Metformin improves cognition of aged mice by promoting cerebral angiogenesis and neurogenesis.

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.