Research on the Antiaging Activity of Licorice Water Extract in Aging Mice via Antioxidation, Neuronal Protection, Gut Microbiota Restoration, and PI3K/AKT/mTOR Modulation.

Background: Aging is a multifaceted physiological process characterized by progressive multiorgan dysfunction, oxidative stress, neuronal injury, cognitive impairment, and alterations in gut microbiota composition. Licorice, a widely used traditional medicinal herb, contains diverse bioactive constituents; however, its overall antiaging properties and mechanistic basis in aging models have not been systematically elucidated. Methods: Aging mice model was established using D-galactose (D-Gal). Body weight, organ indices, senescence markers, antioxidant activity, neuronal integrity, and behavioral performance were assessed to evaluate the protective role of licorice water (LW) extract. Further, gut microbiota profiling, network pharmacology, and western blotting were employed to investigate further the potential mechanisms underlying the antiaging effects of LW. Results: LW administration significantly improved body weight gain, organ indices, and hippocampal structure in aging mice, increased antioxidant enzyme activity, and decreased the proportion of SA-β-Gal-positive cells. Moreover, LW treatment reshaped gut microbiota composition by lowering the Firmicutes/Bacteroidota (F/B) ratio and increasing the relative abundance of beneficial bacterial taxa. Network pharmacology analysis identified 66 licorice-associated antiaging genes, with quercetin, kaempferol, naringenin, formononetin, and licochalcone A as key active components. The principal molecular targets included AKT1, TP53, ESR1, CASPASE3, and BCL2, while the major enriched pathways involved PI3K-Akt, lipid and atherosclerosis, AGE-RAGE, MAPK, and IL-17 pathway. Furthermore, Western blot analysis revealed that LW significantly downregulated the expression of p-PI3K, p-AKT, and p-mTOR in brain tissue. Conclusion: These findings demonstrate that LW exerts protective antiaging effects in D-Gal-induced mice by enhancing antioxidant activities, safeguarding neuronal function to improve cognition, restoring gut microbiota balance, and modulating the PI3K/AKT/mTOR pathway, supporting its promise as a candidate for antiaging interventions.