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

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, Hongli Li, Changhong Wang, Xiaojun Wu, Huanhu Zhu (), Yu Cao () and Cheng Huang ()
Additional contact information
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
Zhenyu Zhou: Shanghai University of Traditional Chinese Medicine
Lingling Luo: Shanghai University of Traditional Chinese Medicine
Mengnan Zhu: ShanghaiTech University
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
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
Cheng Huang: Shanghai University of Traditional Chinese Medicine

Nature Communications, 2023, vol. 14, issue 1, 1-23

Abstract: 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.

Date: 2023
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DOI: 10.1038/s41467-023-39118-9

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