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Fisetin is a senotherapeutic that extends health and lifespan

机译：非瑟定是一种可以延长健康和寿命的治疗药物

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Background Senescence is a tumor suppressor mechanism activated in stressed cells to prevent replication of damaged DNA. Senescent cells have been demonstrated to play a causal role in driving aging and age-related diseases using genetic and pharmacologic approaches. We previously demonstrated that the combination of dasatinib and the flavonoid quercetin is a potent senolytic improving numerous age-related conditions including frailty, osteoporosis and cardiovascular disease. The goal of this study was to identify flavonoids with more potent senolytic activity. Methods A panel of flavonoid polyphenols was screened for senolytic activity using senescent murine and human fibroblasts, driven by oxidative and genotoxic stress, respectively. The top senotherapeutic flavonoid was tested in mice modeling a progeroid syndrome carrying a p16INK4a-luciferase reporter and aged wild-type mice to determine the effects of fisetin on senescence markers, age-related histopathology, disease markers, health span and lifespan. Human adipose tissue explants were used to determine if results translated. Findings Of the 10 flavonoids tested, fisetin was the most potent senolytic. Acute or intermittent treatment of progeroid and old mice with fisetin reduced senescence markers in multiple tissues, consistent with a hit-and-run senolytic mechanism. Fisetin reduced senescence in a subset of cells in murine and human adipose tissue, demonstrating cell-type specificity. Administration of fisetin to wild-type mice late in life restored tissue homeostasis, reduced age-related pathology, and extended median and maximum lifespan. Interpretation The natural product fisetin has senotherapeutic activity in mice and in human tissues. Late life intervention was sufficient to yield a potent health benefit. These characteristics suggest the feasibility to translation to human clinical studies. Fund NIH grants P01 AG043376 (PDR, LJN), U19 AG056278 (PDR, LJN, WLL), R24 AG047115 (WLL), R37 AG013925 (JLK), R21 AG047984 (JLK), P30 DK050456 (Adipocyte Subcore, JLK), a Glenn Foundation/ American Federation for Aging Research (AFAR) BIG Award (JLK), Glenn/AFAR (LJN, CEB), the Ted Nash Long Life and Noaber Foundations (JLK), the Connor Group (JLK), Robert J. and Theresa W. Ryan (JLK), and a Minnesota Partnership Grant (AMAY-UMN#99)-P004610401–1 (JLK, EAA).
机译：背景衰老是一种在应激细胞中激活的肿瘤抑制机制，可防止受损DNA的复制。已经证明，使用遗传和药理学方法，衰老细胞在驱动衰老和与年龄有关的疾病中起因果作用。我们先前证明，达沙替尼和类黄酮槲皮素的组合具有很强的抗衰老性，可改善许多与年龄相关的疾病，包括脆弱，骨质疏松和心血管疾病。这项研究的目的是鉴定具有更强的senolytic活性的类黄酮。方法使用衰老的鼠和人成纤维细胞，分别在氧化应激和遗传毒性应激的驱动下，筛选一组类黄酮多酚的衰老活性。在模拟带有p16 INK4a -荧光素酶报告基因的早老症候群的小鼠和衰老的野生型小鼠中测试了最高的治疗类黄酮，以确定非瑟酮对衰老标志物，年龄相关的组织病理学，疾病标志物，健康寿命和寿命。人类脂肪组织外植体用于确定结果是否翻译。结果在测试的10种黄酮类化合物中，非瑟汀是最有效的镇静剂。用非瑟酮急性或间歇治疗早衰小鼠和老小鼠减少了多个组织的衰老标记，这与即席即走的衰老机理相符。 Fisetin减少了鼠类和人类脂肪组织中一部分细胞的衰老，表明了细胞类型的特异性。在生命后期向野生型小鼠施用非瑟酮可恢复组织稳态，减少与年龄有关的病理，并延长中位寿命和最大寿命。解释天然产物非瑟酮在小鼠和人体组织中具有抗癌活性。后期生活干预足以产生有效的健康益处。这些特征表明翻译为人类临床研究的可行性。 NIH基金会授予P01 AG043376（PDR，LJN），U19 AG056278（PDR，LJN，WLL），R24 AG047115（WLL），R37 AG013925（JLK），R21 AG047984（JLK），P30 DK050456（Adipocyte Subcore，JLK），Glenn基金会/美国衰老研究联合会（AFAR）BIG奖（JLK），格伦/ AFAR（LJN，CEB），泰德纳什长寿和诺贝尔基金会（JLK），康纳集团（JLK），罗伯特J.瑞恩（JLK）和明尼苏达州合伙人资助（AMAY-UMN＃99）-P004610401-1（JLK，EAA）。

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