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Morusin and mulberrin extend the lifespans of yeast and C. elegans via suppressing nutrient-sensing pathways

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Abstract

Compounds with lifespan extension activity are rare, although increasing research efforts have been invested in this field to find ways to extend healthy lifespan. By applying a yeast-based high-throughput assay to identify the chronological lifespan extension activity of mulberry extracts rapidly, we demonstrated that a group of prenylated flavones, particularly morusin and mulberrin, could extend the chronological lifespan of budding yeast via a nutrient-dependent regime by at least partially targeting SCH9. Their antiaging activity could be extended to C. elegans by promoting its longevity, dependent on the full functions of genes akt-1 or akt-2. Moreover, additional benefits were observed from morusin- and mulberrin-treated worms, including increased reproduction without the influence of worm health (pumping rate, pumping decline, and reproduction span). In the human HeLa cell model, morusin and mulberrin inhibited the phosphorylation of p70S6K1, promoted autophagy, and slowed cell senescence. The molecular docking study showed that mulberrin and morusin bind to the same pocket of p70S6K1. Collectively, our findings open up a potential class of prenylated flavones performing their antiaging activity via nutrient-sensing pathways.

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Data availability

The raw data tables are available upon request from the corresponding author.

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Funding

The research is sponsored by an in-house grant of the NUS (Suzhou) Research Institute (NUSRI) under the Peak of Excellent for Health and a Tier 1 grant (R-160–000-B04-114) from the Singapore Ministry of Health. ZW is sponsored by the Shanghai Pujiang Program (20PJ1405400) and the National Natural Science Foundation of China (No. 82171550). Some C. elegans strains were provided by CGC, which is funded by the NIH Office of Research Infrastructure Programs (P40 OD010440).

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Author notes

  1. Pingkang Xu and Qimin Chen contributed equally to this work.

Authors and Affiliations

  1. Department of Food Science and Technology, National University of Singapore, 2 Science Drive 2, Singapore, 117542, Singapore

    Pingkang Xu, Qimin Chen, Xiaoman Chen, Weiqi Li, Xin Yang, Amelia Gunawan, Shuoyu Chen & Dejian Huang

  2. National University of Singapore (Suzhou) Research Institute, 377 Linquan St, Suzhou, Jiangsu, China

    Pingkang Xu, Xiaoman Chen, Weiqi Li & Dejian Huang

  3. Department of Physiology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore

    Hao Qi & Han-Ming Shen

  4. Jiangsu Key Laboratory of Infection and Immunity, Institutes of Biology and Medical Sciences, Soochow University, Suzhou, China

    Yuyan Yang & Huimin Zhang

  5. Faculty of Health Sciences, University of Macau, Macau, China

    Han-Ming Shen

  6. Healthy Longevity Translational Research Program, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore

    Brian Kennedy

  7. State Key Laboratory of Silkworm Genome Biology, College of Sericulture, Textile and Biomass Sciences, Southwest University, Chongqing, 400716, China

    Li Xu

  8. Department of Food Science and Engineering, School of Agriculture and Biology, Shanghai Jiao Tong University, Shanghai, China

    Ziyun Wu

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  1. Pingkang Xu
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  2. Qimin Chen
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Contributions

Qimin Chen, with the assistance of Shuoyu Chen and Amelia Gunawan, designed and conducted high-throughput screening of the mulberry samples; isolated the active compounds, morusin, and cudraflavone C, from mulberry twigs; as well conducted experiments on the structure and activity relationship on yeast model. Pingkang Xu (PX) designed and conducted the experiments on structural and activity relationships (assisted by Xiaoman Chen and Weiqi Li) and conducted the experiment related to C. elegans (assisted by Yuyan Yang and Weiqi Li) and HeLa cells (assisted by Yao Qi and Xiaoman Chen). Xin Yang performed the crystal growth and structural analysis of morusinol and molecular docking study. Li Xu collected the authentic mulberry samples for screening, and Ziyun Wu (ZW) conducted experiments on HeLa cells and provided general advice on the project. Han-Ming Shen (HMS) advised on autophagy and HeLa cell aging experiments. Brian Kennedy (BK) provided yeast strains and recommended investigating the action mechanisms. Huimin Zhang (HZ) guided the C. elegans study conducted in his lab. Dejian Huang (DH) conceived the project. The manuscript was drafted by PX, QC, ZW, and DH. The subsequent refinement of the manuscript was contributed by ZW, BK, HMS, and HZ.

Corresponding authors

Correspondence to Dejian Huang, Brian Kennedy, Li Xu or Ziyun Wu.

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Xu, P., Chen, Q., Chen, X. et al. Morusin and mulberrin extend the lifespans of yeast and C. elegans via suppressing nutrient-sensing pathways. GeroScience 45, 949–964 (2023). https://doi.org/10.1007/s11357-022-00693-2

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  • DOI: https://doi.org/10.1007/s11357-022-00693-2

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