Targeting Senescence with Apigenin Improves Chemotherapeutic Efficacy and Ameliorates Age‐Related Conditions in Mice
Abstract Cellular senescence is a cell fate triggered by stressful stimuli and displays a hypersecretory feature, the senescence‐associated secretory phenotype (SASP). Senescent cell burden increases with aging and contributes to age‐related organ dysfunction and multiple chronic disorders. In this...
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Wiley
2025-05-01
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| Series: | Advanced Science |
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| Online Access: | https://doi.org/10.1002/advs.202412950 |
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| author | Hongwei Zhang Qixia Xu Zhirui Jiang Rong Sun Qun Wang Sanhong Liu Xin Luan Judith Campisi James L. Kirkland Weidong Zhang Yu Sun |
| author_facet | Hongwei Zhang Qixia Xu Zhirui Jiang Rong Sun Qun Wang Sanhong Liu Xin Luan Judith Campisi James L. Kirkland Weidong Zhang Yu Sun |
| author_sort | Hongwei Zhang |
| collection | DOAJ |
| description | Abstract Cellular senescence is a cell fate triggered by stressful stimuli and displays a hypersecretory feature, the senescence‐associated secretory phenotype (SASP). Senescent cell burden increases with aging and contributes to age‐related organ dysfunction and multiple chronic disorders. In this study, a large scale screening of a natural product library for senotherapeutic candidates is performed. Apigenin, a dietary flavonoid previously reported with antioxidant and anti‐inflammatory activities, exhibits capacity for targeting senescent cells as a senomorphic agent. This compound blocks the interactions between ATM/p38MAPK and HSPA8, preventing the transition of an acute stress‐associated phenotype (ASAP) toward the SASP. Mechanistically, apigenin targets peroxiredoxin 6 (PRDX6), an intracellular redox‐active molecule, suppressing the iPLA2 activity of PRDX6 and disrupting downstream reactions underlying SASP development. Apigenin reduces the severity of cancer cell malignancy promoted by senescent stromal cells in culture, while restraining chemoresistance when combined with chemotherapy in anticancer regimens. In preclinical trials, apigenin improves the physical function of animals with a premature aging‐like state, alleviating physical frailty and cognitive impairment. Together, the study demonstrates the feasibility of exploiting a natural compound with senomorphic capacity to achieve geroprotective effects by modulating the SASP, thus providing a baseline for future exploration of natural agents for alleviating age‐related conditions. |
| format | Article |
| id | doaj-art-c7bf5cfa291d4380a6539573b6fd7c0c |
| institution | DOAJ |
| issn | 2198-3844 |
| language | English |
| publishDate | 2025-05-01 |
| publisher | Wiley |
| record_format | Article |
| series | Advanced Science |
| spelling | doaj-art-c7bf5cfa291d4380a6539573b6fd7c0c2025-08-20T03:20:10ZengWileyAdvanced Science2198-38442025-05-011220n/an/a10.1002/advs.202412950Targeting Senescence with Apigenin Improves Chemotherapeutic Efficacy and Ameliorates Age‐Related Conditions in MiceHongwei Zhang0Qixia Xu1Zhirui Jiang2Rong Sun3Qun Wang4Sanhong Liu5Xin Luan6Judith Campisi7James L. Kirkland8Weidong Zhang9Yu Sun10Shanghai Frontiers Science Center of TCM Chemical Biology Institute of Interdisciplinary Integrative Medicine Research Shanghai University of Traditional Chinese Medicine Shanghai 201203 P. R. ChinaCAS Key Laboratory of Tissue Microenvironment and Tumor Shanghai Institute of Nutrition and Health Chinese Academy of Sciences Shanghai 200031 P. R. ChinaCAS Key Laboratory of Tissue Microenvironment and Tumor Shanghai Institute of Nutrition and Health Chinese Academy of Sciences Shanghai 200031 P. R. ChinaDepartment of Discovery Biology Bioduro‐Sundia Zhangjiang Hi‐Tech Park Shanghai 201210 P. R. ChinaShanghai Frontiers Science Center of TCM Chemical Biology Institute of Interdisciplinary Integrative Medicine Research Shanghai University of Traditional Chinese Medicine Shanghai 201203 P. R. ChinaShanghai Frontiers Science Center of TCM Chemical Biology Institute of Interdisciplinary Integrative Medicine Research Shanghai University of Traditional Chinese Medicine Shanghai 201203 P. R. ChinaShanghai Frontiers Science Center of TCM Chemical Biology Institute of Interdisciplinary Integrative Medicine Research Shanghai University of Traditional Chinese Medicine Shanghai 201203 P. R. ChinaBuck Institute for Research on Aging Novato CA 94945 USACenter for Advanced Gerotherapeutics Cedars‐Sinai Medical Center Pacific Design Center West Hollywood CA 90069 USAShanghai Frontiers Science Center of TCM Chemical Biology Institute of Interdisciplinary Integrative Medicine Research Shanghai University of Traditional Chinese Medicine Shanghai 201203 P. R. ChinaCAS Key Laboratory of Tissue Microenvironment and Tumor Shanghai Institute of Nutrition and Health Chinese Academy of Sciences Shanghai 200031 P. R. ChinaAbstract Cellular senescence is a cell fate triggered by stressful stimuli and displays a hypersecretory feature, the senescence‐associated secretory phenotype (SASP). Senescent cell burden increases with aging and contributes to age‐related organ dysfunction and multiple chronic disorders. In this study, a large scale screening of a natural product library for senotherapeutic candidates is performed. Apigenin, a dietary flavonoid previously reported with antioxidant and anti‐inflammatory activities, exhibits capacity for targeting senescent cells as a senomorphic agent. This compound blocks the interactions between ATM/p38MAPK and HSPA8, preventing the transition of an acute stress‐associated phenotype (ASAP) toward the SASP. Mechanistically, apigenin targets peroxiredoxin 6 (PRDX6), an intracellular redox‐active molecule, suppressing the iPLA2 activity of PRDX6 and disrupting downstream reactions underlying SASP development. Apigenin reduces the severity of cancer cell malignancy promoted by senescent stromal cells in culture, while restraining chemoresistance when combined with chemotherapy in anticancer regimens. In preclinical trials, apigenin improves the physical function of animals with a premature aging‐like state, alleviating physical frailty and cognitive impairment. Together, the study demonstrates the feasibility of exploiting a natural compound with senomorphic capacity to achieve geroprotective effects by modulating the SASP, thus providing a baseline for future exploration of natural agents for alleviating age‐related conditions.https://doi.org/10.1002/advs.202412950agingapigenincellular senescenceSASPsenomorphics |
| spellingShingle | Hongwei Zhang Qixia Xu Zhirui Jiang Rong Sun Qun Wang Sanhong Liu Xin Luan Judith Campisi James L. Kirkland Weidong Zhang Yu Sun Targeting Senescence with Apigenin Improves Chemotherapeutic Efficacy and Ameliorates Age‐Related Conditions in Mice Advanced Science aging apigenin cellular senescence SASP senomorphics |
| title | Targeting Senescence with Apigenin Improves Chemotherapeutic Efficacy and Ameliorates Age‐Related Conditions in Mice |
| title_full | Targeting Senescence with Apigenin Improves Chemotherapeutic Efficacy and Ameliorates Age‐Related Conditions in Mice |
| title_fullStr | Targeting Senescence with Apigenin Improves Chemotherapeutic Efficacy and Ameliorates Age‐Related Conditions in Mice |
| title_full_unstemmed | Targeting Senescence with Apigenin Improves Chemotherapeutic Efficacy and Ameliorates Age‐Related Conditions in Mice |
| title_short | Targeting Senescence with Apigenin Improves Chemotherapeutic Efficacy and Ameliorates Age‐Related Conditions in Mice |
| title_sort | targeting senescence with apigenin improves chemotherapeutic efficacy and ameliorates age related conditions in mice |
| topic | aging apigenin cellular senescence SASP senomorphics |
| url | https://doi.org/10.1002/advs.202412950 |
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