Fisetin can be found in a wide variety of plants. Along with myricetin, fisetin provides the color of the traditional yellow dye young fustic, which was extracted from the Eurasian smoketree (Rhus cotinus). Many fruits and vegetables also contain fisetin, including strawberries apples, and grapes. Fisetin can be extracted from fruit and herbal sources in juices, wines, and infusions such as teas. It is also found in Monocotyledons such as onions.
Fisetin is a polyphenol, which is a flavonoid subgroup. Flavonoid synthesis begins with the phenylpropanoid pathway, in which phenylalanine, an amino acid, is transformed into 4-coumaroyl-CoA. This is the compound that enters the flavonoid biosynthesis pathway. Chalcone synthase, the first enzyme of this pathway, produces chalcone from 4-coumaroyl-CoA. All flavonoids are derived from this chalcone backbone (this family being the so-called chalconoids). 
Research on Longevity
Fisetin, like other polyphenols such as resveratrol, is a sirtuin-activating compound and has been shown in laboratory studies to extend the life of simple organisms like yeast, worms, and flies.
Dietary supplementation with a strawberry extract (which is said to have the highest levels of fisetin) improved the performance of rats in a rodent model of accelerated aging (R).
Fisetin is a naturally occurring plant polyphenol from the flavonoid group, similar to quercetin. It is present in many plants, where it acts as a colouring agent. It is also found in many fruits and vegetables, such as strawberries, apples, persimmons, onions, and cucumbers.
It has also been found to be a senolytic compound able to clear senescent cells, at least it does in vitro studies in a petri dish
As people age, they accumulate damaged cells. When the cells get to a certain level of damage they go through an aging process of their own, called cellular senescence. The cells also release inflammatory factors that tell the immune system to clear those damaged cells. A younger person’s immune system is healthy and is able to clear the damaged cells. But as people age, they aren’t cleared as effectively. Thus they begin to accumulate, cause low-level inflammation and release enzymes that can degrade the tissue.
Researchers found a natural product, called fisetin, reduces the level of these damaged cells in the body. They found this by treating mice towards the end of life with this compound and see improvement in health and lifespan. “These results suggest that we can extend the period of health, termed healthspan, even towards the end of life. But there are still many questions to address, including the right dosage, for example.” One question they can now answer, however, is why haven’t they done this before? There were always key limitations when it came to figuring out how a drug will act on different tissues, different cells in an aging body. Researchers didn’t have a way to identify if a treatment was actually attacking the particular cells that are senescent, until now. Fisetin is a senotherapeutic that extends health and lifespan
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.
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.
Like the other compounds, it has also been shown to be reactive in many different assays of biological activities, raising the possibility that any drug generated from fisetin would have too many side effects to be useful.
Fisetin has shown anti-cancer activity in studies on cells and model animals conducted in laboratories, and appears to block the PI3K/AKT/mTOR pathway. In lab studies it also has been shown to be an anti-proliferative agent, interfering with the cell cycle in several ways. Fisetin, like some other flavonoids, has been found in lab studies to be a topoisomerase inhibitor, which may turn out to be a carcinogenic activity or an anti-cancer activity – further research is needed.
In studies conducted on cells in a laboratory, fisetin inhibits the activity of several pro-inflammatory cytokines, including tumor necrosis factor alpha, interleukin 6, and Nuclear factor kappa B. It has also been shown in lab studies to upregulate glutathione, an endogenous antioxidant.
Fisetin also has direct activity as a reducing agent, chemically reacting with reactive oxygen species to neutralize them.
Based on lab studies, it appears that fisetin lodges in cell membranes and prevents oxidative damage to lipids in the cell membrane.
Fisetin, like other flavonoids, has a planar structure, with multiple carbon rings. Fisetin is able to scavenge free radicals as a result of its electron donating capacity, which is due to the presence of two hydroxyl groups on one ring and a hydroxyl group on another ring.
In vitro screening has identified fisetin as an antimitotic compound.
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^ Sahu, Bidya Dhar; Kalvala, Anil Kumar; Koneru, Meghana; Kumar, Jerald Mahesh; Kuncha, Madhusudana; Rachamalla, Shyam Sunder; Sistla, Ramakrishna (September 3, 2014). “Ameliorative Effect of Fisetin on Cisplatin-Induced Nephrotoxicity in Rats via Modulation of NF-κB Activation and Antioxidant Defence”. PLOS ONE. 9 (9): e105070. doi:10.1371/journal.pone.0105070.
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^ Herzig, J. (1891). “Studien über Quercetin und seine Derivate, VII. Abhandlung” [Studies on Quercetin and its Derivatives, Treatise VII]. Monatshefte für Chemie (in German). 12 (1): 177–90. doi:10.1007/BF01538594.
3^ Jump up to:
a b Forbes TDA, Clement BA. “Chemistry of Acacia’s from South Texas” (PDF). Texas A&M Agricultural Research and Extension Center at. Archived from the original (PDF) on May 15, 2011. Retrieved 2010-04-14.
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^ Fiorani, M.; Accorsi, A. (2005). “Dietary flavonoids as intracellular substrates for an erythrocyte trans-plasma membrane oxidoreductase activity”. The British Journal of Nutrition. 94 (3): 338–345. doi:10.1079/bjn20051504. PMID 16176603.
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^ Maher, Pamela; Dargusch, Richard; Ehren, Jennifer L.; Okada, Shinichi; Sharma, Kumar; Schubert, David (2011). Deli, Maria A., ed. “Fisetin Lowers Methylglyoxal Dependent Protein Glycation and Limits the Complications of Diabetes”. PLoS ONE. 6 (6): e21226. doi:10.1371/journal.pone.0021226. PMC 3124487. PMID 21738623. Lay summary – ScienceDaily (June 28, 2011).
7^ Jump up to:
a b c d Arai, Y.; Watanabe, S.; Kimira, M.; Shimoi, K.; Mochizuki, R.; Kinae, N. (2000). “Dietary intakes of flavonols, flavones and isoflavones by Japanese women and the inverse correlation between quercetin intake and plasma LDL cholesterol concentration”. The Journal of Nutrition. 130 (9): 2243–2250. PMID 10958819.
8^ Jump up to:
a b Viñas, P.; Martínez-Castillo, N.; Campillo, N.; Hernández-Córdoba, M. (2011). “Directly suspended droplet microextraction with in injection-port derivatization coupled to gas chromatography–mass spectrometry for the analysis of polyphenols in herbal infusions, fruits and functional foods”. Journal of Chromatography A. 1218 (5): 639–646. doi:10.1016/j.chroma.2010.12.026. PMID 21185565.
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^ De Santi, C.; Pietrabissa, A.; Mosca, F.; Pacifici, G. M. (2002). “Methylation of quercetin and fisetin, flavonoids widely distributed in edible vegetables, fruits and wine, by human liver”. International journal of clinical pharmacology and therapeutics. 40 (5): 207–212. doi:10.5414/cpp40207. PMID 12051572.
10^ Jump up to:
a b Ferreyra, M.L.; Rius, S.P.; Casati, P. (September 28, 2012). “Flavanoids: biosynthesis, biological functions, and biotechnological applications”. Frontiers in Plant Science. 3 (222). doi:10.3389/fpls.2012.00222. PMC 3460232. PMID 23060891.
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^ Zoratti, L.; Karppinen, K.; Escobar, A.L.; Haggman, H.; Jaakola, L. (October 9, 2014). “Light-controlled flavanoid biosynthesis in fruits”. Frontiers in Plant Science. 5 (534). doi:10.3389/fpls.2014.00534. PMC 4191440. PMID 25346743.
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^ Kroon, PA; Clifford, MN; Crozier, A; et al. (July 2004). “How should we assess the effects of exposure to dietary polyphenols in vitro?”. Am. J. Clin. Nutr. 80 (1): 15–21. PMID 15213022.
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^ Syed, DN; et al. (Sep 2013). “Inhibition of Akt/mTOR signaling by the dietary flavonoid fisetin”. Anticancer Agents Med Chem. 13 (7): 995–1001. doi:10.2174/18715206113139990129. PMC 3985520. PMID 23293889.
15^ Jump up to:
a b c Gupta, SC; et al. (1 October 2014). “Downregulation of tumor necrosis factor and other proinflammatory biomarkers by polyphenols”. Archives of Biochemistry and Biophysics. 559: 91–9. doi:10.1016/j.abb.2014.06.006. PMID 24946050.
17^ Jump up to:
a b c d Khan, N; Syed, DN; Ahmad, N; Mukhtar, H (Jul 2013). “Fisetin: a dietary antioxidant for health promotion”. Antioxidants. 19 (2): 151–62. doi:10.1089/ars.2012.4901. PMC 3689181. PMID 23121441.
Fisetin May Protect the Brain from Dementia and Memory Loss
The study published in Aging Cell showed that fisetin may be a groundbreaking preventative strategy in protecting the brain from dementia, Alzheimer’s disease, and age-related memory loss. Using mice that were genetically programmed to develop Alzheimer’s, researchers fed one group water with fisetin in it, where the other group of mice received water without fisetin. Nine months into the study, the mice that did not receive fisetin began showing signs of cognitive decline while the mice who had consumed fisetin showed no sign of decline.
Upon exploring the brains of the mice who consumed fisetin, researchers found that there were actually anti-inflammatory molecules that were not in the brains of those mice who developed Alzheimer’s disease. The mice who consumed fisetin supplemented water remained healthy even though they were genetically programmed to develop Alzheimer’s disease.
Where to Find Fisetin
Fisetin is a relatively new compound, identified only a little more than ten years ago. The compound has been widely studied for anti-cancer and diabetes methods, but is now showing promise to preserve brain health. Unfortunately, fisetin is only found in small amounts of particular fruits and vegetables and it is hard to consume it from diet alone. However, it is most commonly found in these superfoods:
Previous research published earlier this year in Nature Medicine involving University of Minnesota Medical School faculty Paul D. Robbins and Laura J. Niedernhofer and Mayo Clinic investigators James L. Kirkland and Tamara Tchkonia, showed it was possible to reduce the burden of damaged cells, termed senescent cells, and extend lifespan and improve health, even when treatment was initiated late in life. They now have shown that treatment of aged mice with the natural product Fisetin, found in many fruits and vegetables, also has significant positive effects on health and lifespan.
As people age, they accumulate damaged cells. When the cells get to a certain level of damage they go through an aging process of their own, called cellular senescence. The cells also release inflammatory factors that tell the immune system to clear those damaged cells. A younger person’s immune system is healthy and is able to clear the damaged cells. But as people age, they aren’t cleared as effectively. Thus they begin to accumulate, cause low level inflammation and release enzymes that can degrade the tissue.
Robbins and fellow researchers found a natural product, called Fisetin, reduces the level of these damaged cells in the body. They found this by treating mice towards the end of life with this compound and see improvement in health and lifespan. The paper, “Fisetin is a senotherapeutic that extends health and lifespan,” was recently published in EBioMedicine.
“These results suggest that we can extend the period of health, termed healthspan, even towards the end of life,” said Robbins. “But there are still many questions to address, including the right dosage, for example.”
One question they can now answer, however, is why haven’t they done this before? There were always key limitations when it came to figuring out how a drug will act on different tissues, different cells in an aging body. Researchers didn’t have a way to identify if a treatment was actually attacking the particular cells that are senescent, until now.
Under the guidance of Edgar Arriaga, a professor in the Department of Chemistry in the College of Science and Engineering at the University of Minnesota, the team used mass cytometry, or CyTOF, technology and applied it for the first time in aging research, which is unique to the University of Minnesota.
“In addition to showing that the drug works, this is the first demonstration that shows the effects of the drug on specific subsets of these damaged cells within a given tissue.” Robbins said.
More information: Matthew J. Yousefzadeh et al, Fisetin is a senotherapeutic that extends health and lifespan, EBioMedicine(2018). DOI: 10.1016/j.ebiom.2018.09.015
Ming Xu et al. Senolytics improve physical function and increase lifespan in old age, Nature Medicine (2018). DOI: 10.1038/s41591-018-0092-9
If you add plant flavones like apigen or luteolin, found throughout the plant kingdom—like in citrus, celery, and peppers—you can see they help block cancer angiog the tube formation. Here’s the effect of fisetin, a phytonutrient found in strawberries, and other fruits and veggies. It just shrinks the beginnings of new blood vessel formation right on down.
But, either way, you can stimulate blood vessel formation like cancer does with the tumor compound VEGF, and then abolish that effect with plant compounds—in this case, from purple rice. “Therefore, the daily consumption of natural foods containing adequate flavonoids could be beneficial for the prevention of cancer metastasis or could improve cancer prognosis.”
Credit: CC Public Domain