Fisetin

Fisetin is naturally found at very low levels in some plants, fruits and vegetables. Some cell and animal studies suggest that fisetin may protect brain cells from damage and potentially reduce diabetes and cancer risk, but there is no evidence yet that it does the same in humans. While concentrated fisetin is commercially available as a dietary supplement and often marketed as a “memory enhancer”, almost nothing is known about how it acts in the human body to cause either harm or benefit.

EFFICACY
Possibly
with   Very limited  evidence
SAFETY WHEN
USED AS DIRECTED
Probably
with   Very limited  evidence

Fisetin is a natural plant “flavonoid” found in some trees, fruits and vegetables. Many flavonoids have been found to have anti-inflammatory, antioxidant and anti-bacterial properties and are being investigated for treatment of cancer and heart disease. For example, some flavonoids found in coffee are thought to confer benefits to the human cardiovascular system.

Did You Know? Flavonoids like fisetin protect plants from insects and harmful oxidative stress induced by the ultraviolet wavelengths in sunlight.

Fisetin is available as a nutritional supplement from different manufacturers and is also found in low levels in fruits and vegetables like strawberries, grapes and onions. However, it has been estimated that a person would have to eat 37 strawberries every day to reach the doses used in animal experiments that showed potential benefits of fisetin.

Possibly, based on very limited evidence from experiments in cells and animals.

There is no evidence yet that fisetin can prevent dementia, although evidence from isolated cells and some animal disease models suggest it may be possible [1,2,4].

Possibly, based on very limited evidence from experiments in cells and animals.

There is no evidence yet that fisetin can help someone who already has dementia or mild cognitive impairment. However, evidence from isolated cells and animal experiments suggests it may be possible [1,2,4].

Possibly, based on very limited evidence from experiments in cells and animals.

There is no evidence that fisetin extends human lifespans. Fisetin gained notoriety after it was shown to extend the lifespans of yeast cells, nematode worms and fruit flies [11,12]. These were the same experiments that first identified similar properties in resveratrol, a chemical closely-related to fisetin. Fisetin is thought to act similarly to resveratrol to extend lifespan in these organisms, by activating the enzyme called sirtuin 2 and can mimic some of the effects of caloric restriction.

In experiments in test tubes, cells and laboratory animals, fisetin protects brain cells in several ways, although currently there is no evidence it does the same in humans. In test tube experiments fisetin and several chemically modified versions of fisetin prevent the Alzheimer’s protein beta-amyloid from clumping together, a step in the process that forms the hallmark “plaques” in the brains of Alzheimer’s disease patients [1,2]. Several animal experiments also suggest that fisetin fed to mice might improve their ability to learn and remember as well as protect brain cells from chemical damage in several ways, including lowering inflammation [3-5]. Fisetin may have anti-inflammatory actions that could potentially help diseases like Alzheimer’s [6,7], but so far this hasn’t been shown in humans. In other animal experiments, fisetin has been shown to help slow the symptoms of Huntington’s disease [8], another neurodegenerative disease, but again there is no evidence that it does the same in humans. Chemically modified fisetin derivatives are also being explored as protective agents for brain cells damaged by stroke [9].

Additionally, fisetin appears to improve symptoms of diabetes in mice genetically-engineered to develop the disease [10], but it remains unknown if it will do the same in people with diabetes. Since diabetes is a risk factor for Alzheimer’s disease, these findings provide new paths to potential future drugs for both diseases.

Probably safe, based on very limited evidence and public use of fisetin supplements with no reports of toxicity.

NOTE: This is not a comprehensive safety evaluation or complete list of potentially harmful drug interactions.  It is important to discuss safety issues with your physician before taking any new supplement or medication.

The fisetin found naturally in fruits and other foods is certainly safe. Concentrated fisetin supplements are sold over-the-counter and we are aware of no reports of toxicity. However, there have been no safety tests conducted in humans. Additionally, laboratory experiments have shown that fisetin can inhibit two enzymes that are critical to proper DNA replication, called topoisomerases 1 and II [13]. Because of this inhibition, fisetin has the potential to cause cancer, although at what levels it could be carcinogenic in humans remains unknown.

No human research, to date, suggests taking fisetin will reduce risk for dementia and cancer, or improve aging and longevity. Although some scientific research in cells and animals has shown some anti-cancer effects of fisetin [7,14-17], fisetin also has the potential to cause cancer [13]. It is important to consult your primary care provider before taking fisetin supplements.

To our knowledge, there are no planned or on-going trials in the United States or Europe to test fisetin for any disease condition. However, you can check clinicaltrials.gov and clinicaltrialsregister.eu for updates on possible fisetin trials.

• Click here to read a news story about fisetin’s benefits to mice with Alzheimer’s disease.

1.  Kim H, Park BS, Lee KG, Choi CY, Jang SS, Kim YH, Lee SE (2005) Effects of naturally occurring compounds on fibril formation and oxidative stress of beta-amyloid. J Agric Food Chem 53:8537-8541.

2.  Ushikubo H, Watanabe S, Tanimoto Y, Abe K, Hiza A, Ogawa T, Asakawa T, Kan T, Akaishi T (2012) 3,3',4',5,5'-Pentahydroxyflavone is a potent inhibitor of amyloid beta fibril formation. Neurosci Lett 513:51-56.

3.  Cho N, Lee KY, Huh J, Choi JH, Yang H, Jeong EJ, Kim HP, Sung SH (2013) Cognitive-enhancing effects of Rhus verniciflua bark extract and its active flavonoids with neuroprotective and anti-inflammatory activities. Food Chem Toxicol 58:355-361.

4.  Currais A, Prior M, Dargusch R, Armando A, Ehren J, Schubert D, Quehenberger O, Maher P (2013) Modulation of p25 and inflammatory pathways by fisetin maintains cognitive function in Alzheimer's disease transgenic mice. Aging Cell pp:1-12.

5.  Maher P, Akaishi T, Abe K (2006) Flavonoid fisetin promotes ERK-dependent long-term potentiation and enhances memory. Proc Natl Acad Sci U S A 103:16568-16573.

6.  Geraets L, Haegens A, Brauers K, Haydock JA, Vernooy JH, Wouters EF, Bast A, Hageman GJ (2009) Inhibition of LPS-induced pulmonary inflammation by specific flavonoids. Biochem Biophys Res Commun 382:598-603.

7.  Park HH, Lee S, Son HY et al (2008) Flavonoids inhibit histamine release and expression of proinflammatory cytokines in mast cells. Arch Pharm Res 31:1303-1311.

8.  Maher P, Dargusch R, Bodai L, Gerard PE, Purcell JM, Marsh JL (2011) ERK activation by the polyphenols fisetin and resveratrol provides neuroprotection in multiple models of Huntington's disease. Hum Mol Genet 20:261-270.

9.  Lapchak PA (2012) A series of novel neuroprotective blood brain barrier penetrating flavonoid drugs to treat acute ischemic stroke. Curr Pharm Des 18:3694-3703.

10.  Maher P, Dargusch R, Ehren JL, Okada S, Sharma K, Schubert D (2011) Fisetin lowers methylglyoxal dependent protein glycation and limits the complications of diabetes. PLoS One 6:e21226.

11.  Howitz KT, Bitterman KJ, Cohen HY et al (2003) Small molecule activators of sirtuins extend Saccharomyces cerevisiae lifespan. Nature 425:191-196.

12.  Wood JG, Rogina B, Lavu S, Howitz K, Helfand SL, Tatar M, Sinclair D (2004) Sirtuin activators mimic caloric restriction and delay ageing in metazoans. Nature 430:686-689.

13.  Lopez-Lazaro M, Willmore E, Austin CA (2010) The dietary flavonoids myricetin and fisetin act as dual inhibitors of DNA topoisomerases I and II in cells. Mutat Res 696:41-47.

14.  Adhami VM, Syed DN, Khan N, Mukhtar H (2012) Dietary flavonoid fisetin: a novel dual inhibitor of PI3K/Akt and mTOR for prostate cancer management. Biochem Pharmacol 84:1277-1281.

15.  Bothiraja C, Yojana BD, Pawar AP, Shaikh KS, Thorat UH (2014) Fisetin-loaded nanocochleates: formulation, characterisation, in vitro anticancer testing, bioavailability and biodistribution study. Expert Opin Drug Deliv 11:17-29.

16.  Lim dY, Park JH (2009) Induction of p53 contributes to apoptosis of HCT-116 human colon cancer cells induced by the dietary compound fisetin. Am J Physiol Gastrointest Liver Physiol 296:G1060-G1068.

17.  Syed DN, Suh Y, Afaq F, Mukhtar H (2008) Dietary agents for chemoprevention of prostate cancer. Cancer Lett 265:167-176.

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