Research Paper Volume 12, Issue 18 pp 17845—17862

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

Xiaoqi Zhu1, , Junyan Shen1, , Shengyu Feng1, , Ce Huang1, , Zhongmin Liu1, , Yi Eve Sun1, , Hailiang Liu1, ,

  • 1 Institute for Regenerative Medicine, Shanghai East Hospital, Tongji University School of Medicine, Shanghai 200123, China

Received: March 6, 2020       Accepted: June 9, 2020       Published: September 16, 2020
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Copyright: © 2020 Zhu et al. This is an open access article distributed under the terms of the Creative Commons Attribution License (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.


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.


NSC: neural stem cell; GAPDH: glyceraldehyde-3-phosphate dehydrogenase; ROS: reactive oxygen species; SEZ/SVZ: subependymal zone/subventricular zone; MWM: Morris water maze; CBF: cerebral blood flow; Sox2: SRY-box 2; DCX: doublecortin; BrdU: bromodeoxyuridine; bFGF: basic fibroblast growth factor; PFA: paraformaldehyde; GFAP: glial fibrillary acidic protein; WGCNA: weighted gene co-expression network analysis; FOXO: Forkhead box; AMPK: AMP-activated protein kinase; qRT-PCR: quantitative real-time polymerase chain reaction; PFKP: phosphofructokinase; IA: iodoacetic acid; VEGFR2: vascular endothelial growth factor receptor 2.