Fisetin: Antioxidant and Senolytic

Aging brings with it a myriad of health issues including an increased risk of diabetes, heart disease, cancer, and neurodegenerative diseases. A supplement that can mitigate the root cause of some of these age-related conditions is a very alluring idea. But does the research back it up?

This article delves into the recent research on a natural compound called fisetin that may prove to be a key anti-aging component. Or… it could be just one more way to keep mice healthy. Read through the research and decide for yourself whether fisetin is worth trying or is something to keep an eye on for the future.

Fisetin

Fisetin is a natural flavonol found in several types of fruits and vegetables. It is being studied for a variety of health benefits including preventing complications from diabetes to heart disease, and as a longevity compound. Fisetin has been shown in several recent studies to clear out senescent cells, which holds a lot of promise for healthy aging.

This article probes the evidence for using fisetin as a longevity compound and explores the research on supplemental fisetin’s health benefits. We will also explore the timing and dosages of fisetin used in clinical trials. Finally, you will be able to draw your own conclusions as to whether there is sufficient evidence for using fisetin at this time.

Cellular senescence

At the end of a cell’s life, a cell becomes senescent, giving off signals that it needs to be removed by the immune system. The chemical signals that it gives off are pro-inflammatory cytokines, so it becomes a source of low-level inflammation. Senescent cells are sometimes called ‘zombie cells‘ because they aren’t quite dead, but they are no longer functioning cells.

The process of cellular senescence is a natural part of the cell cycle, and it is important in both wound healing and in stopping cells from becoming cancerous. You want a cell that is damaged (or cancerous) to stop the cell cycle and hang out a flag saying that it is time to be killed off and recycled.

Cellular senescence is triggered by a number of circumstances including[ref]:

  • Telomeres being too short for replication (learn more about telomeres here)
  • Injuries, burns, UV exposure, etc
  • Too much oxidative stress in the cell
  • Mitochondrial dysfunction
  • Toxicity due to misfolded proteins

Younger people with a good immune system have no problem clearing out senescent cells, and this process of cell-cycle arrest and clearing out cellular insults works well. Just as it is supposed to.

The number of senescent cells increases with age. Older people often have a problem clearing out all of the senescent cells, and this is directly linked to some of the diseases associated with aging.

I mentioned above that cells hang out a flag when they become senescent. The ‘flag’ that senescent cells wave when they need to be killed off and recycled is a chemical signal of inflammatory cytokines.  When senescent cells aren’t cleared quickly, this can leads to local inflammation and neighboring cells also becoming senescent. This secretion of inflammatory cytokines by senescent cells is known as ‘senescence-associated secretory phenotype’ (SASP).[ref]  Stopping this low-grade inflammation is one goal in longevity science.

Clearing out senescent cells has been shown in animal studies to prevent the onset of age-related diseases. This increases healthspan (number of years of healthy living), as well as increasing lifespan (in animals). [ref]

The animal studies on this are pretty cool, and they clearly show that a buildup of senescent cells is one major aspect of the diseases of aging. Human studies on longevity are harder to fund and take a much longer time (of course).

Targeting senescent cells, likewise, seems to be an effective way to combat some of the problems of aging. [ref]

There are two pathways through which increased senescent cells could lead to the chronic diseases of aging:

  • First, stem cells becoming senescent can lead to a decreased ability for stem cells to renew tissue.
  • Second, an increased number of senescent cells can cause chronic inflammation. [ref]

Why don’t senescent cells die?  In addition to the SASP signals that are calling for the cell to stop dividing and be destroyed through apoptosis, senescent cells also upregulate something called the senescent-cell anti-apoptotic pathway (SCAP). This pathway prevents apoptosis, or the clearing out of cells.

Clearing out senescent cells with senolytics:

Senolytics are compounds that target and clear out senescent cells. They do this by targeting the SCAP pathway. Senolytics are a relatively new concept, with the first studies on them published in 2015. This concept of being able to clear out senescent cells in aging has prompted a lot of interests, and a bunch of studies have been published on senolytics in the past few years. [ref]

Initial work with senolytics focused on the similarities between cancer cells that don’t divide and senescent cells. This led researchers to experiment with a chemotherapy drug called dasatinib. Further research showed that dasatinib plus quercetin, a natural compound found in fruits and vegetables, was even more effective at clearing senescent cells and increasing healthspan (animal studies).[ref][ref

Fisetin has been shown in several promising new studies to act as a senolytic.

Studies on fisetin as a senolytic:

A study investigating natural senolytic compounds found that fisetin was the most effective flavonoid for reducing senescent markers — and more potent than quercetin. The study also showed that fisetin increased the lifespan and healthspan of mice. Of note here is that the mice were given fisetin starting when they were 85 weeks of age, which is equivalent to 75-years-old for a human.[ref]

That same animal study showed the fisetin, when given at a high dose for a few days, was able to clear out 25-50% of senescent cells in different organs. [ref]

A different cell study showed that fisetin causes cell death (apoptosis) in certain types of senolytic cells including endothelial cells. It was not shown to be a senolytic for lung fibroblast cells. [ref]

I want to note here that while the animal studies on fisetin as a senolytic are very promising, the human studies are not yet complete. This is all really new research. 

Studies on fisetin as an antioxidant for protection against neurodegeneration:

Fisetin has been shown to act both as a direct antioxidant and to also increase the body’s antioxidant system via activating glutathione. Fisetin’s actions as an antioxidant may have important implications for reducing age-related neurodegenerative diseases.[ref]

Cell studies show that fisetin may reduce amyloid-beta, the protein that accumulates in the brain with Alzheimer’s. The study showed the reduction fisetin to be similar to the reduction due to melatonin [ref]. (Read more about melatonin and Alzheimer’s)

Cell studies and animal studies also show that fisetin inhibits microglial

Studies on fisetin and AGEs:

Advanced glycation endproducts (AGEs) are another natural occurrence that both increases with age and can increase the problems with the diseases of aging.  Methylglyoxal is a breakdown product in the body that can react to form advanced glycation end products. This can lead to complications in diabetes, such as diabetic retinopathy. (Read more about AGEs and genetic variants)

Fisetin has been shown in animal studies to decrease the formation of methylglyoxal. Fisetin was shown to upregulate the Nrf2 pathway, increasing glutathione which reduces methylglyoxal levels. The animal studies in mice bred to be diabetes showed that fisetin didn’t change blood glucose levels or alter weight, but it did reduce the complications of diabetes such as kidney disease. The mice that had consumed fisetin (0.05% of their diet) had decreased levels of oxidative stress and reduced the formation of advanced glycation endproducts.[ref].  One thing to note here is that fisetin reduced AGEs and oxidative stress in the mouse models of diabetes — but it didn’t have an effect on normal mice with normal levels of AGEs and oxidative stress.

Other animal studies do show a decrease in blood glucose levels with fisetin, which may indicate that it should be investigated further for diabetes prevention or treatment.[ref]

Fisetin and mast cell inhibition:

In cell studies, fisetin has been shown to inhibit mast cells from releasing inflammatory cytokines (IL-31, IL1B, IL4, IL6, TNF-alpha, and NF-κB) along with inhibiting histamine release. [ref] [ref] [ref] Another study shows that fisetin inhibits mast cell activation due to stimulation from T-cells. [ref]

While I am not finding any human trials using fisetin as a mast cell stabilizer, the animal studies on this are intriguing.

Studies on fisetin for other purposes:

Please bear in mind that animal studies and cell studies don’t always show the same results in human studies.

  • A cell study showed that combining melatonin with fisetin enhanced the anti-tumor properties of fisetin in melanoma cells. [ref]
  • Fisetin has been shown in cell studies to be an effective anti-viral therapy against dengue fever.[ref]
  • Neuropathy pain is inhibited by fisetin (animal studies). [ref][ref][ref]
  • Fibromyalgia pain is reduced by fisetin (in mice). [ref]
  • There are many cell and animal studies showing that fisetin may have anti-cancer effects and prolong survival rates in cancer (in mice and rats). [ref][ref][ref][ref]
  • A December 2019 study in leukemia cells showed that some caution may be warranted in using fisetin as a dietary supplement when being treated for chronic myeloid leukemia. [ref]
  • A Feb. 2020 study found that fisetin is a promising candidate for use after a heart attack.[ref]
  • In mice with food allergies, fisetin decreased the allergic reaction. [ref]

Safety and bioavailability:

Clinical trials:

As a senolytic:
There are currently a couple of phase 2 clinical trials underway by the Mayo Clinic using fisetin in older people as a senolytic.  No results have been posted yet, though.  Both of the clinical trials used a dosage of 20mg/kg/day for two days. [ref]  [ref] This would be equivalent to 1,600mg/day for someone who weighs 175 lbs.

A 2018 clinical trial of fisetin administered via IV after a stroke concluded that “Fisetin dramatically improved the treatment outcomes of the patients with stroke in the delayed OTT [onset-to-treatement time] strata, as revealed by lower NIHSS scores.” The clinical trial used a one-time treatment of 0.9mg/kg given via IV followed by 7 days of 100mg of fisetin per day.  [ref]

As an antioxidant:

A 2012 clinical trial investigated freeze-dried strawberry powder to see if it could prevent pre-cancerous lesions of the esophagus from progressing. The results showed that the higher dosage of 60g/day (for 6 months) of freeze-dried strawberries had the potential for preventing esophageal cancer. [ref] Strawberries contain the highest amount of fisetin of any fruit or vegetable – along with other vitamins and micronutrients.[ref]

A clinical trial in colorectal cancer patients showed that fisetin (100mg/day) given along with their chemotherapy significantly reduced IL-8 and hs-CRP, which are markers of inflammation.[ref]

Bioavailability and Timing:

Animal studies show that fisetin is moderately bioavailable — but it is hard to know how well this translates to humans. Once absorbed, fisetin is methylated into geraldol. [ref][ref]

Senolytics are usually used in brief periods of time – often for a few days per month or quarterly. Senescence is an important bodily function, and clearing out senescent cells continually is not usually recommended.  All of this is fairly new research, so there doesn’t seem to be a consensus yet on the most effective timing of senolytics.

Fisetin is not very water-soluble, and studies show that fisetin encapsulated in micelles (surrounded by fat) may be more effective. [ref]

The study referenced above on the combination of melatonin and fisetin is interesting. It may be that fisetin is more effective when taken at night — possibly depending on your goals for the compound.[ref]

Drug interactions with supplemental fisetin:

It is always important to keep in mind interactions between any prescription medications and supplements, even herbal supplements that seem safe.  A recent study showed that fisetin inhibits CYP2C8, a liver enzyme that is important in the metabolism of several drugs. (More information on CYP2C8 and genetic variants).

Another study showed that fisetin may moderately inhibit CYP2C19, CYP2C9, and CYP1A2.[ref]  CYP2C19 is notable in that it is the only enzyme that converts Plavix into the active form of the drug that inhibits clotting.  (Read more about CYP2C19 genetic variants and Plavix.)

Food sources of fisetin:

Fruits and vegetables contain small amounts of fisetin. Strawberries are by far the largest dietary source of fisetin with 160mg in a kg of strawberries.

Fruit/Vegetable Amount µg/g
Strawberry 160
Apple 26.9
Persimmon 10.6
Lotus Root 5.8
Onion 4.8
Grape 3.9
Kiwi 2.0

Rhus verniciflua stokes, which is known as a Korean herbal supplement, contains fisetin as one of its active components. Notably, it also contains urushiol, which is what causes the skin reaction in poison ivy. Studies on Rhus verniciflua stokes with urushiol removed show that is may have positive pharmacological properties. It contains about 2% fisetin. [ref]

Conclusion:

There are a lot of interesting animal and cell studies on fisetin which show a lot of promise as far as a senolytic and as a possible cancer therapeutic (for certain types of cancer). But… there is a lack of human trials that make it difficult to know if the results of animal studies will hold true for humans. Lots of things look good in animal studies.

The human studies on fisetin at lower levels as an antioxidant seem promising as well.

If you want to learn more about fisetin as a senolytic and read user comments on trying fisetin both at lower and higher dosages, check out fightaging.org’s article.

 

 

 

 



Author Information:   Debbie Moon
Debbie Moon is the founder of Genetic Lifehacks. She holds a Master of Science in Biological Sciences from Clemson University. Debbie is a science communicator who is passionate about explaining evidence-based health information. Her goal with Genetic Lifehacks is to bridge the gap between scientific research and the lay person's ability to utilize that information. To contact Debbie, visit the contact page.