Research Paper Volume 12, Issue 1 pp 931—944

Upregulation of flavin-containing monooxygenase 3 mimics calorie restriction to retard liver aging by inducing autophagy

Donghao Guo1,2, , Yun Shen1, , Wei Li1, , Qinjie Li1, , Ya Miao1, , Yuan Zhong1, ,

  • 1 Department of Geriatrics, Shanghai Jiao Tong University Affiliated Sixth People’s Hospital, Shanghai, China
  • 2 Department of Medicine and Therapeutics, Faculty of Medicine, The Chinese University of Hong Kong, Shatin, Hong Kong

Received: September 21, 2019       Accepted: December 24, 2019       Published: January 11, 2020      

https://doi.org/10.18632/aging.102666
How to Cite

Copyright © 2020 Guo 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.

Abstract

Flavin-containing monooxygenase 3 (FMO3) gene expression is often upregulated in long-lived murine models. However, the specific relationship between FMO3 and aging remains unknown. Here, we show that 40% calorie restriction (CR), which is considered to be one of the most robust interventions to delay aging progression, markedly upregulates FMO3. Most importantly, upregulation of hepatocyte FMO3 in murine models prevented or reversed hepatic aging. Accordingly, the upregulation of FMO3 mimicked the effects of CR: reduced serum levels of pro-inflammatory cytokine interleukin-6 and fasting insulin; relief of oxidative stress, with lower hepatic malondialdehyde levels and higher superoxide dismutase activity; reduced serum and hepatic levels of total cholesterol and triglyceride, as well as reduced lipid deposition in the liver; and diminished levels of aging-related markers β-gal and p16. There were also synergistic effects between FMO3 upregulation and CR. Inhibition of autophagy blocked the anti-aging effects of upregulation of hepatocyte FMO3, including reversing the amelioration of the serum and hepatic parameters related to inflammation, oxidative stress, lipid metabolism, liver function, and hepatocyte senescence. Our results suggest that the upregulation of FMO3 mimics CR to prevent or reverse hepatic aging by promoting autophagy.

Abbreviations

AL: ad libitum-fed; CR: calorie restriction; FMO: flavin-containing monooxygenase; MDA: malondialdehyde; SOD: superoxide dismutase; TC: total cholesterol; TG: triglyceride; TMA: trimethylamine; TMAO: trimethylamine-N-oxide.