Lycopene alleviates age-related cognitive deficit via activating liver-brain fibroblast growth factor-21 signalling
Jia Wang, Lu Li, Li Li, Yuqi Shen, Fubin Qiu
Abstract
Brain function is linked with many peripheral tissues, including the liver, where hepatic fibroblast growth factor 21 (FGF21) mediates communication between the liver and brain. Lycopene (LYC), a naturally occurring carotenoid, posses multiple health-promoting properties, including neuroprotective function. Here, we investigated the effects of LYC on age-related memory impairment and the relative contribution of liver-brain FGF21 signaling in these process. The results showed that after treatment with LYC for 3 months, brain aging and age-related cognitive deficits were effectively managed. In addition, LYC ameliorated neuronal degeneration, mitochondrial dysfunction and synaptic damage, and promoted synaptic vesicle fusion in 18-month-old mice. Notably, LYC activated liver-brain FGF21 signalling in aging mice. Whereas all these central effects of LYC were negated by blocking FGF21 via i. v. injection of adeno-associated virus in aging mice. Furthermore, recombinant FGF21 elevated mitochondrial ATP levels and enhanced synaptic vesicle fusion in mouse hippocampal HT-22 cells, which promoted neurotransmitter release. Additionally, we co-cultured hepatocytes and neurons in Transwell and found that LYC enhanced hepatocytes' support for neurons. This support included improved cell senescence, enhanced mitochondrial function, and increased axon length in co-cultured neurons. In conclusion, LYC protects against age-related cognitive deficit, partly explained by activating liver-brain FGF21 signalling, hence promoting neurotransmitters release via increasing mitochondrial ATP levels and enhancing synaptic vesicle fusion. These findings revealed that FGF21 could be a potential therapeutical target in nutritional intervention strategies to improve cognitive damage caused by aging and age-related neurodegenerative diseases.