Glycyrrhizic Acid Inhibits Myeloid Differentiation of Hematopoietic Stem Cells by binding S100 Calcium Binding Protein A8 to Improve Cognition in Aged Mice

<title>Abstract</title> <bold>Background:</bold>Glycyrrhizic acid (GA), a saponin compound often used as a flavoring, can elicit anti-inflammatory and anti-tumor effects, and alleviate aging. However, the specific mechanism by which GA alters immune cell populations to produce these beneficial effects is currently unclear.<bold>Results:</bold>In this study, we systematically analyzed single-cell sequencing data of peripheral blood mononuclear cells from young mice, aged mice, and GA-treated aged mice. Our<italic>in vivo</italic>results show that GA reduced senescence-induced increases in macrophages and neutrophils, and increased numbers of lymphoid lineage subpopulations specifically reduced by senescence.<italic>In vitro</italic>, GA significantly promoted differentiation of Lin^-CD117⁺hematopoietic stem cells toward lymphoid lineages, especially CD8⁺T cells. Moreover, GA inhibited differentiation of CD4⁺T cells and myeloid (CD11b⁺) cells by binding to S100 calcium-binding protein 8 (S100A8) protein. Overexpression of S100A8 in Lin^-CD117⁺hematopoietic stem cells enhanced cognition in aged mice and the immune reconstitution of severely immunodeficient B-NDG mice.<bold>Conclusions:</bold>Collectively, GA exerts anti-aging effects by binding to S100A8 to remodel the immune system of aged mice.