Fisetin: An Anti-Aging Natural Flavonoid
Fisetin has many anti-aging properties and is a known to mimic the anti-aging effects of calorie restriction. A natural flavonoid (a type of polyphenol), fisetin occurs in many plants, including strawberries. As a potent sirutin activator, fistein mimics the longevity effects of calorie restriction. Especially impressive is that fisetin has been shown in studies to enhance functioning of the brain, being neuroprotective and as a multi-pathway memory enhancement agent. Furthermore, fisetin has been shown to have an anti-depressant effect in animal research, by increasing levels of serotonin and noradrenaline in the brain.(23)
Neuroprotection and Memory
• Protects against age-related decline of neuron activity of the brain. Fisetin is believed to provide significant protection against decline of brain function because it acts through a diverse set of actions. This is especially important since the decline of the brain is not based upon a single modality.(1)
1. Fisetin provides antioxidant protection, by both acting as an antioxidant, as well as boosting levels of neuron intracellular glutathione levels. Glutathione is the primary antioxidant in inside the neuron, and is vital in sustaining the health and function of the neuron.
2. Increases cellular energy levels (ATP).
3. Reduces activity the inflammatory enzyme 5-lipoxygenase.
4. Helps preserve mitochondria function in neurons, as the brain is subjected to increasing levels of oxidative stress, associated with aging.
5. Promotes memory and strengthens synaptic transmission between neurons. Fisetin facilitates ERK-dependent long-term potentiation (LTP) between neurons. LTP involves the modification (strengthening) of the synaptic signals by which the neurons communicate. LTP is a critical process and forms the foundation for learning and memory.
• Fisetin functions similarly to neurotrophic factors facilitating the growth, maintenance, regeneration and survival of nerve cells. Fisetin has been shown to promote the survival and growth of nerve cells independently of neurotrophic factors. Neurotrophic factors are proteins required for the maintenance and survival of nerve cells. When neurotrophic factors are removed, the nerve cells will die. However, fisetin can replicate the function of neurotrophic factors, maintaining the survival of nerve cells and actually resulting in nerve cell growth.(3,4) • Fisetin is one of only a few molecules known to activate the ERK cascade pathway, which is implicated in the neurodegenerative Huntington’s Disease, an inherited fatal disease affecting motor and other brain activities.(5)
Anti-Cancer Properties: Modulating Inflammation Pathways
• Fisetin is a unique anti-cancer agent. Using potent anti-oxidant, anti-inflammatory and anti-proliferative properties, fisetin acts against a large number of cancers.
• The process of carcinogenesis involves many steps, with the primary facilitator being chronic cellular inflammatory signaling. Pro-inflammatory signaling by NF- kappaB and genes regulated by NF- kappaB play the major role in the chronic inflammatory pathways leading to cancer and the proliferation of tumor cells. Fisetin, as with other flavonoids, has the ability to suppress many of these inflammatory pathways (especially the NF-kappaB pathway), which may lead to the prevention and treatment of many cancers. (6, 7,13)
• Experimental research studies of Fisetin for chemopreventive and chemotherapeutic properties against a number of cancers including: lung cancer(8), bladder cancer(9), prostate cancer(10,11), pancreatic cancer(12), melanoma (18,19). • The pathways in which fisetin works against cancer includes:
1. Inhibition of the NF-kappa B inflammatory pathway.
2. Activation of P53 (9) (protein 53 | a tumor suppressor protein encoded / manufactured in the body and has many anti-cancer functions).
3. Inhibition of the Wingless (Wnt) signaling pathway. (17). The Wnt pathway plays a key role in carcinogenesis, since it regulates many cellular processes including proliferation and survival.
• Pulmonary Inflammation. In experimentally induced acute pulmonary inflammation, fisetin’s anti-inflammatory effects were shown to be more effective than those of the anti-inflammatory glucocorticoid dexamethasone.(14) The authors of the study proposed that fisetin may be a candidate to treat pulmonary inflammatory diseases. Anti-inflammation pf the lung is also demonstrated by the anti-asthma effect of fisetin by downregulating the NF-kB inflammatory pathway.(22)
• Inhibition of Allergy Inflammatory Response. Fisetin, along with several other flavonoids, has been shown to inhibit the allergic inflammatory response by suppressing mast cell activation (which suppresses histamine release). Mast cells play a critical role in the allergic inflammatory response. When mast cells are activated, they secret histamine and other proinflammatory substances.(15)
Anti-Diabetic Effects | Reduction of Complications
• Lowers Protein Glycation and Reduces Possible Complications . Fisetin increases level of an enzyme (glyoxalase 1) which is important for the removal and detoxification of a compound which is involved with damaging protein glycation and diabetic complications. In diabetic mice models, fisetin was shown to reduce glycated proteins in the blood, kidney and brain of these animals. By lowering the levels of glycated proteins, fisetin was able to attenuate diabetic complications in the lab animals. (20) Conversely, a deficiency of the enzyme glyoxalase 1 is associated with significantly higher levels of glycation, and complications.(21) Furthermore, fisetin has been shown to inhibit liver induced hyperglycemia by reducing the release of glucose from the liver.(16)
1. Maher P. Modulation of multiple pathways involved in the maintenance of neuronal function during aging by fisetin. Genes Nutr. 2009 Sep 10.
2. Maher P, et al. Flavonoid fisetin promotes ERK-dependent long-term potentiation and enhances memory. Proc Natl Acad Sci U S A. 2006 Oct 31;103(44):16568-73.
3. Maher P. The flavonoid fisetin promotes nerve cell survival from trophic factor withdrawal by enhancement of proteasome activity. Arch Biochem Biophys. 2008 Aug 15;476(2):139-44.
4. Maher P. A comparison of the neurotrophic activities of the flavonoid fisetin and some of its derivatives. Free Radic Res. 2006 Oct;40(10):1105-11.
5. Maher P, et al. ERK activation by the polyphenols fisetin and resveratrol provides neuroprotection in multiple models of Huntington's disease. Hum Mol Genet. 2011 Jan 15;20(2):261-70.
6. Gupta SC, et al. Regulation of survival, proliferation, invasion, angiogenesis, and metastasis of tumor cells through modulation of inflammatory pathways by nutraceuticals. Cancer Metastasis Rev. 2010 Sep;29(3):405-34.
7. Prasad S, et al. Targeting inflammatory pathways by flavonoids for prevention and treatment of cancer. Planta Med. 2010 Aug;76(11):1044-63.
8. Ravichandran N, et al. Fisetin, a novel flavonol attenuates benzo(a)pyrene-induced lung carcinogenesis in Swiss albino mice. Food Chem Toxicol. 2011 Feb 17.
9. Li J, et al. Fisetin, a dietary flavonoid, induces cell cycle arrest and apoptosis through activation of p53 and inhibition of NF-kappa B pathways in bladder cancer cells. Basic Clin Pharmacol Toxicol. 2011 Feb;108(2):84-93.
10. Haddad AQ, et al. Antiproliferative mechanisms of the flavonoids 2,2'-dihydroxychalcone and fisetin in human prostate cancer cells. Nutr Cancer. 2010;62(5):668-81.
11. Suh Y, et al. Fisetin induces autophagic cell death through suppression of mTOR signaling pathway in prostate cancer cells. Carcinogenesis. 2010 Aug;31(8):1424-33.
12. Murtaza I, et al. Fisetin, a natural flavonoid, targets chemoresistant human pancreatic cancer AsPC-1 cells through DR3-mediated inhibition of NF-kappaB. Int J Cancer. 2009 Nov 15;125(10):2465-73.
13. Sung B, et al. Fisetin, an inhibitor of cyclin-dependent kinase 6, down-regulates nuclear factor-kappaB-regulated cell proliferation, antiapoptotic and metastatic gene products through the suppression of TAK-1 and receptor-interacting protein-regulated IkappaBalpha kinase activation. Mol Pharmacol. 2007 Jun;71(6):1703-14.
14. Geraets L, et al. Inhibition of LPS-induced pulmonary inflammation by specific flavonoids. Biochem Biophys Res Commun. 2009 May 8;382(3):598-603.
15. Park HH, et al. Flavonoids inhibit histamine release and expression of proinflammatory cytokines in mast cells. Arch Pharm Res. 2008 Oct;31(10):1303-11.
16. Constantin RP, et al. The actions of fisetin on glucose metabolism in the rat liver. Cell Biochem Funct. 2010 Mar;28(2):149-58.
17. Teiten MH, et al. Targeting the Wingless Signaling Pathway with Natural Compounds as Chemopreventive or Chemotheraputic Agents. Curr Pharm Biotechnol. 2011 Apr 5.
18. Syed DN, et al. Inhibition of Human Melanoma Cell Growth by the Dietary Flavonoid Fisetin Is Associated with Disruption of Wnt/B-Catenin Signaling and Decreased Mitf Levels. J Invest Dermatol. 2011 Jun; 131(6):1291-9.
19. Arbiser JL, et al. Fisetin: A Natural Fist Against Melanoma? J Invest Dermatol. 2011 Jun;131(6):1187-9.
20. Maher P, et al. Fisetin lowers methylglyoxal dependent protein glycation and limits the complications of diabetes. PLoS One. 2011;6(6):e21226.
21. Miyata T, et al. Glyoxalase I deficiency is associated with an unusual level of advanced glycation end products in a hemodialysis patient. Kidney Int. 2001 Dec;60(6):2351-9.
22. Wu MY, et al. Immunosuppressive effects of fisetin in ovalbumin-induced asthma through inhibition of NF-κB activity. J Agric Food Chem. 2011 Sep 7.
23. Zhen L, et al. The antidepressant-like effect of fisetin involves the serotonergic and noradrenergic system. Behav Brain Res. 2011 Dec 19.