Microbiota-derived indole acetic acid extends lifespan through the AhR-Sirt2 pathway in Drosophila
Zheng Cao,
Cui Zhang,
Lijun Liu,
Hehua Lei,
Huabao Zhang,
Yanmeng He,
Xinzhi Li,
Qingwei Xiang,
Yu-Feng Wang,
Limin Zhang,
Gang Chen
Affiliations
Zheng Cao
State Key Laboratory of Magnetic Resonance and Atomic and Molecular Physics, National Centre for Magnetic Resonance in Wuhan, Innovation Academy of Precision Measurement Science and Technology, Chinese Academy of Sciences (CAS), Wuhan, China
Cui Zhang
State Key Laboratory of Magnetic Resonance and Atomic and Molecular Physics, National Centre for Magnetic Resonance in Wuhan, Innovation Academy of Precision Measurement Science and Technology, Chinese Academy of Sciences (CAS), Wuhan, China
Lijun Liu
State Key Laboratory of Magnetic Resonance and Atomic and Molecular Physics, National Centre for Magnetic Resonance in Wuhan, Innovation Academy of Precision Measurement Science and Technology, Chinese Academy of Sciences (CAS), Wuhan, China
Hehua Lei
State Key Laboratory of Magnetic Resonance and Atomic and Molecular Physics, National Centre for Magnetic Resonance in Wuhan, Innovation Academy of Precision Measurement Science and Technology, Chinese Academy of Sciences (CAS), Wuhan, China
Huabao Zhang
State Key Laboratory of Magnetic Resonance and Atomic and Molecular Physics, National Centre for Magnetic Resonance in Wuhan, Innovation Academy of Precision Measurement Science and Technology, Chinese Academy of Sciences (CAS), Wuhan, China
Yanmeng He
State Key Laboratory of Magnetic Resonance and Atomic and Molecular Physics, National Centre for Magnetic Resonance in Wuhan, Innovation Academy of Precision Measurement Science and Technology, Chinese Academy of Sciences (CAS), Wuhan, China
Xinzhi Li
School of Pharmacy, Faculty of Medicine, Laboratory for Drug Discovery from Natural Resource, State Key Laboratory of Quality Research in Chinese Medicine, Macau University of Science and Technology, Macao, China
Qingwei Xiang
Hubei Shizhen Laboratory, Department of Geriatrics, Hubei Provincial Hospital of Traditional Chinese Medicine, Hubei University of Chinese Medicine, Wuhan, China
Yu-Feng Wang
School of Life Sciences, Key Laboratory of Pesticide & Chemical Biology of Ministry of Education, Hubei Key Laboratory of Genetic Regulation and Integrative Biology, Central China Normal University, Wuhan, China
Limin Zhang
State Key Laboratory of Magnetic Resonance and Atomic and Molecular Physics, National Centre for Magnetic Resonance in Wuhan, Innovation Academy of Precision Measurement Science and Technology, Chinese Academy of Sciences (CAS), Wuhan, China
Gang Chen
Hubei Shizhen Laboratory, Department of Geriatrics, Hubei Provincial Hospital of Traditional Chinese Medicine, Hubei University of Chinese Medicine, Wuhan, China
ABSTRACT Disruption of aryl hydrocarbon receptor (AhR) signaling and aberrant tryptophan metabolism have been shown to be highly associated with aging and age-related disorders. However, the underlying molecular mechanisms by which the AhR-mediated signaling pathway contributes to the aging process remain largely unknown. In this study, we find that aged Drosophila exhibits markedly reduced tryptophan metabolism leading to impaired AhR ligands, especially indole acetic acid (IAA), compared with their young controls. Supplementation with IAA, produced from Lactobacillus spp., dose-dependently extends the lifespan of Drosophila and improves healthy aging with resistance to starvation and oxidative stress. Mechanistically, activation of AhR by IAA markedly enhances Sirt2 activity by binding to its promoter, thereby inhibiting downstream TOR signaling and related fatty acid and amino acid metabolism. Both Ahr and Sirt2 mutant flies with IAA supplementation display a negligible lifespan extension, suggesting that AhR-mediated Sirt2 signaling contributes to lifespan extension in flies upon IAA supplementation. From the perspective of host metabolism, IAA supplementation significantly increases unsaturated fatty acids (UFAs) in aged flies, which are regarded to be beneficial for healthy status. These findings provide new insights into the physiological functions of AhR involved in the aging process by mediating Sirt2 signaling.IMPORTANCEDisruption of aryl hydrocarbon receptor (AhR) signaling and aberrant tryptophan metabolism contribute to aging and age-related disorders, but the underlying molecular mechanisms are largely unknown. Using multiomics analyses combined with biochemical assays, this study reveals that AhR activation by indole acetic acid (IAA) effectively extends the lifespan accompanied by improved healthy aging in Drosophila via the AhR-Sirt2 pathway.
