Fisetin: A Powerful Senolytic that Slows Aging

You must have heard the proverb, “An apple a day keeps the doctor away.” But in reality, it may be strawberries. This is because strawberries contain fisetin, a plant compound known for its anti-inflammatory and antioxidant properties, as well as its potential to increase lifespan. Fisetin has been shown to have positive effects on health, including acting as a senolytic agent, which induces cell death in senescent/unhealthy cells, and mimicking the effects of calorie restriction. In this article, we will explore the current state of research on fisetin’s potential health benefits for longevity.

How Fisetin Senolytic Slows Down Your Aging

Fisetin, a flavonoid commonly found in fruits and vegetables like strawberries, grapes, cucumbers, and onions, has shown significant effect as an anti-aging compound. It acts as a senotherapeutic, inducing cell death in unhealthy cells. This process helps to reduce chronic inflammation and improve overall cellular health, which in turn can lead to healthier and longer life.

Scientists have examined the effects of fisetin on aging and longevity in rodents. They found that fisetin can extend lifespan by up to 10% and improve age-related issues even in older age (1). A clinical trial was done to examine the direct effects of fisetin on age related dysfunction in humans (2).

Another study demonstrated the effects of fisetin on brain health and found that fisetin has been shown to have neuroprotective and memory enhancing properties (3) and it has even delayed the onset of motor defects (symptoms that affect movement) in mice with Huntington’s Disease (an inherited disease that damages and destroys neurons in brain), helping them to live 30% longer (4).

Fisetin: A senolytic that extends lifespan

As we age, our body accumulates senescent cells, old cells that can no longer divide due to the damaged DNA. These zombie-like cells don’t die but instead accumulate and cause inflammation in surrounding tissues, contributing to the gradual deterioration of an organism and promoting age-related diseases. Senolytic are compounds that target and remove senescent cells, potentially preventing and mitigating age-related disease. Studies have demonstrated fisetin is a powerful senolytic among all the flavonoids.

A study (5) found that fisetin significantly removed senescent cells when applied to human umbilical vein endothelial cells. Compared to other plant-derived senolytics, fisetin is most effective at destroying senescent cells in animal models and human cell cultures. By eradicating senescent cells, fisetin holds promise for promoting healthy aging and reducing the risk of age-related disease.

Decoding the antioxidant properties of Fisetin

 

Fisetin acts as an antioxidant by neutralising free radicals in the body, which are unstable molecules that can damage cells and contribute to various diseases. As a flavonoid, fisetin has a unique chemical structure that enables it to donate an electron to stabilise free radicals, thereby preventing them from causing harm. In this way, fisetin helps to protect cells and tissues from oxidative stress and inflammation, which can lead to age-related diseases. It is a highly lipid soluble compound that can easily travel through cellular membranes, assemble inside cells and yield substantial antioxidant activity. Fisetin works as an antioxidant by protecting cells from free radical damage (6). It also exhibits anti-inflammatory properties by turning off pathways that promote inflammation and decreasing the production of inflammatory compounds (7).

As we age, the amount of glutathione in our body decreases, which can leave our cells more vulnerable to damage from oxidative stress. This reduction in glutathione has been linked to a greater risk of developing age-related illnesses, i.e., cancer,diabetes and heart disease. However, studies suggest that fisetin may help to maintain healthy levels of glutathione, potentially providing a natural way to protect against these diseases (8).

Calorie restriction and Fisetin, the surreal resemblance

There is a widely accepted belief among scientists that reducing overall calorie intake through calorie restriction, typically by 10-40%, can lead to improved health and longevity.

Fisetin has been shown to mimic some of the effects of calorie restriction, which is known to promote longevity and health. Specifically, fisetin has been found to activate a cellular pathway known as AMPK, which is also stimulated by calorie restriction. This pathway plays an important role in energy metabolism and has been shown to improve glucose regulation, reduce inflammation and promote healthy aging. Additionally, fisetin has been found to increase the activity of sirtuins, a group of proteins that are involved in various cellular processes related to aging and disease. It also helps in promoting autophagy (a form of cellular housekeeping). Studies indicate that fisetin can trigger the same response as calorie restriction by activating these three pathways in the body. However, the activity of these pathways declines with age, but mice models show that fisetin can boost their activity and keep the cells youthful (9).

Where can you get Fistein from and what are the doses?

Fisetin can be found naturally in fruits and vegetables i.e., strawberries, apples, onions, grapes, persimmons and kiwi. On average, the daily intake of fisetin through food sources is relatively low, estimated to be around 0.4 mg per day. However, fisetin supplements usually contain a much higher concentration of fisetin compared to the amounts obtained from food sources. Fisetin supplements usually recommend a daily usage of 100-500 mg, as seen in studies involving cancer patients and healthy older adults (10). For daily consumption, it is safer to take a smaller amount of fisetin. Higher doses of fisetin i.e., 1000 mg or more are recommended to be taken only a few days per month. However, more human clinical studies are required to establish a more comprehensive recommended dosage for fisetin.

What are Side effects of fisetin?

Since fisetin is a relatively new dietary supplement, the long-term effects of its usage are not yet known. Nevertheless, animal studies have shown no indication of fisetin toxicity even at high doses. A clinical study (11) was conducted on humans and the results revealed that people with colorectal cancer who consumed 100 mg of fisetin for seven weeks did not experience significantly different side effects from the control group.

As there is no sufficient data, pregnant women and children are advised to avoid fisetin supplements.

Conclusion:

Fisetin, an antioxidant derived from plants, is gaining attention for its potential to provide health benefits by combatting various diseases. It has the ability to eliminate malfunctioning senescent cells that reduce the risk of disease and enhance longevity. Hence, it has been identified as a potent senolytic compound among plant polyphenols.

References:

1. Yousefzadeh, M. J., Zhu, Y. I., McGowan, S. J., Angelini, L., Fuhrmann-Stroissnigg, H., Xu, M., & Niedernhofer, L. J. (2018). Fisetin is a senotherapeutic that extends health and lifespan. EBioMedicine, 36, 18-28.
2. Gerdes, E. O. W., Misra, A., Netto, J. M. E., Tchkonia, T., & Kirkland, J. L. (2021). Strategies for late phase preclinical and early clinical trials of senolytics. Mechanisms of Ageing and Development, 200, 111591.
3. Maher, P., Salgado, K. F., Zivin, J. A., & Lapchak, P. A. (2007). A novel approach to screening for new neuroprotective compounds for the treatment of stroke. Brain research, 1173, 117-125.
4. Maher, P., Dargusch, R., Bodai, L., Gerard, P. E., Purcell, J. M., & Marsh, J. L. (2011). ERK activation by the polyphenols fisetin and resveratrol provides neuroprotection in multiple models of Huntington's disease. Human molecular genetics, 20(2), 261-270.
5. Zhu, Y., Doornebal, E. J., Pirtskhalava, T., Giorgadze, N., Wentworth, M., Fuhrmann-Stroissnigg, H., & Kirkland, J. L. (2017). New agents that target senescent cells: the flavone, fisetin, and the BCL-XL inhibitors, A1331852 and A1155463. Aging (Albany NY), 9(3), 955.
6. Naeimi, A. F., & Alizadeh, M. (2017). Antioxidant properties of the flavonoid fisetin: An updated review of in vivo and in vitro studies. Trends in food science & technology, 70, 34-44.
7. Pal, H. C., Pearlman, R. L., & Afaq, F. (2016). Fisetin and its role in chronic diseases. Anti-inflammatory Nutraceuticals and Chronic Diseases, 213-244.
8. Ehren, J. L., & Maher, P. (2013). Concurrent regulation of the transcription factors Nrf2 and ATF4 mediates the enhancement of glutathione levels by the flavonoid fisetin. Biochemical pharmacology, 85(12), 1816-1826.
9. Yang, W., Tian, Z. K., Yang, H. X., Feng, Z. J., Sun, J. M., Jiang, H., & Liu, C. M. (2019). Fisetin improves lead-induced neuroinflammation, apoptosis and synaptic dysfunction in mice associated with the AMPK/SIRT1 and autophagy pathway. Food and chemical toxicology, 134, 110824.
10. Syed, D. N., Afaq, F., Maddodi, N., Johnson, J. J., Sarfaraz, S., Ahmad, A., & Mukhtar, H. (2011). Inhibition of human melanoma cell growth by the dietary flavonoid fisetin is associated with disruption of Wnt/β-catenin signaling and decreased Mitf levels. Journal of Investigative Dermatology, 131(6), 1291-1299.
11. Naeimi, A. F., Alizadeh, M., Esfahani, A., & Aminabad, E. D. (2018). Effect of fisetin supplementation on inflammatory factors and matrix metalloproteinase enzymes in colorectal cancer patients. Food & function, 9(4), 2025-2031.