Is Fisetin the Fountain of Youth?

A  naturally occurring flavonoid, fisetin is a plant pigment from different fruits and vegetables. It’s subcategorized as a flavonol subgroup of flavonoids. Fisetin is especially high in strawberries and other foods like cucumbers, apples, onions and persimmons. 

According to currently available research, fisetin has many health benefits. These benefits primarily relate to its anti-inflammatory, antioxidant, and neuroprotective properties. Many studies of fisetin’s benefits have focused on its ability to prevent age-related cognitive decline, reduce inflammation, and protect against some cancer types. 

Fisetin benefit studies have also examined how it can help cardiovascular health and expand lifespan. Current research on fisetin’s benefits also looks at its potential to help with diabetes, obesity, and other metabolic disorders.

What Does It Mean That Fisetin is a Flavonoid?

The key to understanding many of fisetin’s benefits lies in the fact that it’s a flavonoid. Flavonoids are part of the larger polyphenol class. They are naturally occurring plant compounds in fruits, tea, grains, wine, vegetables, and other plant-based foods.

Flavonoids are known for antioxidant and anti-inflammatory benefits, primarily contributing to their health benefits. Flavonoids like fisetin have been studied for their role in reducing chronic disease risks like neurodegenerative disorders, cancer and cardiovascular disease. They’re also thought to support overall health and wellness by promoting immune function, improving vascular health, and modulating cellular signaling pathways.

Fisetin Supplement Benefits

So, what is fisetin good for? As it turns out, fisetin has potentially extensive health benefits.

Broadly, fisetin benefits include:

Antioxidant properties

Fisetin acts as an antioxidant, so it can scavenge free radicals and eliminate reactive oxygen species (ROS) in the body. These cause oxidative stress and damage cells. The antioxidant activities involve neutralizing free radicals through the donation of electrons. This helps to prevent cellular damage and reduce the risk of diseases linked with chronic stress.

Anti-inflammatory effects

Fisetin stops the production of pro-inflammatory cytokines and enzymes, reducing inflammation in the body. It suppresses the activity of inflammatory signaling pathways like NF-kB and MAPK, modulating the expression of inflammatory genes and decreasing inflammatory mediators’ production.

Neuroprotection

Fisetin may protect against neurodegenerative diseases through neuroprotective effects, like promoting neuronal survival, reducing neuroinflammation and enhancing cognitive function. Fisetin supplements can modulate different molecular pathways, playing a role in neuron health. This includes the activation of the NrF2-ARE pathway, which serves to regulate antioxidant defense. It also inhibits neuroinflammatory pathways and suppresses neurotoxic processes.

Anti-Cancer Activity

There’s been an investigation into the potential of fisetin to inhibit the growth and proliferation of cancer cells. Some evidence also shows it can induce apoptosis or the programmed cell death of cancerous cells and suppress the progression of tumors.

It’s thought that fisetin health benefits related to cancer stem from its ability to inhibit cell cycle production and start apoptosis through different signaling pathways. It might modulate cancer signaling pathways and prevent new blood vessels from forming that supply tumors.

Cardioprotective Health Benefits

Also among the health benefits of fisetin are potential heart health benefits. It may help protect against cardiovascular diseases by reducing inflammation, oxidative stress, and endothelial dysfunction to promote vascular health.

Fisetin’s heart benefits stem from improving nitric oxide production, preventing inflammation and platelet aggregation, and reducing stress-induced damage to blood vessels. It may also regulate cholesterol levels and lipid metabolism.

What Are the Anti-Aging Benefits of Fisetin?

Fisetin is thought to have powerful anti-aging benefits.

A lot of this stems from its antioxidant properties. Aging is linked to increases in oxidative stress. Oxidative stress occurs as there are imbalances between your body’s antioxidant defenses and the production of free radicals. Oxidative stress leads to inflammation and cellular damage, speeding up aging.

Fisetin is a free radical scavenger. It donates electrons to stabilize free radicals, neutralize oxidative stress, protect cellular components like DNA and proteins from damage, and help maintain cellular integrity.

Anti-Inflammatory Effects and Fisetin

Chronic inflammation is a key hallmark of the aging process. It’s also involved in the development of age-related diseases like metabolic syndrome, neurodegenerative disorders, and cardiovascular disease.

Fisetin can block the production of pro-inflammatory cytokines and enzymes and modulate signaling pathways involved in inflammation. Since it can reduce the inflammatory response, it can mitigate these processes related to aging.

Senolytic Activity

We’ll talk more about the senolytic activity of fisetin below in detail, but senescent cells are damaged or aged and accumulate in tissues as we age. These cells contribute to age-related decline. They secrete pro-inflammatory cytokines, growth factors and something called matrix metalloproteinases. Together, these are known as senescence-associated secretory phenotypes or SASP. SASP induces inflammation and tissue dysfunction.

Fisetin is a senolytic compound that can selectively lead to the cellular death of senescent cells, slowing down aging.

Neuroprotection

As we age, it’s associated with cognitive decline and a higher risk of diseases like Alzheimer’s and Parkinson’s, which are classified as neurodegenerative diseases. Fisetin has neuroprotective effects that could help preserve cognitive function, reducing the risk of neurodegeneration related to aging.

Fisetin may protect neurons from damage stemming from oxidative stress. It’s also thought to reduce brain inflammation and promote plasticity in the brain, enhancing memory and learning abilities. It modulates different signaling pathways associated with neuron health, including the Nrf2-ARE, BDNF/TrkB, and PI3K/Akt pathways.

Fisetin’s Effect on Senolytic Cells

Senescent cells and senolytic activities play critical roles in health, disease, and aging, which we detail below. Understanding the complexities of fisetin’s effects on senolytic cells is essential to understanding how the supplement benefits health, especially regarding aging.

Senescent Cells

Senescent cells have stopped dividing, and in doing so, they’ve entered a state of growth arrest that can’t be reversed. This usually happens in response to damage or stress. The state prevents potentially damaged DNA from replicating, so that’s beneficial. At the same time, the presence of these senescent cells can be problematic on its own.

Senescent cells secrete bioactive molecules, including pro-inflammatory cytokines. Collectively known as the SASP, these molecules contribute to chronic inflammation, tissue dysfunction, and the spreading of senescence to neighboring cells.

These cells can accumulate in different tissues throughout the body and are associated with age-related declines in health. They contribute to most age-related diseases.

Senolytic Activities

Senolytics broadly refer to interventions or compounds that induce programmed cell death selectively in senescent cells but spare the healthy cells. Natural senolytic therapy’s goal is to eliminate senescent cells from tissues selectively. This reduces the burden of senescent cell accumulation, alleviating dysfunction related to aging.

Senolytics target specific vulnerabilities or signaling pathways enhanced in senescent cells compared to healthy ones. Other senolytic compounds include quercetin, dasatinib and piperlongumine. 

These compounds with senolytic activity in preclinical studies are thought to mitigate age-related dysfunction, and they have been proven to extend life spans in animal models.

While senescent cells are initially a protective means to stop the proliferation of damaged or potentially cancerous cells, their accumulation over time becomes problematic, leading to tissue dysfunction, chronic inflammation and age-related diseases.

Senescent cells are considered major aging drivers, including impaired tissue regeneration and repair, diminished immune function, and loss of organ function. These cells change the tissue microenvironment and promote chronic inflammation, speeding up the aging process and increasing your susceptibility to age-related diseases.

When senescent cells are targeted through natural or prescribed senolytic interventions, it shows promise in attenuating aging dysfunction and delaying the onset or progression of age-related diseases. So far, most of the research has been in preclinical models. Still, there are ongoing human clinical trials to evaluate the safety and effectiveness of senolytic therapies in humans for various aging-related conditions.

The key benefit of fisetin may lie in its senolytic activities. It targets the cells that are thought to lead to rapid aging, diseases and disease burden.

How Does Fisetin Target Senescent Cells?

The mechanism of action of fisetin on senescent cells involves several pathways. These include:

Anti-Apoptotic Pathways

Senescent cells often upregulate anti-apoptotic pathways to evade cell death. Fisetin can interfere with these pathways, making senescent cells more susceptible to apoptosis. For example, it can inhibit the activity of Bcl-2, a protein that blocks apoptosis.

Pro-Apoptotic Pathways

Fisetin can not only help interfere with pathways that block old, damaged cells from dying, but it can also activate pro-apoptotic pathways in senescent cells. One pathway involves the activation of the p53 protein. The p53 protein has a central role in apoptosis and is a tumor suppressor. Studies have shown fisetin to increase the levels of p53 and activity in senescent cells, leading to apoptosis.

Modulating SASP

We’ve discussed the inflammatory molecules that senescent cells secrete and the growth factors collectively known as SASP. These contribute to various issues primarily related to chronic inflammation and tissue dysfunction. Fisetin has been found to suppress the SASP in senescent cells, possibly reducing their harmful effects on surrounding tissues.

Immune Clearance

Fisetin is thought to improve the immune clearance of senescent cells by stimulating the activity of immune cells, including natural killer (NK) cells and macrophages. These immune cells are crucial in identifying and eliminating senescent cells from tissues, and fisetin’s immunomodulatory effects can potentially enhance their senolytic activity.

Tissue Regeneration

Because fisetin can selectively promote the elimination of senescent cells, it can also help promote tissue repair and regeneration. Senescent cells accumulate in damaged, aged tissues, impairing tissue function. By removing dysfunctional cells, fisetin can help with tissue renewal and overall tissue health.

Fisetin Benefits for Cancer

There has been an investigation into fisetin for cancer prevention and treatment. Research is in the early stages still, but there are several proposed ways that fisetin might be beneficial for cancer, including:

Antioxidant and Anti-Inflammatory Effects

Fisetin is a strong antioxidant with potent anti-inflammatory properties. These properties are beneficial for reducing chronic inflammation and oxidative stress linked to the development and progression of cancer. Fisetin may help protect cells from DNA damage and prevent the initiation of tumors.

Apoptosis

Fisetin can induce apoptosis in various cancer cell lines. It can trigger pathways within cancer cells that lead to their programmed death, preventing the growth and spread of tumors.

Cell Cycle Arrest

Fisetin can potentially arrest the cell cycle at different stages, especially the G2/M phase. Through interference with cell cycle progression, fisetin might prevent cancer cells from uncontrollable growth and division, slowing tumor growth.

Anti-Angiogenic Effects

Angiogenesis is new blood vessel formation. Tumor growth and metastasis depend on this process. Fisetin can inhibit angiogenesis by suppressing the expression of vascular endothelial growth factor (VEGF) and pro-angiogenic factors. The anti-angiogenic activity can limit the blood supply that tumors can receive, inhibiting their growth and spread.

Blocking Metastasis

A fisetin supplement may prevent the spread of metastatic cancer cells. It could do this by suppressing a process called epithelial-mesenchymal transition or EMT. This is the process that cancer cells require to develop invasive, migratory properties. By inhibiting EMT and other pathways that promote metastasis, fisetin may help prevent the spread of cancerous cells to distant organs and parts of the body.

Synergistic with Chemotherapy

Some studies show that fisetin may enhance the effectiveness of chemotherapy drugs when they are used in combination. It could sensitize cancer cells to death from chemotherapy and inhibit drug resistance.

Additionally, fisetin may protect normal cells from the toxicity of chemotherapy and radiation, reducing the risk of side effects.

The proposed benefits of fisetin for cancer are supported by preclinical studies and some early-stage clinical trials, but more research is needed to entirely understand how it works and the therapeutic potential it may hold for cancer prevention and treatment.

Studies have looked at some of the following types of cancer in terms of the benefits of fisetin:

• Breast: Fisetin has been researched to inhibit the growth and proliferation of breast cancer cells. Studies have found fisetin can induce breast cancer cell death, stop cell cycle progression, and suppress the invasion and metastasis of these cells.
• Prostate: Research suggests fisetin may induce cell death and suppress the expression of genes that play a role in prostate tumor progression.
• Colon: Studies have shown that fisetin may inhibit the growth and block the metastasis of colon cancer cells, induce cell cycle arrest, encourage cell death, and suppress inflammation associated with colon cancer.
• Lung: Preliminary studies have examined the effects of fisetin on lung cancer, including inhibiting the activation of signaling pathways that are part of its growth and metastasis.
• Skin: Fisetin has been explored for its potential to prevent and treat skin cancers. This includes melanoma and non-melanoma. Research suggests the compound could block the growth of skin cancer cells, induce apoptosis, and protect against DNA damage from UV rays.
• Pancreatic: It may inhibit the proliferation and invasion of pancreatic cancer cells, encourage apoptosis, and modulate signaling pathways in tumor metastasis and growth.

Other cancers that fisetin could benefit include ovarian, gastric and liver cancers and leukemia.

Fisetin Benefits for Skin

Potential fisetin benefits for skin, whether it’s taken orally or used topically, might include:

• Prevention of premature aging. Fisetin has strong antioxidant properties, helping to neutralize free radicals and skin oxidative stress. Fisetin can potentially protect skin cells from damage caused by factors in the environment like UV radiation, pollution and toxins, helping with skin health and slowing aging signs.
• For people with inflammation-related skin conditions like acne, eczema or rosacea, fisetin can calm inflammation and soothe sensitive or irritated skin.
• Research indicates fisetin has photoprotective effects against skin damage from UV rays. It’s not a sunscreen replacement, but it may improve your skin’s natural defense against UV radiation.
• Fisetin can support the skin’s collagen production. Collagen is a protein that structurally helps maintain your skin’s elasticity, hydration, and firmness. By promoting collagen synthesis, fisetin may improve texture and reduce fine lines and wrinkles.
• Flavonoids like fisetin have skin-brightening effects, helping to inhibit melanin production and reduce hyperpigmentation. This can then help reduce the appearance of age dark spots and sun damage.
• Early research shows that fisetin may help with wound healing by helping to repair and regenerate damaged skin tissues.

Is Fisetin Safe?

As a supplement, fisetin is considered safe. It is something that comes from dietary sources as well, such as fruits and vegetables. That said, most available research on fisetin safety comes from animal research and preclinical studies. So far, the research suggests fisetin is well-tolerated with low toxicity, but human studies are limited within the context of supplementation.

Few reported side effects are linked to fisetin supplements, but some people experience mild stomach upset or discomfort. The effects are usually temporary and subside on their own.

Fisetin may interact with certain medications, especially if they’re metabolized by certain liver enzymes (CYP34A and CYP2C9). In vitro, fisetin has been shown to inhibit the enzymes, potentially affecting the metabolism and effectiveness of medicines metabolized by these pathways.

Pregnant and lactating women should talk to a healthcare professional before taking fisetin supplements.

As is true with other supplements, there is an individual variable in responses to fisetin. Some people may experience side effects, while others find it well tolerated.

Fisetin’s Bioavailability

People need to carefully consider the concept of bioavailability, not just with fisetin supplements but all supplements. Fisetin has poor bioavailability. That means only a tiny amount of what you ingest in supplement form or from food will be absorbed into the bloodstream, reaching circulation at a systemic level necessary for health benefits.

Limited bioavailability hinders the effectiveness of fisetin supplements and requires thinking about strategies to improve them and make them more well-absorbed.

Reasons for the poor bioavailability of fisetin include:

• Limited solubility: Fisetin is poorly soluble in water, so this can reduce the absorption by the gastrointestinal tract.
• Metabolism: The liver extensively metabolizes fisetin, forming metabolites that may have lower bioactivity or be quickly eliminated from the body.
• Efflux transporters: There are efflux transporters in the intestinal epithelium. They pump fisetin out of the cells and back into the intestinal lumen, reducing the absorption.

Other flavonoids aside from fisetin have similar bioavailability issues.

So what can you do?

Improving the bioavailability of fisetin is essential to ensure you’re maximizing the health benefits, which is a significant consideration when choosing a particular version of the supplement.

• Liposomal formulas: A liposomal fisetin supplement significantly improves bioavailability. Liposomes are microscopic lipid vesicles. They encapsulate fisetin, enhance solubility, and protect it from degradation in the GI tract, improving absorption. Similarly, fisetin can be encapsulated in polymeric or lipid nanoparticles, protecting it from degradation and enhancing its absorption and distribution throughout the body.
• Phytosomes: Fisetin can be complexed with a phospholipid to form a phytosome. A phytosome formula will improve fisetin’s solubility and absorption by mimicking a cell membrane’s natural structure.
• Taking it with piperine: Piperine is a compound in black pepper that can help increase the absorption of fisetin and other flavonoids. You can take it as a supplement; some supplements include the formulation.
• Co-administration with fats: Taking fisetin with fats in a meal can enhance absorption because fats increase the solubility and absorption of lipophilic compounds, such as fisetin.

Bioavailability is one of the most critical considerations when taking a fisetin supplement because it determines the fraction of the compound that will reach systemic circulation to achieve biological effects. When a supplement like fisetin has poor bioavailability, it limits its effectiveness, and you may need very unrealistically high doses for the therapeutic effects. 

Improving the bioavailability of fisetin and supplements can lead to better absorption and health benefits.

Fisetin vs. Other Flavonoids

Fisetin is often compared with two other flavonoids—quercetin and kaempferol.

When comparing fisetin to other flavonoids, its pros include its strong anti-inflammatory effects and identification as a senolytic compound. It may also help inhibit the growth and metastasis of many types of cancer.

The cons are the limited bioavailability unless you choose certain formulations and the fact that it can be more expensive to take as a supplement because of its low abundance in natural sources.

Quercetin is found in fruits, vegetables and plant-based foods, and it’s relatively cost-effective as a supplement. It has properties that can help protect against chronic diseases, and it’s been studied for its potential to prevent and treat cancers, including colon, breast, and prostate cancer. Quercetin may improve heart health by reducing blood pressure, lowering cholesterol, and improving endothelial function.

The downside of quercetin is similar to that of fisetin—it has limited water solubility and bioavailability, hindering its absorption and efficacy when taken orally unless you choose something like a liposomal or Phyto version. Also, some people experience side effects like nausea and upset stomach when taking high doses of a quercetin supplement.

Kaempferol is in plant-based foods like kale, spinach, and tea. It’s an antioxidant, and it’s been studied to help prevent cancer cell growth and induce apoptosis, especially in breast, lung and prostate cancers. Research also shows kaempferol may have neuroprotective effects and could protect against diseases like Parkinson’s and Alzheimer’s.

Similar to fisetin and quercetin, it has limited availability. High kaempferol doses may also have estrogenic effects. This could be a problem for someone with a hormone-sensitive condition like breast cancer.

How To Take Fisetin

Based on current research and opinions from experts, general guidelines for fisetin dosages and how to take it for various conditions include:

Anti-Aging and Longevity Benefits

Animal studies have used fisetin doses ranging from 10 to 100 mg/kg of your weight. For humans, based on this, the range of fisetin supplementation could be 100 to 500 mg a day.

Cancer Prevention and Treatment

The anti-cancer effects of fisetin have been demonstrated in cell culture and animal models, but human doses still need to be established. Some studies have shown a typical supplement dose of 100 to 500 mg per day could be beneficial, and in some cases, higher doses may be more advantageous.

Anti-Inflammatory and Antioxidant Benefits

Consider a dose of 100 to 500 mg daily for cardiovascular disease, metabolic syndrome, neurodegenerative disorders, and general anti-inflammatory and antioxidant benefits.

Fisetin supplements aren’t regulated, so quality and purity can vary significantly between brands. When choosing a fisetin supplement, look for brands that undergo third-party testing to determine purity and quality. Also, follow the recommended dosage instructions for the individual product.

As far as the time to take fisetin, there’s no “best” time, but there are some considerations to keep in mind.

• Be consistent. You want to try to take fisetin supplements consistently at the same time every day because this will help you maintain steady blood levels and maximize potential benefits.
• Take fisetin with meals. You can take it with or without food, but fisetin tends to do well when taken with meals, especially when they contain fat. This can also reduce the risk of gastrointestinal symptoms.
• Some people take fisetin before bed because it helps with sleep and relaxation.
• Taking fisetin in divided doses daily can help you maintain consistent blood levels.

Ultimately, when it comes to taking fisetin, the best time to take it is what works for you based on your schedule and lifestyle.

Who Should Consider Taking Fisetin?

Fisetin supplements may have many potential health benefits, and certain groups of people may be most interested in trying them, including:

• Adults who want to age well. Fisetin has shown promising results in preclinical studies regarding its anti-aging effects, including the ability to support cellular health, reduce inflammation and promote longevity. If you’re an adult who’d like to maintain your overall vitality and health as you age, consider fisetin supplementation.
• Suppose you’re concerned about oxidative stress, which can occur for many reasons, including poor diet, chronic inflammation or pollution exposure. In that case, you might benefit from fisetin supplementation to support your natural antioxidant defenses.
• Fisetin has been studied for its anti-inflammatory effects on people struggling with joint health. It may be beneficial for individuals with osteoarthritis or rheumatoid arthritis.
• Individuals interested in improving their cognitive health could consider fisetin for its brain health benefits. It may support memory, focus and overall mental performance.
• If you’re someone at risk for age-related diseases, such as cardiovascular disease, neurodegenerative disorders, or certain types of cancer, you might take fisetin to mitigate your risk factors.
• If you have cancer, you could consider fisetin as part of a complementary or integrative approach to support conventional therapies.
• Because of the broad range of possible health benefits, anyone who wants to support their general health and well-being could consider supplementing with fisetin.

Final Thoughts

Fisetin supplements are promising for promoting health and well-being because of their potent anti-inflammatory, anti-aging, and antioxidant properties. Fisetin is a natural flavonoid, as outlined in this guide, and it’s garnered attention for its diverse range of health benefits, including heart health support, brain function promotion, and possibly reducing the risk of chronic diseases like cancer.