Glycyrrhizic acid inhibits myeloid differentiation of hematopoietic stem cells by binding S100 calcium binding protein A8 to improve cognition in aged mice

Background: Glycyrrhizic acid (GA), a saponin compound often used as a flavoring agent, 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. Results: 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 in vivo results show that GA reduced senescence-induced increases in macrophages and neutrophils, and increased numbers of lymphoid lineage subpopulations specifically reduced by senescence. In vitro, GA significantly promoted differentiation of LinCD117 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 (NOD.CB17-Prkdcscid/l2rgtm1/Bcgen) mice. Conclusions: Collectively, GA exerts anti-aging effects by binding to S100A8 to remodel the immune system of aged mice.