The Anti-aging Effect Of FMO3 Overexpression That Mimics Caloric Restriction And Its Action Mechanism

Aim: The content of FMO3 in liver was significantly increased in the anti-aging models with 40% caloric restriction,but the role and mechanism of FMO3 in the aging process remains unclear.This study investigated the role of hepatic FMO3 in retarding liver aging through the evaluation of the effects resulting from upregulating FMO3 or inhibiting autophagy.Content: By evaluating the effects of 40% caloric restriction on mice,we investigated the effects of caloric restriction on hepatic senescence markers,autophagy-related indicators,and the protein expression of FMO3 in liver.The FMO3 in liver was upregulated by injection of adenovirus,and the effect of FMO3 overexpression on liver aging and its synergistic effect with caloric restriction were analysed,and the effects of FMO3 overexpression on autophagy and autophagy related pathways were further investigated.The mice treated with FMO3 overexpression were injected with autophagy inhibitors to observe whether inhibition of autophagy could block the anti-aging effect of FMO3 overexpression on the liver of mice,and whether autophagy is the mechanism of action of FMO3 delaying liver aging.Method: The hepatic FMO3 was upregulated by tail vein injection of adeno-FMO3.Autophagy was inhibited by intraperitoneal injection of bafilomycin A1.Plasma TC,TG and hepatic TC,TG,MDA,SOD and other indicators were detected by commercial kit;Serum insulin,IL-6,etc.was detected by ELISA.Western blotting was used to detect agingrelated indicators including ?-gal and p16,autophagy indicators including LC3 and p62,and Akt/mTOR pathway-related proteins.Lipid deposition in liver was detected by oil red O staining.The electron microscopy was used to observe autophagosomes to further evaluate the activation of autophagy.Outcome: FMO3 overexpression had synergistic effects with caloric restriction of delaying liver aging,improving liver oxidative stress,alleviating inflammatory response,and ameliorating lipid metabolism in mice.FMO3 overexpression inhibited mTOR pathway and promoted autophagy,while inhibiting autophagy reversed the anti-aging effect of FMO3 overexpression on the mouse aging liver.Conclusion: FMO3 overexpression mimics the anti-aging effect of caloric restriction on the mouse aging liver,and retards the aging process by inducing the mTOR-regulated autophagy.