC1 (Takei & Nawa, 2014); the importance understood (Moreau et al., 2019), their involvement, along with phos-
of various AAs as precursors for brain neurotransmitters is well phatidylcholines, in chondrogenesis may explain the association seen
established. with linear growth faltering (Baron et al., 2015). Sphingomyelins, a
As growth and neurocognitive development are dependent on major lipid component of myelin, are critical for myelination of the
the same regulatory pathway, controlled by common stimuli (i.e., AAs) central nervous system (Semba, Shardell, Sakr Ashour, et al., 2016),
(Jewell et al., 2013; Semba, Trehan, Gonzalez-Freire, et al., 2016), which may account for the observed association with neurocognitive
effects on linear growth can occur in tandem with cognitive effects outcomes in the study of Moreau et al. (2019).
(Uauy et al., 2015). If there are nutritional deficiencies during this The synthesis of sphingomyelins depends on phosphatidylcho-
vulnerable phase, linear growth will falter (Uauy et al., 2015) and lines, which are synthesised in the CDP–choline pathway that begins
cognitive development as well as cognitive functioning can be with the absorption of dietary choline in the small intestine (Semba,
affected (Uauy et al., 2015; Wu, 2010). Shardell, Sakr Ashour, et al., 2016). Choline also serves as a precursor
8 of 12 PARIKH ET AL.

for the neurotransmitter acetylcholine (Zeisel & Da Costa, 2009). A source foods—the richest sources of EAAs—is therefore encouraged
recent study reports lower levels of choline in the serum of stunted to improve the quality of the predominantly cereal/vegetal-based
Malawian children (Semba, Shardell, Sakr Ashour, et al., 2016). The local diets. Beside EAAs, animal source foods are sources of other
lower excretion of betaine and dimethylglycine seen in undernour- essential macronutrients (energy, high-quality protein and fatty acids)
ished Brazilian children further supports the observation of distur- and micronutrients (such as zinc, iron, iodine, magnesium, calcium,
bances in choline metabolism with stunting (Mayneris-Perxachs B-vitamins, vitamin A and vitamin D) (Dror & Allen, 2011;
et al., 2016). Penny, 2012) that supply building blocks as well as regulate the
Animal source foods, which are often lacking in the diets in LMICs processes involved in growth and development (Table 2). Not all
(Aguayo, 2017; Dewey, 2013; FAO, 2019; Lee, 2014; White animal source foods contain the same nutrients and, thus, diet
et al., 2017), represent the richest source of choline (Zeisel & Da diversity is important. An analysis of 130,432 children aged
Costa, 2009). 6–23 months from 49 countries confirms the strong protective
advantage of consuming multiple animal source foods over a single
source against stunting (Headey et al., 2018). In a systematic review,
4 | DISCUSSION Dror and Allen (2011) show the link between animal source food
consumption and cognitive function among undernourished children
The first 1000 days of life are critical for child development. This in low-income settings.
crucial period is by no means homogeneous. Different phases can be EAA requirements for infants and young children are based on
identified (e.g., pregnancy, exclusive breastfeeding [0–6 months of the estimated physiological needs under ideal conditions but do not
age] and complementary feeding [6–24 months of age]) that are all consider the extra requirements for catch-up growth or the burden of
characterised by different growth requirements and growth infectious disease (Pillai & Kurpad, 2012; Uauy, 2013; WHO &
determinants. Therefore, each phase requires a unique approach in FAO, 2007).
ensuring optimal growth and development (Park et al., 2019). There is therefore a need to re-evaluate the EAA requirements
Unfortunately, globally, stunting remains a serious problem in children for infants and young children in developing countries. In-depth
under the age of 5, and a sizeable number of children who do not research characterising AA intakes and concentrations in infants and
meet the stunting threshold still fail to reach proper growth and young children presenting with varying physiological states across a
development milestones. A growing body of work suggests that wide range of geographical regions can provide valuable insights for
children experiencing growth faltering have inadequate levels of EAAs designing appropriate nutritional guidance and complementary
and other diverse metabolic perturbations. This is partly attributed to feeding in order to promote optimal growth and neurocognitive
the poor protein quality of the LMIC diets, and inclusion of animal development, particularly in children in LMICs.

TABLE 2 Nutrients (other than amino acids) provided by animal source foods that are essential for healthy growth and development

Nutrient(s) Function
Essential fatty acids (long-chain ω-3 Constituent of cell membrane phospholipids; influences membrane protein function, lipid rafts and
fatty acid and DHA) intracellular signalling; highly concentrated in grey matter of the brain and photoreceptors in the retina;
accumulates at a very high rate during the first 2 years of life.
Calcium Major structural element in bones and teeth; plays a role in mediating the constriction and relaxation of
blood vessels, nerve impulse transmission, muscle contraction and the secretion of hormones like insulin;
involved in regulation of protein function, including enzymes, optimising their activity.
Zinc Constituent of over 200 metalloenzymes in the human body; important catalyst for metabolic processes
linked to linear growth and cognitive development; present in synaptic vesicles and has a role in
neurotransmission mediated by glutamate and GABA.
Iodine Required for the synthesis of thyroid hormones that regulate a number of physiological processes, including
growth, development, metabolism and reproduction, as well as for myelination of the central nervous
system.
Iron Essential component of hundreds of proteins and enzymes involved in various aspects of cellular
metabolism, including those associated with oxygen transport and storage, electron transport and energy
generation; needed for proper development of myelin sheaths; required cofactor for neurotransmitter
synthesis.
Magnesium Involved in over 300 metabolic reactions; critical roles in energy production, cell signalling, and fatty acid
and protein synthesis; structural role in bone, cell membrane and chromosomes.
Vitamin A Essential for visual development and acuity; important for immunity and defence against infections.
B-vitamins Roles in nerve cell myelination, neurotransmitter synthesis and regulation of gene expression in the central
nervous system.
Vitamin D Essential for bone mineralisation through the regulation of calcium and phosphorous homeostasis.
PARIKH ET AL. 9 of 12

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