Fisetin is a senotherapeutic that extends health and lifespan

作者：Matthew J. Yousefzadeh, Yi Zhu, Sara J. McGowan, Luise Angelini, Heike Fuhrmann‐Stroissnigg, Ming Xu, Yuan Yuan Ling, Kendra I. Melos, Tamar Pirtskhalava, Christina L. Inman, Collin A. McGuckian, Erin A. Wade, Jonathon I. Kato, Diego Grassi, Mark Wentworth, Christin E. Burd, Edgar A. Arriaga, Warren Ladiges, Tamar Tchkonia, James L. Kirkland, Paul D. Robbins, Laura J. Niedernhofer · 发表于：EBioMedicine · 年份：2018 · DOI：10.1016/j.ebiom.2018.09.015 · 被引用次数：1036 · 研究领域：Telomeres, Telomerase, and Senescence、Mangiferin and Mango Extracts、Antioxidants, Aging, Portulaca oleracea

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: -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...