Effects of Metformin on Life Span, Cognitive Ability, and Inflammatory Response in a Short-Lived Fish

Metformin, an oral antidiabetic drug, prolongs the life span in nematode, silkworm, and other transgenic rodents, but its effects on longevity and aging-related cognitive ability using natural aging vertebrate models remain poorly understood. The genus of annual fish Nothobranchius show accelerated growth and expression of aging biomarkers. Here, using the short-lived fish Nothobranchius guentheri, we investigated effects of metformin on life span and aging-related cognitive ability and inflammation. Total of 145 fish, 72 fish were fed with metformin in the concentration of 2 mg/g food and 73 fish without metformin from 16 weeks of age until the end of their lives. The chronic feeding with metformin prolonged the life span of the fish and delayed aging with retarded accumulation of lipofuscin in liver, senescence-associated beta-galactosidase (SA-β-gal) activity in skin and serum levels of cholesterol and triglyceride significantly in the 10-month-old fish. Furthermore, metformin improved motor, learning, and memory skills by behavior tests accompanying with reduction of SA-β-gal activity and neurofibrillary degeneration and inhibition of inflammatory response including downregulated NF-κB and proinflammatory cytokines IL-8, TNF-α, and IL-1β expression and enhanced anti-inflammatory cytokine IL-10 level in brain. These findings demonstrate that metformin prolongs the life span and exerts neuroprotective and anti-inflammation function to improve cognitive ability in annual fish. It might be an effective strategy by using metformin to raise the possibility of promoting healthy aging of old population in aging process.