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Pregnane X receptor agonist nomilin extends lifespan and healthspan in preclinical models through detoxification functions

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Listed:
  • Shengjie Fan

    (Shanghai University of Traditional Chinese Medicine)

  • Yingxuan Yan

    (Shanghai University of Traditional Chinese Medicine)

  • Ying Xia

    (Shanghai Jiao Tong University School of Medicine
    Shanghai Jiao Tong University School of Medicine)

  • Zhenyu Zhou

    (Shanghai University of Traditional Chinese Medicine)

  • Lingling Luo

    (Shanghai University of Traditional Chinese Medicine)

  • Mengnan Zhu

    (ShanghaiTech University
    Shanghai; University of Chinese Academy of Sciences)

  • Yongli Han

    (Shanghai University of Traditional Chinese Medicine)

  • Deqiang Yao

    (ShanghaiTech University)

  • Lijun Zhang

    (Shanghai University of Traditional Chinese Medicine)

  • Minglv Fang

    (Shanghai University of Traditional Chinese Medicine)

  • Lina Peng

    (ShanghaiTech University
    Shanghai; University of Chinese Academy of Sciences)

  • Jing Yu

    (Shanghai University of Traditional Chinese Medicine)

  • Ying Liu

    (Shanghai University of Traditional Chinese Medicine)

  • Xiaoyan Gao

    (Shanghai University of Traditional Chinese Medicine)

  • Huida Guan

    (Shanghai University of Traditional Chinese Medicine)

  • Hongli Li

    (Shanghai University of Traditional Chinese Medicine)

  • Changhong Wang

    (Shanghai University of Traditional Chinese Medicine)

  • Xiaojun Wu

    (Shanghai University of Traditional Chinese Medicine)

  • Huanhu Zhu

    (ShanghaiTech University)

  • Yu Cao

    (Shanghai Jiao Tong University School of Medicine
    Shanghai Jiao Tong University School of Medicine)

  • Cheng Huang

    (Shanghai University of Traditional Chinese Medicine)

Abstract

Citrus fruit has long been considered a healthy food, but its role and detailed mechanism in lifespan extension are not clear. Here, by using the nematode C. elegans, we identified that nomilin, a bitter-taste limoloid that is enriched in citrus, significantly extended the animals’ lifespan, healthspan, and toxin resistance. Further analyses indicate that this ageing inhibiting activity depended on the insulin-like pathway DAF-2/DAF-16 and nuclear hormone receptors NHR-8/DAF-12. Moreover, the human pregnane X receptor (hPXR) was identified as the mammalian counterpart of NHR-8/DAF-12 and X-ray crystallography showed that nomilin directly binds with hPXR. The hPXR mutations that prevented nomilin binding blocked the activity of nomilin both in mammalian cells and in C. elegans. Finally, dietary nomilin supplementation improved healthspan and lifespan in D-galactose- and doxorubicin-induced senescent mice as well as in male senescence accelerated mice prone 8 (SAMP8) mice, and induced a longevity gene signature similar to that of most longevity interventions in the liver of bile-duct-ligation male mice. Taken together, we identified that nomilin may extend lifespan and healthspan in animals via the activation of PXR mediated detoxification functions.

Suggested Citation

  • Shengjie Fan & Yingxuan Yan & Ying Xia & Zhenyu Zhou & Lingling Luo & Mengnan Zhu & Yongli Han & Deqiang Yao & Lijun Zhang & Minglv Fang & Lina Peng & Jing Yu & Ying Liu & Xiaoyan Gao & Huida Guan & H, 2023. "Pregnane X receptor agonist nomilin extends lifespan and healthspan in preclinical models through detoxification functions," Nature Communications, Nature, vol. 14(1), pages 1-23, December.
  • Handle: RePEc:nat:natcom:v:14:y:2023:i:1:d:10.1038_s41467-023-39118-9
    DOI: 10.1038/s41467-023-39118-9
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