Linear growth is recognized as a reliable indicator of a child’s general health. Growth pattern varies during life, being particularly fast during fetal life and the first two years of life, then slowing during childhood until puberty, when growth spurt occurs [1].

Though growth potential is genetically determined, growth pattern is deeply influenced by endocrine and environmental factors, including psychosocial distress and nutrient availability. These factors act in an extremely sophisticated interplay, differentially intervening during the various phases of growth. Nutrition seems to be particularly relevant during fetal life and the first year of postnatal life, whereas the endocrine control becomes predominant during childhood and puberty.

Nutrition in early life has not only an immediate effect on growth but also affects future health. Undernourished fetuses and infants are more likely to be short adults, to have increased cardiometabolic risk in adulthood, to give birth to smaller infants, to have lower educational achievement and to experience a lower economic status in adulthood ^[2][3][2,3].

2. Endocrinological Regulators

2.1. GH Axis

GH and its main effector, IGF-I, are recognized to be the main regulators of linear growth, by acting mainly but not exclusively in the growth plate. GH regulation is sensitive to different nutritional cues, such as glucose. GH secretion is inhibited by glucose load ^[4][10], an effect that may be mediated by ghrelin ^[5][11], whereas hypoglycemia stimulates GH release ^[6][12]. GH has a lipolytic action ^[7][13] and influences the distribution of adipose tissue. On the other hand, GH secretion is affected by lipids. Animal models of exposure to high-fat diet showed impairment of GH synthesis and decreased circulating GH levels, likely through the activation of endoplasmic reticulum stress ^[8][14]. Other nutrients, which presumably influence the GH axis, include vitamins and microelements ^[9][15]. Short fasting stimulates GH secretion, coherently with the lipolytic and hyperglycemic properties of GH ^[9][15]. By contrast, prolonged fasting induces peripheral GH resistance ^[10][16]. Data from animal studies have shown that inadequate caloric intake inhibits longitudinal bone growth. In male rabbits undergoing 48 h fasting, a significant reduction in the number of both proliferative and hypertrophic chondrocytes was observed ^[11][17]. Despite increased GH levels, the hepatic expression of IGF-I was significantly down-regulated and circulating IGF-I was significantly reduced compared with fed controls. These results suggest that the inhibition of longitudinal bone growth and the associated structural changes observed in the growth plate during fasting may be secondary to the low levels of circulating IGF-I. The reduced expression of IGF-I in liver despite increased GH levels, indicates a status of GH resistance induced by fasting. GH resistance has been described in different forms of undernutrition, such as decreased total energy intake, isolated protein calorie malnutrition and isolated micronutrient deficiencies ^[10][16]. IGF-I is sensitive to both protein and total energy intake. An adequate intake of both protein and energy is required to normalize IGF-I levels ^[12][20]. Dietary essential amino acid intake is important for IGF-I restoration after fasting ^[13][21]. Notably, other macronutrients, such as fat, influence IGF-I levels ^[14][22], but at a lower degree than protein or total energy. In the growth plates of food-restricted mice, decreased IGF-I levels and lower GHR expression have been found ^[15][23] and may explain the reduced response to GH administration observed in malnourished animals and children.

2.2. FGF21

Fibroblast growth factors (FGFs) are a family of proteins that regulate different biological processes, including growth and development. FGF21 is an endocrine factor primarily produced by the liver and adipocytes that acts as a signal of protein restriction. FGF21 regulates metabolism and growth during periods of reduced protein intake and contributes to the adaptation to fasting by stimulation of gluconeogenesis, fatty acid oxidation, and ketogenesis ^[16][17][18][27,28,29]. In humans, both fasting and protein deprivation are associated with increased FGF21 levels ^[18][19][20][29,30,31]. FGF21 may mediate GH resistance induced by malnutrition, thus contributing to the consequent impaired skeletal growth ^[16][27]. The chronic exposure to FGF21 is associated with reduced expression of hepatic GH receptors, inhibition of GH signaling and disruption of GH action in the growth plate ^[21][32]. 

2.3. Insulin

Insulin is a peptide hormone that binds to membrane-bound receptors in target cells to orchestrate an integrated anabolic response to nutrient availability. Beyond its fundamental metabolic actions, insulin is a potent mitogen, exerting its growth-promoting effects mainly by binding to the IGF-I receptor. Insulin induces chondrocyte differentiation and maturation, and the administration of insulin in hypophysectomized rats stimulates tibial growth ^[22][36]. Abnormal insulin secretion is associated with alterations of growth. Pancreatic agenesis is associated with intrauterine growth restriction ^[23][37], which also occurs in patients with insulin receptor gene mutations ^[24][38]. The impairment of growth observed in children with poorly controlled type 1 diabetes depends, in part, on low insulin levels. The insulin growth-promoting action is exerted directly or, indirectly, through the regulation of IGF-I release ^[25][39]. Insulin signaling induces IGF-I independent actions on chondrocytes, stimulating them to proliferate, differentiate and achieve their final size ^[26][40].

2.4. Leptin

Leptin is a hormone mainly but not exclusively secreted by white adipose cells. It regulates sense of satiety and metabolism but also acts as a mediator of nutritional effects on growth ^[27][41]. Leptin stimulates GH secretion by acting on the hypothalamus ^[27][28][41,42] and, interestingly, exerts a direct peripheral growth-promoting effect in the growth plate by stimulating chondrocyte proliferation and differentiation ^[29][30][43,44].  Specific hypothalamic areas are the target of hormones such as leptin and insulin, which provide information regarding nutrient availability, and connect nutritional status to linear growth and the onset of puberty. Melanocortin-3-receptor (MC3R) is a melanocortin receptor, mainly expressed in the brain, whose lack in animals impairs linear growth. Genetic variants of MC3R are associated with adult height in humans ^[31][50]. In humans, MC3R deficiency is associated with delayed puberty, impaired growth, reduced adult height and decreased IGF-I levels ^[32][51]. MC3R may thus represent a pivotal mediator between nutritional status and linear growth.

2.5. Thyroid Hormone

Thyroid hormone secretion is deeply influenced by nutrition, requiring iodine as a key component, and being also affected by other micronutrients such as selenium, zinc, iron, and vitamin A ^[33][52]. The thyroid hormone plays a well-recognized role in regulating growth and skeletal development from the late fetal life to the onset of puberty, as confirmed by growth alterations occurring in case of either excess or deficiency [1]. Thyroid hormone influences endochondral ossification, by regulating chondrocyte maturation as well as cartilage matrix synthesis, mineralization, and degradation both directly and indirectly through GH-mediated effects ^[34][35][24,53].

3. Nutritional Regulators

3.1. Macronutrients

Protein and amino acids are recognized as the main nutrients involved in linear growth. Proteins play a permissive role in growth, since they fulfill the metabolic demand of amino acids, required for tissue growth, and increase levels of hormones, such as insulin and IGF-I, which stimulate endochondral ossification. Amino acids are critical for normal growth and matrix formation by chondrocytes ^[36][54]. Leucine is a ubiquitous amino acid particularly present in milk and some cereals ^[37][61]. Leucine regulates insulin metabolism and exerts anabolic and anticatabolic actions. Leucine stimulates growth through the activation of the mTOR signaling pathway. This pathway integrates different environmental cues to regulate cell growth and homeostasis ^[38][62]. mTOR is a serine/threonine protein kinase that belongs to the phosphoinositide 3-kinase (PI3K)-related kinase family and interacts with several proteins to form two distinct complexes, named mTOR complex 1 (mTORC1) and 2 (mTORC2). mTORC1 upstream signals include amino acids (especially leucine and arginine), stress, oxygen, energy, and growth factors ^[39][63]. mTORC1 favors cell growth by promoting anabolic processes such as protein and lipid synthesis and by simultaneously inhibiting autophagy. Moreover, activated mTOR stimulates angiogenesis, which allows nutrients to reach the cells ^[40][47] and influences osteoblast differentiation ^[41][64]. mTOR signaling stimulates chondrocyte differentiation ^[42][65] and affects chondrocyte autophagy in the growth plate ^[40][47]. Notably, mTORC1 signaling is active in the hypothalamus, where it integrates signals from circulating nutrients (glucose, amino acids, lipids) and hormones (leptin, insulin) to synchronize energy balance and growth. Intracerebroventricular administration of leucine and leptin promotes mTORC1 activity and reduces food intake in rats.

3.2. Micronutrients

The effects of single or micronutrient mixture supplementation on linear growth have been investigated in different studies, which have yielded conflicting results. This inconsistency may depend on the extreme variability of nutritional interventions as well as differences in control groups and study cohorts. It has to be pointed out that malnourished children have multiple nutrient deficiencies that affect the efficacy of single supplementations. Zinc is a central component of hundreds of enzymes involved in cell growth and differentiation as well as immune function. The first evidence of zinc involvement in growth derived from the observation that human zinc deficiency secondary to acrodermatitis enteropathica, an inborn metabolic error causing reduced intestinal absorption of zinc, was associated with impaired growth and increased susceptibility to infections ^[43][66]. A growth-promoting effect of zinc supplementation has been observed in animals ^[44][67]. Vitamin D influences endochondral ossification by stimulating cellular maturation through the vitamin D receptor ^[40][47]. The vitamin D receptor (VDR) is a member of the nuclear receptor superfamily and regulates the expression of numerous genes involved in calcium/phosphate homeostasis, cellular proliferation and differentiation, and immune response, largely in a ligand-dependent manner. VDR is largely expressed in chondrocytes. In the human fetal growth plate, vitamin D promotes chondrocyte differentiation by stimulating the expression of IGF-I and GH receptor genes ^[34][45][24,78]. A recent extensive meta-analysis aimed at evaluating the effects of vitamin D supplementation on several clinical outcomes in children under five years of age found little or no effect of vitamin D on linear growth ^[46][79]. Calcium homeostasis is essential for bone health and growth. In animals, calcium deficiency causes reduced bone mineralization and reduced bone strength without affecting linear growth ^[47][80]. Vitamin D and calcium administration restore normal bone growth in children with nutritional rickets ^[48][81]. Low intake of calcium and vitamin D, likely due to inadequate milk intake after weaning, may favor stunting in African children ^[49][82]. In adolescent boys (aged 16–18), 13 months of calcium supplementation was associated with increased height ^[50][83]. Vitamin A and its derivative, retinoic acid, have no clear effects on growth ^[51][84]. Trials based on vitamin A supplementation have reported little or no benefit on linear growth ^[52][53][73,74]. By contrast, according to a recent extensive meta-analysis including five studies assessing the effect of vitamin A on linear growth in children, vitamin A supplementation may exert a positive effect on linear growth in children older than 2 years ^[54][77]. Iron supplementation was reported to stimulate growth only in children with iron deficiency anemia ^[55][75]. Consistently, a meta-analysis of randomized controlled trials assessing the effect of iron interventions on the growth of children younger than 5 years showed no significant effects ^[42][65]. These results were confirmed by a meta-analysis including 14 studies, performed in low- and middle-income countries on subjects with ages ranging from 34 to 167 months ^[54][77]. High dietary copper intake promotes growth in pigs ^[56][85], whereas in rats its deficiency results in low serum IGF-I levels but high IGF-I in bones ^[57][86]. Copper supplementation increases IGF-I and IGFBP-3 concentrations in culture media of chondrocytes, promoting their proliferation. Data about copper supplementation trials in infants and children are scant. Iodine is an essential component of the thyroid hormone, through which it exerts its main effects on growth. Iodine deficiency affects people of all ages, children and adolescents being the most vulnerable. The widespread salt iodization programs have lowered the risk of iodine deficiency, which is nevertheless still present in many regions ^[58][59][87,88]. Data on the effect of iodine supplementation show no effect of this micronutrient on linear growth ^[54][77]. By evaluating a cohort of approximately 300 children followed up to 4 years after the assumption of iodized oil, an improvement of linear growth was observed ^[60][89].