No abstract

The intestinal microbiota is a dynamic community of hundreds of millions of microorganisms that play important roles in human health. However, treatment with antibiotics can disrupt the delicate balance of this community, leading to deleterious effects on the host such as inflammation and enhanced susceptibility to infection.

Metformin is a widely used drug for type 2 diabetes that is considered to have potential anti-aging effects. However, the beneficial effects of metformin in middle-aged normoglycemic mice are less explored. Here, we report that metformin treated by tail vein injection improved cognitive function of aged mice better than oral administration, which seem to show a dose-dependent manner. Correspondingly, long-term oral administration of metformin was associated with significant disability rates. Further, metformin restored cerebral blood flow and brain vascular density and promoted neurogenic potential of the subependymal zone/subventricular zone both in vivo and in vitro . RNA-Seq and q-PCR results indicated that metformin could enhance relative mRNA glycolysis expression in blood and hippocampal tissue, respectively. Mechanistically, glyceraldehyde-3-phosphate dehydrogenase (GAPDH), a key enzyme in glycolysis pathway, may contribute to angiogenic and neurogenic potentials of NSCs. Interestingly, the relative GAPDH mRNA expression of peripheral blood mononuclear cell was gradually decreased with aging. Meanwhile its expression level positively correlated with cognitive levels. Our results indicated that metformin represents a candidate pharmacological approach for recruitment of NSCs in aged mouse brain by enhancing glycolysis and promoting neurovascular generation, a strategy that might be of therapeutic value for anti-aging in humans.

Glycyrrhizic acid (GA) is the substance with the highest content of triterpenoid saponins that can be extracted from licorice, and has anti-inflammatory, neuroprotective, and anticancer functions, among others. The aim of this study was to investigate the protective effect of GA on cognitive decline in middle-aged mice and explore its mechanisms. We injected GA by the tail vein of C57BL/6 mice and measured their cognitive levels using the Morris water maze. The Morris water maze results demonstrated that GA improved learning and memory abilities in middle-aged mice. Furthermore, the RNA-sequencing and flow cytometric analyses revealed that GA could increase T and B cells. We then confirmed the relationship between cognition and the immune system in the immune-deficient B-NDG mouse model. Our results suggest that GA improves cognition in aging mice by regulating T/B cell proliferation.

Background Metformin, a type 2 diabetes treatment, improves the cognitive function of aged mice; however, whether the protective effects of metformin on cognitive function in aged mice are associated with the gut microbiome is poorly understood. Although some studies suggest that the gut microbe composition influences cognitive function and that manipulating the gut microbiota might protect against age-related cognitive dysfunction, there is no direct evidence to validate that the gut microbiota mediates the effect of metformin on cognitive improvement. Results In this study, we show that the gut microbiota is altered by metformin, which is necessary for protection against ageing-associated cognitive function declines in aged mice. Mice treated with antibiotics did not exhibit metformin-mediated cognitive function protection. Moreover, treatment with Akkermansia muciniphila, which is enriched by metformin, improved cognitive function in aged mice. Mechanistically, A. muciniphila decreased pro-inflammatory-associated pathways, particularly that of the pro-inflammatory cytokine interleukin (IL)-6, in both the peripheral blood and hippocampal profiles, which was correlated with cognitive function improvement. An IL-6 antibody protected cognitive function, and an IL-6 recombinant protein abolished the protective effect of A. muciniphila on cognitive function in aged mice. Conclusion This study reveals that A. muciniphila, which is mediated in the gut microbiota by metformin, modulates inflammation-related pathways in the host and improves cognitive function in aged mice by reducing the pro-inflammatory cytokine IL-6. Graphical Abstract