Found in nature in a wide variety of fruits, vegetables, nuts and wines, fisetin is a polyphenol, which is part of the flavonoid group of compounds. Fisetin is well known for its yellow colour contributing role and has been shown in animal studies to have great potential as a potent anti-inflammatory, anti-oxidant, anti-tumour, anti-invasive, anti-angiogenic and anti-diabetic that may also offer neuro- and cardio-protective effects (1)

How fisetin exerts its therapeutic effects

Initially, research showed that fisetin had two major roles in the body: acting as an anti-inflammatory and antioxidant compound. Further research has shown it to be so much more powerful than that, exerting extensive effectives on multiple pathways that may promote health. 

There are three pathways through which fisetin exerts its effects as a potential compound that improves health- and lifespan: 

  1. It acts on sirtuins, which has been shown to mimic calorie restriction and is a well-known process that has anti-ageing effects (2)
  2. It has senolytic properties, which means that it is able to destroy sencesent, or old, damaged cells. This has been said to help both prevent age-related disease and even alleviate those that may have already developed (3)
  3. It has also been shown to increase the activity of the master antioxidant produced in the liver, called glutathione (4), which has been shown to be a property of only two flavonoids to do so, fisetin being one of them.  

Cancer fighting properties 

Fisetin has long been studied as a chemoprotective agent and the interest in this natural agent has developed over the last few years with more research being conducted into its mode of action . Cancer cell development involves the activation of multiple disease pathways including transformation, cell survival, proliferation of mutant cells, invasion of surrounding tissues, the development of new blood vessels and the metastasis of cancerous cells. Various bodies of research have found that fisetin plays a role in a number of these pathways and has been shown to act on multiple mechanisms of cell proliferation and programmed cell death, and in addition, has a potent role as an antioxidant and free-radical scavenger. 

Inhibiting the proliferative ability of cancerous cells is one of the most important aspects of anticancer treatment. If the initial proliferation of mutant cells can be inhibited, tumors will be unable to develop. Fisetin may be able to stabilize cellular structures, which improves the morphology of the cell, preventing destructive changes to the cells and reducing proliferative activity. Additionally, fisetin is able to perturb cell signalling, which contributes to the compound’s antiproliferative effects. 

The PI3-K/Akt/mTOR pathway has become of significant interest in different cancer lines. Along with the NF-kB, MAPK and Wnt pathways, the PI3-K/Akt/mTOR signalling pathways are commonly associated with cell survival and proliferation. 

The Phosphoinositide 3-kinases (PI3-K) enzymes are powerful intracellular signalling pathways, which generate phospholipids. These phospholipids interact with Akt and cause its translocation to the inner membrane of the cell. When Atk is translocated, it becomes phosphorylated itself, which activates the compound. When activated, Atk plays an important role in regulating multiple proteins which are implicated in programmed cell death, the repair of DNA, cell metabolism, protein synthesis and cell division. 

The mammalian target of rapamycin (mTOR) protein kinase is involved in the activation of Akt and belongs to the PI3-K kinase family. When cancer cells are involved in the stimulation of mTOR, it may induce cancer cell growth, improve cancer cell survival and promote proliferation.  

In lung cancer, the mTOR, Akt and MAPKs pathways have become a therapeutic target for the treatment of this type of cancer, which is one of the leading causes of cancer death across the globe. Using fisetin in lung cancer therapy has revealed that the compound has a profound effect on PI3-K/Akt and mTOR signaling, downregulating the processes. In tissue studies, fisetin reduced cancer cell viability without having any negative effects on the surrounding healthy lung tissue. Additionally, fisetin decreased the activation of mTOR by cancer cells (5) reducing their ability to grow, survive and proliferate.  

Prostate cancer is a serious risk for men over the age of 50. Many natural compounds have been studied in their effects against the proliferation of prostate cancer cells, with fistein coming out on top in its ability to inhibit their growth. Using a mouse model, researchers have found that fisetin, given to live animals as well as introduced into human prostate cancer cells in a laboratory setting, was able to decrease cancer cell viability without any negative impact on surrounding healthy tissues (6). It was also shown that when fisetin was used in these settings, there was a decrease in the protein expression of PI3-K and Akt. Inhibition of the Akt signalling increases pro-apoptotic pathways and suppression of anti-apoptotic signals, which further shows the benefits of the use of fistein as a therapeutic agent in prostate cancer. 

Breast cancer deaths rank highest among all cancer-related deaths in women. While there have been more recent breakthroughs in treatment and preventative options, these often only target certain patients, and certain groups do not benefit, particularly those with triple-negative breast cancer and those with a significant cancer cell burden. As with other cancer lines, the PI3K/Akt/mTOR pathway appears to have a significant impact on the development of malignant forms of breast cancer. Fisetin, through regulation at various levels of these pathways, induces cancer cell suicide, reduces the viability of cancer cells and inhibits the proliferative activity of mutant cells (7), which may offer an alternative therapeutic option to women who don’t benefit from currently offered therapies.  

Another common risk of cancer is related to the skin changes due to UV irradiation. In a 2015 study on mice exposed to UVB radiation, fisetin was found to block chemical mediators of inflammation and reduce the capacity of inflammatory cells to infiltrate into exposed sites. The topical fisetin treatment used in this research also shown to have the potential to decrease DNA damage within the skin cells exposed to UVB, which may have antitumor effects (8)

Heart disease

As an antioxidant, fisetin is able to help the body to manage the effect that free radicals may have on fats, amino acids, carbohydrates and nucleic acids, preventing their oxidation from damaging other tissues. 

One of the most significant is fisetin’s binding capacity to phospholipids. Phospholipids have a polar head and hydrophobic tail, with a region in between that allows for binding of other compounds. It’s this binding region that is easily available for free radicals to attach, which causes an unstable phospholipid molecule, leaving it vulnerable to oxidation. Fisetin is also more likely to bind to this site, which prevents the binding of free radicals. 

Lipid peroxidation is one of the greatest risks that leads to coronary artery disease, particularly as a result of the oxidation of low density lipoproteins (LDL). It’s this peroxidation of LDL that causes it to become sticky, leading to it accumulating along the endothelial cells of the artery walls. This sticky accumulation of cholesterol and other immune cells causes atherosclerosis that, when it is significant enough, can cause complete occlusion of the artery, which stops blood flow and can result in an ischaemic heart attack. 

Research shows that fistein may protect from endothelial dysfunction as a result of oxidation of LDL cholesterol via the extracellular signal regulated kinase-5 (Erk-5) pathway, which is a transcriptional activator and regulator of endothelial cells (ECs) homeostasis. Upregulation of this pathway improves endothelial markers which reduces endothelial dysfunction (9), it reduces the effects of inflammation and offers overall cardioprotective benefits. 

Fisetin can protect from cardiovascular events in another way: reducing the serious effects that a heart attack may have on the overall function of the cardiovascular system. In a study on rats, researchers fed one group of them with fisetin before inducing a heart attack over a span of 2 days with a toxic chemical. When researchers assessed the damage to their cardiovascular system, it was found that fisetin had normalised all biochemical parameters that were supposed to be abnormal following the inflammatory and oxidative stress that the heart attack and chemical had caused. The conclusion of the study was thus that it was the role of fistein in stabilizing the free radical membrane activity due to its potent antioxidant properties (10)

Treatment of heart attack typically takes the approach of rapidly increasing oxygenation of the tissue that has been affected by ischaemia due to the infarction. While this approach is essential to prevent necrosis of the tissue, there is a high risk of development of free radicals (reactive oxygen species), which further exacerbates the tissue injury. It leads to a phenomenon called ischaemic reperfusion injury.

A study to evaluate the treatment for both MI and IRI in zebrafish indicated that fisetin may reduce the serious effects of both. In a subsequent study, this time conducted on mammalian cardiac cells, fisetin enhanced the activity of cardiac tissue that had been affected by the infarction, it protected against DNA damage by reactive oxygen species and overall prevented cell suicide. The researchers thus concluded that clinical trials should be conducted as a means to evaluate these potential therapeutic properties of fisetin in humans (11)

Brain health

Fisetin has been shown to improve the risk of neuronal cell death as a result of increased cellular stress. This has serious therapeutic implications in brain health as it may improve neurotrophic activity, which has an influence on learning and memory. A study conducted in rats showed that by activating specific signalling pathways within the central nervous system, fisetin could be useful in treating CNS disorders via regulating of the ERK and cAMP pathways. Fisetin improves long-term potentiation of neural pathways in the hippocampal areas of rats, which enhances their object recognition and thus was concluded to facilitate learning and memory (12)

One of the areas of interest in the use of fisetin is in its ability to reduce the rate of age-related cognitive decline. Fisetin has been found across varying cell lines to prevent neuronal dysfunction and preserve brain health in different species. This may have serious implications in the treatment of some of the most common neurological diseases of our time, including Alzheimer’s disease, Parkinson’s disease, Huntington’s disease, stroke, depression and even the neurological implications associated with diabetes. 

Alzheimer’s

Fisetin has been researched in its ability to influence learning and memory, and with Alzheimer’s disease (AD) being one of the most common forms of dementia affecting cognitive function, the role of fisetin is a critical one in the effects it may have on possibly the most devastating neurological diseases of the 21st century. Current therapies for AD provide only supportive effects, with moderate improvements in memory, however, without effect on the progression of the disease (13). Also, due to the complex nature of the disease, and multiple dysfunctional pathways that are involved in its progression, it is difficult for one therapeutic strategy to be developed with a single target in mind. Natural compounds, such as fisetin, however, which have an array of biological actions, may act on many of the pathways and so, are proposed as having a greater impact on both the prevention and progression of the disease. 

Fisetin has been tested in mice to determine whether oral administration may change the pathological processes associated with AD, including those affecting behaviour. While there was no effect on physiologically normal mice when they were provided with finestin, those that had AD and received the finestin intervention behaved almost indistinguishable from the normal mice. When recall was tested, the fisetin-fed AD mice also showed clear improvement in memory. 

When tested in 12 months, these same finestin-fed AD mice performed with continued indistinction from the physiologically normal mice, which included reduced social anxiety, showing both improved cognition and neuropsychiatric behaviours (14).

While old age is the greatest risk factor for Alheimer’s disease, there are additional factors that need to be considered as influencing the overall risk of AD development. One environmental factor, exposure to the heavy metal lead, which is widespread in the environment, may damage the nervous system and result in cognitive deficits that are as a result of inflammation, oxidative stress and neuronal cell apoptosis. Lead has been found to act via the AMPK/SIRT1 pathway, modulating the activation of its response, which results in neuroinflammation. 

Fisetin may attenuate the effects of lead-induced deficits in learning and memory. When tested in mice, compared to the control group, fisetin-fed animals who had been exposed to lead improved behaviors and showed a significant reduction in the learning and memory deficits brought about by lead exposure. Inflammatory levels were lower in the fisetin-fed mice, with notable differences in the production of inflammatory cytokines in the treatment group. The expression of NEP, a protein that helps to remove AB proteins that accumulate, was severely decreased in the control group of lead-exposed mice, however, in the fisetin-treated mice, expression was far higher (15)

Fisetin also reduced apoptosis of neuronal tissue as a result of lead exposure, and there was significantly lower toxicity noticed in the brains of the treatment group, with reduced production of tau and AB-protein accumulation and deposition. 

Depression

Fistein may also provide a therapeutic target for depression. Studies in two mouse models shows that during behavioral tests, fisetin may inhibit immobility time. In addition, higher doses of fisetin attenuated the effects of induced hypothermia and improved the release of serotonin and noradrenaline, which had antidepressant-like effects on the animals (16)

Stroke

One of the major concerns for stroke is neuronal cell death as a result of increased oxidative stress in the brain that most commonly develops in conjunction with arteriosclerosis. Fisetin may reduce oxidative damage owing to its antioxidant activity, which reduces the behavioural deficits that are common following a stroke. 

Bone and joint health

One of the most common degenerative diseases associated with ageing is osteoarthritis (OA). It is widely associated with inflammation, in particular, production of the IL-1b inflammatory compound, and fisetin has been shown to possess anti-inflammatory effects. 

In a 2017 study in mice with OA, fisetin was either given on its own or with a combined inhibitor of SIRT1, called sirtinol. Not only did the intervention of fisetin on its own inhibit the production of IL-1b, it was determined that a wide variety of other inflammatory molecules were also inhibited at the same time. With fisetin inhibiting IL-1b, there was also a marked decrease in the degradation of collagen, where collagen loss is a critical part of the disease etiology of OA. 

In a 2019 study, the aim was to evaluate the effect of fistein on the progression of arthritis induced by an adjuvant in rats and to determine the mechanisms involved in immunomodulation of the disease. Adjuvant induced arthritis causes paw swelling and arthritic effects in the animals. Both lipid peroxidation and antioxidant activity was measured as were multiple inflammatory markers. 

Fistein treated animals were observed to have a higher degree of antiarthritic effects as well as improved antioxidant capacity. Fisetin thus significantly reduced the development of arthritis and reduced the expression of inflammatory compounds typical of the etiology and progression of cartilage damage. In addition, fiestin was shown to improve bone mineral density loss (17). As a successful arthritis suppressant, clinical studies in humans are needed to replicate these effects. 

Anti-ageing

Of noteworthy to mention is the combined use of fisetin and sirtinol. The use of sirtinol cancelled out these protective effects of fisetin, which shows that the anti-inflammatory actions of fisetin are through the SIRT1 pathway5, which is supported by other studies on the mechanism (18)

Senescence is a process of biological ageing and is the gradual deterioration of function of an organism. Cellular senescence is associated with the accumulation of cells with damaged DNA, where their ability to replicate has been terminated as a result. Numerous natural compounds have been studied in their ability to act as senolytics, and fistein is one of them. The senotherapeutic activity of this compound has recently been studied in mice and in human tissues, where the results in mice have shown that fisetin has potent senotherapeutic activity, reducing senescent markers in multiple tissues and cell types. Long-term administration of fisetin also shows improved overall tissue health with a reduction in age-related disease and improved median lifespan, even when administration of the compound was started later in their life (19)

The third mechanism of action that has been implicated in the role that fisetin has in reducing the impact of ageing involves preservation of the body’s master antioxidant, called glutathione, often referred to as GSH. It has been called one of the most important antioxidants for defense against oxidative and other forms of toxic stress, where its decline has been associated with heightened processes that drive ageing (20)

Preservation of GSH by fisetin has been shown to involve the increase in two compounds called Nrf2 and ATF4. They are present in nerve cells and regulate genetic pathways that maintain GSH levels. In a mouse model, where ATF4 was inhibited in the brain, it reduced the presence of ATF4, which subsequently reduced the capacity of fisetin to maintain GSH under normal physiological conditions, as well as during oxidative stress. When the same inhibition was performed on Nrf2, the effect was only measurable under oxidative stress conditions, which showed a 30% reduction in the ability of fisetin to maintain GSH (21)

Fisetin has been demonstrated as having a good safety profile in humans, which is promising given the significant health impact it has been shown to have in animal models. Clinical trials are currently underway to determine the effectiveness of these treatments and how they will translate from the animal into humans, in particular, relating to the reduction of the senescent burden in the ageing population (22).  

We strongly believe in the beneficial effects of fisetin and the unique mechanisms in which it functions to preserve health and improve the outlook on healthy ageing. We trust that the study results found in human trials will show just as much promise as they do in animal models.

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Selection of studies used for this article:

  1. Pal, H., et al. Fisetin and Its Role in Chronic Diseases. Adv Exp Med Biol. 2016;928:213-244.
  2. Kim, A., et al. Luteolin and fisetin suppress oxidative stress by modulating sirtuins and forkhead box O3a expression under in vitro diabetic conditions. Nutr Res Pract. 2017 Oct;11(5):430-434.
  3. Childs BG, Durik M, Baker DJ, van Deursen JM (2015). “Cellular senescence in aging and age-related disease: from mechanisms to therapy”. Nature Medicine. 21 (12): 1424–35. 
  4. Manorma, S. Study on potential antioxidant activity of Fisetin against oxidative stress in vivo. 2018.
  5. Khan N, et al. Dual inhibition of phosphatidylinositol 3-kinase/Akt and mammalian target of rapamycin signaling in human nonsmall cell lung cancer cells by a dietary flavonoid fisetin. Int J Cancer. 2012. 130(7):1695–1705.
  6. Khan N, et al. Fisetin, a novel dietary flavonoid, causes apoptosis and cell cycle arrest in human prostate cancer LNCaP cells. Carcinogenesis. 2008;29(5):1049–1056.
  7. Sun, X., et al. Anti-cancer effects of fisetin on mammary carcinoma cells via regulation of the PI3K/Akt/mTOR pathway: In vitro and in vivo studies. Int J Mol Med. 2018 Aug; 42(2): 811–820.
  8. Pal, H., et al. Fisetin inhibits UVB-induced cutaneous inflammation and activation of PI3K/AKT/NFκB signaling pathways in SKH-1 hairless mice. Photochem Photobiol. 2015 Jan-Feb;91(1):225-34.
  9. Patel, R., et al. Induction of endothelial dysfunction by oxidized low-density lipoproteins via downregulation of Erk-5/Mef2c/KLF2 signaling: Amelioration by fisetin. Biochiemie. 2019. 163:152-162.
  10. Panneerselvam, M., & Devika, P. Cardio protective efficacy of fisetin on glycoprotein and membrane bound enzymes against isoproterenol induced cardiotoxicity in wistar rats. Journal of Pharmacognosy and Phytochemistry. 2019; 8(3): 2271-2274. 
  11. Rodius, S., et al. Fisetin protects against cardiac cell death through reduction of ROS production and caspases activity. Sci Rep 10, 2896 (2020).
  12. Maher P., et al. Flavonoid fisetin promotes ERK-dependent long-term potentiation and enhances memory. Proc Natl Acad Sci U S A. 2006;103(44):16568‐16573.
  13. Haas C. Strategies, development, and pitfalls of therapeutic options for Alzheimer’s disease. J Alzheimers Dis. 2012; 28(2):241-81.
  14. Maher P. How fisetin reduces the impact of age and disease on CNS function. Front Biosci (Schol Ed) 2015;7:58–82.
  15. Yang, W., et al. Fisetin improves lead-induced neuroinflammation, apoptosis and synaptic dysfunction in mice associated with the AMPK/SIRT1 and autophagy pathway. Food and Chemical Toxicology. 2019. 110824.
  16. Zhen L., et al. The antidepressant-like effect of fisetin involves the serotonergic and noradrenergic system. Behav Brain Res. 2012 Mar 17; 228(2):359-66.
  17. Xiaoming, G., et al. Fisetin Attenuates Cartilage Destruction in Adjuvant-Induced Arthritis by Modulating Cartilage Cytokine Expression Correlated with Oxidative Status in the Early Phase in Experimental Animals. Folia Biologica. 2019. 67(4):177-189.
  18. Kim, S., et al. Fisetin induces Sirt1 expression while inhibiting early adipogenesis in 3T3-L1 cells. Biochemical and Biophysical Research Communications. Volume 467, Issue 4, 27 November 2015, Pages 638-644.
  19. Yousefzadeh, M., et al. Fisetin is a senotherapeutic that extends health and lifespan. EBioMedicine. 2018 Oct; 36: 18–28.
  20. Ballatori N, Krance SM, Notenboom S, Shi S, Tieu K, Hammond CL. Glutathione dysregulation and the etiology and progression of human diseases. Biol Chem. 2009 Mar; 390(3):191-214.
  21. Ehren JL, Maher P. Concurrent regulation of the transcription factors Nrf2 and ATF4 mediates the enhancement of glutathione levels by the flavonoid fisetin. Biochem Pharmacol. 2013 Jun 15; 85(12):1816-26.
  22. Khan, N., et al. Fisetin: A Dietary Antioxidant for Health Promotion. Antioxidants & Redox Signaling  VOL. 19, NO. 2. 2013.
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