Metformin treatment in late middle age improves cognitive function with alleviation of microglial activation and enhancement of autophagy in the hippocampus

• Published in: Aging cell Vol. 20; no. 2; pp. e13277 - n/a
• Main Authors: Kodali, Maheedhar, Attaluri, Sahithi, Madhu, Leelavathi N., Shuai, Bing, Upadhya, Raghavendra, Gonzalez, Jenny Jaimes, Rao, Xiaolan, Shetty, Ashok K.
• Format: Journal Article
• Language: English
• Published: England John Wiley & Sons, Inc 01.02.2021; John Wiley and Sons Inc
• Subjects: activated microglia; Adenosine kinase; Aging; Alzheimer's disease; AMP; Analysis; Animal behavior; Animal cognition; Autophagy; Brain; Cognitive ability; cognitive function; Cytokines; Dementia; Dementia disorders; Diabetes; Diabetes mellitus; Diabetes therapy; Drinking water; Executive function; Health aspects; Hippocampus; Hypertrophy; Inflammation; Insulin; Kinases; Life span; Memory; Metformin; Mice; Microglia; Middle age; Neurogenesis; neuroinflammation; Original Paper; Phagocytosis; Phenotypes; Phosphorylation; Protein kinase; Rapamycin; TOR protein; Type 2 diabetes; Young adults; cognitive function; neurogenesis; metformin; activated microglia; neuroinflammation
• ISSN: 1474-9718; 1474-9726
• DOI: 10.1111/acel.13277

Ten weeks of metformin treatment in late middle age is efficacious for improving cognitive function in the old age. Improved cognitive function following metformin treatment was linked with antiinflammatory effects, the activation of adenosine monophosphate‐activated protein kinase (AMPK), the mammalian target of rapamycin (mTOR) signaling, and increased autophagy in the aged hippocampus. The results suggest that metformin therapy in middle age leads to better cognitive function in old age. Summary Metformin, a drug widely used for treating diabetes, can prolong the lifespan in several species. Metformin also has the promise to slow down age‐related cognitive impairment. However, metformin's therapeutic use as an anti‐aging drug is yet to be accepted because of conflicting animal and human studies results. We examined the effects of metformin treatment in late middle age on cognitive function in old age. Eighteen‐month‐old male C57BL6/J mice received metformin or no treatment for 10 weeks. A series of behavioral tests revealed improved cognitive function in animals that received metformin. Such findings were evident from a better ability for pattern separation, object location, and recognition memory function. Quantification of microglia revealed that metformin treatment reduced the incidence of pathological microglial clusters with alternative activation of microglia into an M2 phenotype, displaying highly ramified processes in the hippocampus. Metformin treatment also seemed to reduce astrocyte hypertrophy. Additional analysis demonstrated that metformin treatment in late middle age increased adenosine monophosphate‐activated protein kinase activation, reduced proinflammatory cytokine levels, and the mammalian target of rapamycin signaling, and enhanced autophagy in the hippocampus. However, metformin treatment did not alter neurogenesis or synapses in the hippocampus, implying that improved cognitive function with metformin did not involve enhanced neurogenesis or neosynaptogenesis. The results provide new evidence that metformin treatment commencing in late middle age has promise for improving cognitive function in old age. Modulation of microglia, proinflammatory cytokines, and autophagy appear to be the mechanisms by which metformin facilitated functional benefits in the aged brain.