Fisetin: the Antioxidant You Need to Know

Fisetin, a naturally occurring plant polyphenol, is joining the ranks of other polyphenols in the supplement world due to its unique properties.  It is a type of polyphenol that is a flavonoid. Flavonoids possess antioxidant properties which help keep the body from accumulating harmful waste.  Like another popular flavonol compound, resveratrol, Fisetin activates sirtuin, a type of protein responsible for regulating cellular health and aging. (1)(2)

Fisetin is found in high amounts in strawberries (160 mcg/g), apples (26.9 mcg/g), onions (4.8 mcg/g), persimmons (10.6 mcg/g), grapes (3.9 mcg/g) and cucumbers (0.1 mcg/g).  Dietary consumption of Fisetin as it naturally occurs in food has been measured at 0.4 mg/day in Japan; a country which has one of the healthiest populations of aged people in the world. It can also be found in many types of plants and trees, such as the acacia trees, the shrubs and trees of the family Fabaceae, and in the yellow cypress tree.  It was chemically identified in 1891 by Josef Herzig, an Austrian chemist. (1)(3)(4)

Fisetin & Senescent Cells

The primary focus of Fisetin studies that have taken place or are currently underway are regarding senescence.  Senescent (or aging) cells have been the main focus for Fisetin.  These types of aged cells are rarely present in younger individuals but can be found as the normal process of aging occurs past youth.  Simply put, senescent cells no longer divide.  Most senescent cells are found in skeletal, fat, and kidney tissue, as well as being found in the skin of all vertebrate forms.  (3)(5)

Senescent cells are hardy and resistant to normal cellular death (apoptosis).  They achieve this resistance through an upregulation of anti-apoptotic pathways.  This resistance has led to a large amount of research to target molecules which can disrupt the pathway and allow more of the senescent cells to fade off, as senescent cells lead to abnormal cell growth, increase oxidative stress on the body, and impact development and tissue repair.  Research conducted with injecting senescent cells into the body has resulted in catalyzing age-related conditions. (3)(5)

Senescent cells rely on the immune system in order to be processed as waste.  A condition in which the immune system ages on a cellular level is called immunosenescence and leads to a further reduced capability to clear these unproductive cells from the body.  Chronic conditions which cause inflammation in the body also hasten the body into immunosenescence. (5)

Within the immune system, macrophage cells and NK (natural killer) cells clear senescent cells from the body.  Unfortunately, even NK cells can become senescent, completing a viscous cycle of the accumulation of deteriorating cells. (5)

To this end, many scientists have aimed to discover anti-senolytic molecules to create medications which can delay the onset of aging, while simultaneously working on finding ways to destroy senescent cells selectively.  Prior research focused on another flavonoid, quercetin, and other flavonoids like resveratrol, luteolin, curcumin, rutin, epigallocatechin gallate (EGCG), myricetin, and others have been explored for their potential to reduce the markers of senescence.  Flavonoids are believed to be instrumental in helping reduce the oxidative stress caused by an overload of senescent cells and through their unique abilities to stimulate sirtuin. (3)

Benefits of Fisetin

Though most of the research conducted with Fisetin has either been in animal models or in-vitro cell studies, a clinical trial in humans is currently underway (3).

References

1. “Fisetin.” doi:https://en.wikipedia.org/wiki/Fisetin.
2. “Sirtuin.” Doi: https://en.wikipedia.org/wiki/Sirtuin
3. Yousefzadeh, Matthew J., et al. “Fisetin Is a Senotherapeutic That Extends Health and Lifespan.” EBioMedicine, Elsevier, 29 Sept. 2018, www.sciencedirect.com/science/article/pii/S2352396418303736.
4. Khan, Naghma et al. “Fisetin: a dietary antioxidant for health promotion.” Antioxidants & redox signaling vol. 19,2 (2013): 151-62. doi:10.1089/ars.2012.4901
5. “Cellular senescence.” https://en.wikipedia.org/wiki/Cellular_senescence
6. Gupta, Subash C., et al. “Downregulation of Tumor Necrosis Factor and Other Proinflammatory Biomarkers by Polyphenols.” Archives of Biochemistry and Biophysics, Academic Press, 16 June 2014, www.sciencedirect.com/science/article/abs/pii/S0003986114002082?via=ihub.
7. Dong, Bin, et al. “Fisetin Inhibits Cardiac Hypertrophy by Suppressing Oxidative Stress.” The Journal of Nutritional Biochemistry, U.S. National Library of Medicine, Dec. 2018, www.ncbi.nlm.nih.gov/pubmed/30312797.
8. Maher, Pamela. “How Fisetin Reduces the Impact of Age and Disease on CNS Function.” Frontiers in Bioscience (Scholar Edition), U.S. National Library of Medicine, 1 June 2015, www.ncbi.nlm.nih.gov/pmc/articles/PMC5527824.
9. Maurya, Brajesh Kumar, and Surendra Kumar Trigun. “Fisetin Modulates Antioxidant Enzymes and Inflammatory Factors to Inhibit Aflatoxin-B1 Induced Hepatocellular Carcinoma in Rats.” Oxidative Medicine and Cellular Longevity, Hindawi Publishing Corporation, 2016, www.ncbi.nlm.nih.gov/pmc/articles/PMC4670673.
10. Prasath, Gopalan Sriram, and Sorimuthu Pillai Subramanian. “Fisetin, a Tetra Hydroxy Flavone Recuperates Antioxidant Status and Protects Hepatocellular Ultrastructure from Hyperglycemia Mediated Oxidative Stress in Streptozotocin Induced Experimental Diabetes in Rats.” Food and Chemical Toxicology : an International Journal Published for the British Industrial Biological Research Association, U.S. National Library of Medicine, Sept. 2013, www.ncbi.nlm.nih.gov/pubmed/23791753.
11. IG. Obrosova, SS. Chung, et al. “Effects of Two Antioxidants; α-Lipoic Acid and Fisetin against Diabetic Cataract in Mice.” International Ophthalmology, Springer Netherlands, 1 Jan. 1970, link.springer.com/article/10.1007/s10792-014-0029-3.
12. Maher, Pamela, et al. “Fisetin Lowers Methylglyoxal Dependent Protein Glycation and Limits the Complications of Diabetes.” PloS One, Public Library of Science, 2011, www.ncbi.nlm.nih.gov/pmc/articles/PMC3124487/).
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15. Nagai, K, et al. “The Hydroxyflavone, Fisetin, Suppresses Mast Cell Activation Induced by Interaction with Activated T Cell Membranes.” British Journal of Pharmacology, Blackwell Publishing Ltd, Oct. 2009, www.ncbi.nlm.nih.gov/pubmed/19702784/.
16. Sahu, Bidya Dhar, et al. “Ameliorative Effect of Fisetin on Cisplatin-Induced Nephrotoxicity in Rats via Modulation of NF-ΚB Activation and Antioxidant Defence.” PloS One, Public Library of Science, 3 Sept. 2014, www.ncbi.nlm.nih.gov/pmc/articles/PMC4153571.
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19. Prasath, Gopalan Sriram, et al. “Fisetin Improves Glucose Homeostasis through the Inhibition of Gluconeogenic Enzymes in Hepatic Tissues of Streptozotocin Induced Diabetic Rats.” European Journal of Pharmacology, U.S. National Library of Medicine, 5 Oct. 2014, www.ncbi.nlm.nih.gov/pubmed/25064342.
20. Prasath, Gopalan Sriram, and Sorimuthu Pillai Subramanian. “Antihyperlipidemic Effect of Fisetin, a Bioflavonoid of Strawberries, Studied in Streptozotocin-Induced Diabetic Rats.” Journal of Biochemical and Molecular Toxicology, U.S. National Library of Medicine, Oct. 2014, www.ncbi.nlm.nih.gov/pubmed/24939606.
21. Prasath, Gopalan Sriram, and Sorimuthu Pillai Subramanian. “Fisetin, a Tetra Hydroxy Flavone Recuperates Antioxidant Status and Protects Hepatocellular Ultrastructure from Hyperglycemia Mediated Oxidative Stress in Streptozotocin Induced Experimental Diabetes in Rats.” Food and Chemical Toxicology : an International Journal Published for the British Industrial Biological Research Association, U.S. National Library of Medicine, Sept. 2013, www.ncbi.nlm.nih.gov/pubmed/23791753.
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25. Lu, Weiqiang, et al. “The Efficient Expression of Human Fibroblast Collagenase in Escherichia Coli and the Discovery of Flavonoid Inhibitors.” Journal of Enzyme Inhibition and Medicinal Chemistry, U.S. National Library of Medicine, Aug. 2013, www.ncbi.nlm.nih.gov/pubmed/22524676.
26. Syed, Deeba N, et al. “Inhibition of Akt/MTOR Signaling by the Dietary Flavonoid Fisetin.” Anti-Cancer Agents in Medicinal Chemistry, U.S. National Library of Medicine, Sept. 2013, www.ncbi.nlm.nih.gov/pmc/articles/PMC3985520/.
27. Weichhart, Thomas. “MTOR as Regulator of Lifespan, Aging, and Cellular Senescence: A Mini-Review.” Gerontology, U.S. National Library of Medicine, 2018, www.ncbi.nlm.nih.gov/pmc/articles/PMC6089343.
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29. Zhu, Yi, et al. “The Achilles' Heel of Senescent Cells: from Transcriptome to Senolytic Drugs.” Aging Cell, John Wiley & Sons, Ltd, Aug. 2015, www.ncbi.nlm.nih.gov/pmc/articles/PMC4531078.
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