Royal jelly ameliorates age-associated stem cell dysfunction with Chi3l1-mediated increase in CD206-positive macrophages

Abstract Nutritional interventions, including Royal Jelly (RJ), are potential modulators of tissue function during aging. However, the molecular mechanisms underlying food-derived modulation of tissue physiology remain poorly understood. Here we show that dietary RJ enhances stem/progenitor cell activity with age- and tissue-dependent Chi3l1 -mediated increases in CD206-positive macrophages. In aged mice, RJ administration increased proliferative activity of stem/progenitor cells in the skin and brain, accompanied by improved hair phenotypes and enhanced neurogenesis. Transcriptomic screening in human mesenchymal stem/stromal cells identified CHI3L1 as an RJ-responsive gene that is downregulated during cellular senescence. Hepatocyte-specific disruption of Chi3l1 using adeno-associated virus-mediated gene editing demonstrated that Chi3l1 is required for maintaining hepatic CD206-positive macrophage populations in vivo. Similar effects were observed with 10-hydroxy-2-decenoic acid, a major RJ component. These findings suggest that Chi3l1 is a physiologically regulated immune mediator, rather than a pathogenic factor in disease contexts, highlighting the importance of mechanistic studies of food-derived biological effects.