Effect of Branched-Chain Amino Acid Supplementation Alone or Combined With Tryptophan or Methionine on Appetite Control and Related Health Outcomes in Older Adults: Protocol for a Randomized Controlled Trial.

Background: Branched-chain amino acids (BCAAs) are essential amino acids for protein metabolism. Preclinical research in mice suggested that BCAA intake relative to other amino acids, in the context of a high-carbohydrate diet, was associated with hyperphagia, obesity, and reduced lifespan. These effects were not attributed to BCAAs alone, nor did they manifest through canonical mechanistic target of rapamycin-insulin-like growth factor 1 pathways; rather, they resulted from indirect effects of other amino acids, notably tryptophan, on appetite. As population aging and obesity-related chronic diseases present significant public health challenges, understanding appetite regulation is critical. To date, no clinical trial has examined the effects of BCAAs on appetite regulation in older adults. On the basis of our preclinical results, we hypothesized that, compared to the control diet, a diet supplemented either with BCAA or with BCAAs and methionine would increase appetite and energy intake, whereas supplementation with BCAA and tryptophan would not increase appetite. Objective: We aimed to translate these preclinical findings to humans by examining the effects of BCAAs per se and in combination with tryptophan and methionine on appetite and other health measures in a cohort of older participants. Methods: This randomized controlled clinical trial recruited 110 adults (aged 65-80 y; BMI 20-35 kg/m2). Participants were randomly allocated to four 4-week intervention groups: (1) control (no supplementation), (2) BCAAs, (3) BCAAs+tryptophan, or (4) BCAAs+methionine. All participants received a controlled diet, with intervention groups additionally receiving amino acid supplements. The primary outcomes are appetite assessed via self-reports and fibroblast growth factor 21 levels (a marker of protein appetite), and energy intake quantified from dietary intake data. Secondary outcomes include body composition, cardiometabolic health, gut microbiota, blood biomarkers, sleep, and physical performance. Descriptive statistics will be used to summarize participant characteristics. Linear mixed models will assess intervention effects, with and without adjustment for relevant covariates. Diet-specific self-reported appetite and palatability scores will be analyzed using generalized additive mixed models. Results: The trial was registered on April 12, 2021. Recruitment commenced in April 2022 and was completed in November 2025, with 308 individuals screened and 100 completing the study. Data analyses are planned for completion by December 2026, with results expected to be published in 2027. Data cleaning and analysis are currently in progress and are expected to be completed by December 2026, with trial results expected to be published in 2027. Conclusions: This study will clarify the effects of BCAAs, either alone or in combination with tryptophan or methionine, on appetite and related outcomes in an older population. The findings may inform nutritional strategies targeting appetite regulation and metabolic health to support healthy aging.