The dose-effect of L-isoleucine on children's growth and development

L-Isoleucine, one of the essential branched-chain amino acids (BCAAs) in humans, participates in important physiological processes such as protein synthesis, energy metabolism, and hormone regulation during children's growth and development. Its dose-response effect needs to be comprehensively analyzed by combining physiological needs, metabolic characteristics, and clinical studies. The following discusses its impacts on children and potential risks from different dosage dimensions:

I. Physiological Requirement and Basic Dose Effect

1. Fundamental Role of Recommended Nutrient Intake (RNI) for Children

According to the World Health Organization (WHO) and national dietary guidelines, children's demand for L-isoleucine varies with age:

1–3 years old: Approximately 28–35 mg/kg body weight per day

4–6 years old: Approximately 30–38 mg/kg

7–10 years old: Approximately 25–32 mg/kg

Adolescence (11–18 years old): Approximately 20–25 mg/kg

This dosage range meets the basic needs for protein synthesis during normal growth and development. Deficiency may lead to growth retardation, poor muscle development, and decreased immune function.

Mechanism: L-Isoleucine promotes skeletal muscle protein synthesis by activating the mammalian target of rapamycin (mTOR) signaling pathway and serves as an energy substrate for mitochondrial β-oxidation to provide energy for growth.

2. Dosage Coverage in Daily Diets

Natural foods such as dairy products, eggs, meats, and legumes are rich in L-isoleucine. For example, a 5-year-old child (weighing ~20 kg) consuming 50 g eggs (containing ~0.6 g isoleucine), 100 g milk (~0.2 g), and 50 g lean meat (~0.8 g) daily receives ~1.6 g isoleucine (80 mg/kg), significantly exceeding the RNI. This indicates normal diets rarely cause deficiency.

II. Dose Effect and Clinical Evidence of Supplement Intervention

1. Growth-Promoting Effects of Low-Dose Supplementation (1.5–2 Times RNI)

Studies on malnourished or growth-retarded children show that daily supplementation with 30–50 mg/kg L-isoleucine (combined with other BCAAs) significantly increases weight and height growth rates within 3–6 months. For instance, a trial in African malnourished children using an amino acid complex containing isoleucine (~40 mg/kg daily) reduced growth retardation incidence by 23%, possibly via promoting insulin-like growth factor-1 (IGF-1) secretion.

Safety: No obvious adverse reactions are observed within this dosage range, with normal metabolic indicators (e.g., liver/kidney function, blood amino acid profiles).

2. Potential Risks and Controversies of High-Dose Supplementation (≥3 Times RNI)

Metabolic burden and toxicity: Doses exceeding 100 mg/kg/day may cause amino acid metabolic imbalance. Animal experiments show high-dose isoleucine inhibits the transport of other amino acids (e.g., tryptophan, tyrosine), interfering with neurotransmitter synthesis and inducing behavioral abnormalities. Additionally, α-ketoisocaproic acid generated by excessive isoleucine deamination increases liver burden, potentially causing steatosis long-term.

Clinical cases: Children with congenital branched-chain ketoacid dehydrogenase deficiency (BCKDHA, a rare inborn error of metabolism) may develop ketoacidosis even with normal isoleucine intake. High-dose supplementation significantly exacerbates the condition, indicating strict dosage control for children with genetic metabolic disorders.

III. Dosage Adjustment and Individualized Needs for Special Populations

1. Preterm and Low-Birth-Weight Infants

Preterm infants require higher isoleucine than full-term infants (~50–60 mg/kg/day) due to higher protein synthesis rates during rapid growth. Studies show adding isoleucine to 55 mg/kg/day in formula increases preterm infant weight gain by 15% within 8 weeks without affecting blood glucose or electrolyte balance.

Note: Maintain the ratio of isoleucine:leucine:valine (≈1:2:1 in BCAAs), as imbalance may reduce absorption efficiency.

2. Children with Athletic Development or Disease States

High-intensity exercise children (e.g., athletes): Isoleucine demand may rise to 30–35 mg/kg/day due to increased energy consumption, but evidence for enhanced athletic performance via isolated isoleucine supplementation is lacking, and excess may cause muscle fatigue.

Children with chronic diseases (e.g., nephropathy, liver disease): Adjust dosage based on metabolic status: restrict to 15–20 mg/kg/day in renal insufficiency to avoid accumulation toxicity; moderately increase to 40–50 mg/kg/day under medical guidance in liver disease to improve nutrition.

IV. Key Conclusions and Recommendations on Dose Effect

1. Basic Principles

Children with normal diets do not need extra L-isoleucine supplementation, as dietary intake sufficiently meets growth needs.

Dosage intervention should only be conducted under confirmed malnutrition, metabolic disorders, or medical guidance.

2. Safety Dosage Threshold

Short-term (≤3 months) tolerance upper limit for healthy children: ~80 mg/kg/day.

Long-term supplementation: ≤50 mg/kg/day, with regular blood amino acid level monitoring.

3. Future Directions

Further clinical studies are needed to clarify the synergistic effects of isoleucine with other nutrients (e.g., vitamin B6, zinc) and establish individualized dose-response curves for different age groups to avoid metabolic risks from blind (blind) supplementation.