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High-content screening identifies ganoderic acid A as a senotherapeutic to prevent cellular senescence and extend healthspan in preclinical models

Author

Listed:
  • Li Chen

    (Huazhong University of Science and Technology
    Ministry of Agriculture, Oil Crops and Lipids Process Technology National & Local Joint Engineering Laboratory)

  • Bangfu Wu

    (Huazhong University of Science and Technology)

  • Li Mo

    (Huazhong University of Science and Technology)

  • Huimin Chen

    (Huazhong University of Science and Technology)

  • Xingzhu Yin

    (Huazhong University of Science and Technology)

  • Ying Zhao

    (Huazhong University of Science and Technology)

  • ZhaoYu Cui

    (Huazhong University of Science and Technology)

  • Feipeng Cui

    (Huazhong University of Science and Technology)

  • Liangkai Chen

    (Huazhong University of Science and Technology)

  • Qianchun Deng

    (Ministry of Agriculture, Oil Crops and Lipids Process Technology National & Local Joint Engineering Laboratory)

  • Chao Gao

    (Chinese Center for Disease Control and Prevention)

  • Ping Yao

    (Huazhong University of Science and Technology)

  • Yanyan Li

    (Shenzhen Center for Chronic Disease Control)

  • Yuhan Tang

    (Huazhong University of Science and Technology)

Abstract

Accumulated senescent cells during the aging process are a key driver of functional decline and age-related disorders. Here, we identify ganoderic acid A (GAA) as a potent anti-senescent compound with low toxicity and favorable drug properties through high-content screening. GAA, a major natural component of Ganoderma lucidum, possesses broad-spectrum geroprotective activity across various species. In C. elegans, GAA treatment extends lifespan and healthspan as effectively as rapamycin. Administration of GAA also mitigates the accumulation of senescent cells and physiological decline in multiple organs of irradiation-stimulated premature aging mice, natural aged mice, and western diet-induced obese mice. Notably, GAA displays a capability to enhance physical function and adapts to conditional changes in metabolic demand as mice aged. Mechanistically, GAA directly binds to TCOF1 to maintain ribosome homeostasis and thereby alleviate cellular senescence. These findings suggest a feasible senotherapeutic strategy for protecting against cellular senescence and age-related pathologies.

Suggested Citation

  • Li Chen & Bangfu Wu & Li Mo & Huimin Chen & Xingzhu Yin & Ying Zhao & ZhaoYu Cui & Feipeng Cui & Liangkai Chen & Qianchun Deng & Chao Gao & Ping Yao & Yanyan Li & Yuhan Tang, 2025. "High-content screening identifies ganoderic acid A as a senotherapeutic to prevent cellular senescence and extend healthspan in preclinical models," Nature Communications, Nature, vol. 16(1), pages 1-23, December.
    • Handle: RePEc:nat:natcom:v:16:y:2025:i:1:d:10.1038_s41467-025-58188-5
    DOI: 10.1038/s41467-025-58188-5
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    References listed on IDEAS

    as
    1. Kevin C. Stein & Fabián Morales-Polanco & Joris Lienden & T. Kelly Rainbolt & Judith Frydman, 2022. "Ageing exacerbates ribosome pausing to disrupt cotranslational proteostasis," Nature, Nature, vol. 601(7894), pages 637-642, January.
    2. Heike Fuhrmann-Stroissnigg & Yuan Yuan Ling & Jing Zhao & Sara J. McGowan & Yi Zhu & Robert W. Brooks & Diego Grassi & Siobhan Q. Gregg & Jennifer L. Stripay & Akaitz Dorronsoro & Lana Corbo & Priscil, 2017. "Identification of HSP90 inhibitors as a novel class of senolytics," Nature Communications, Nature, vol. 8(1), pages 1-14, December.
    3. Megan Scudellari, 2017. "To stay young, kill zombie cells," Nature, Nature, vol. 550(7677), pages 448-450, October.
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