Journal
JOURNAL OF PROTEOME RESEARCH
Volume -, Issue -, Pages -Publisher
AMER CHEMICAL SOC
DOI: 10.1021/acs.jproteome.2c00167
Keywords
aging; redox adaptability; Nrf2; Sirt3; nicotinamide mononucleotide (NMN); liver injury
Categories
Funding
- Postdoctoral Foundation of Tsinghua-Peking Center for Life Sciences
- Beijing Municipal Science and Technology Commission [5214025]
- Ministry of Science and Technology of the People's Republic of China [2017ZX10201101, 2020YFC2002705]
- National Key Research and Development Program of China [2017YFA0505103]
- National Natural Science Foundation of China [21877068]
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In this study, the researchers found that the oxidation-reduction process was associated with aging in the mouse liver. They also discovered that oxidative stress activates Nrf2 and its downstream genes, but supplementation of NMN reduced oxidative stress and restored adaptive homeostasis through the Sirt3-Nrf2 axis.
Altered adaptive homeostasis contributes to aging and lifespan regulation. In the present study, to characterize the mechanism of aging in mouse liver, we performed quantitative proteomics and found that the most upregulated proteins were related to the oxidation-reduction process. Further analysis revealed that malondialdehyde (MDA) and protein carbonyl (PCO) levels were increased, while nuclear Nrf2 and downstream genes were significantly increased, indicating that oxidative stress induced Nrf2 activation in aged mouse liver. Importantly, nicotinamide mononucleotide (NMN) administration decreased the oxidative stress and the nuclear Nrf2 and Nrf2 downstream gene levels. Indeed, aged mice treated with NMN improved stress resistance against acetaminophen (APAP)-induced liver injury, indicating that NMN restored Nrf2-mediated adaptive homeostasis. Further studies found that NMN increased Sirt3 activities to deacetylate age-associated acetylation at K68 and K122 in Sod2, while its effects on nuclear Nrf2 levels were diminished in Sirt3-deficient mice, suggesting that NMN-enhanced adaptive homeostasis was Sirt3-dependent. Taken together, we demonstrated that Nrf2-regulated adaptive homeostasis was decreased in aged mouse liver and NMN supplementation restored liver redox homeostasis via the Sirt3-Nrf2 axis and protected aged liver from oxidative stress-induced injury.
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