Fisetin

Today, we will take a look at the popular supplement fisetin and see how it stacks up as a geroprotector.

History of Fisetin

Fisetin is a plant polyphenol and part of the flavonoid group in the flavonol sub-category. The earliest record of isolated fisetin dates back to 1833 from the smoke bush (Rhus cotinus). Its basic chemical characteristics were later defined by J. Schmidt in 1886, but it was not until the 1890s when S. Kostanecki defined its chemical structure and confirmed it via synthesis. Kostanecki launched a study of plant pigments during this period and coined group names for sub-categories, including flavones, flavonol, chromones, and chalcones.

Fisetin, like many plant polyphenols, is known to have antioxidant properties and demonstrates the specific biological activity of protecting functional macromolecules against stress, resulting in a benefit to cellular cytoprotection. It is also known to have anti-inflammatory, chemopreventive, and chemotherapeutic properties.

Finally, more recently, it has also shown promise as a senolytic, a compound that encourages aged or damaged senescent cells to destroy themselves rather than lingering in the body and contributing to the chronic, age-related inflammation known as “inflammaging”, which is associated with a wide range of age-related diseases.

Fisetin in nature

Fisetin serves as a colouing agent and can be found in many trees and plants, including Eudicotyledons, Acacia greggii, Quebracho colorado, Rhus cotinus, and Butea frondosa. The traditional yellow dye known as young fustic uses fisetin extracted from the wood of the smoke bush (Rhus cotinus) and was a popular way to color fabrics and clothes until synthetic dyes replaced them.

Fisetin can be found in many common fruits and vegetables, although the amounts can vary considerably.

Clearly, strawberries have a much higher concentration of this flavonol than other fruits and vegetables, which may be why people associate it with this fruit in particular. Typical supplement pills are in the 100-mg range, which is significantly higher than dietary sources would typically provide. However, without proper clinical trials, there is no way to know if this 100-mg dose is beneficial or harmful in humans.

Fisetin and its senolytic potential

Fisetin has been in the spotlight most recently for its potential as a senolytic therapeutic, which can destroy harmful senescent cells that linger in the body and cause inflammation. Senescent cell accumulation is thought to be a reason we age, so fisetin may, in a very real sense, be targeting aging directly and has potential as an anti-aging therapeutic.

This interest in the senolytic properties of fisetin was initiated in 2018, when researchers from the University of Minnesota Medical School and Mayo Clinic published “Fisetin is a senotherapeutic that extends health and lifespan” in the journal EBioMedicine [1]. The study showed that fisetin given to aged mice could destroy senescent cells and improved both their healthspan and lifespan. Importantly, no adverse side effects were noted, even when the mice were given very high doses.

The researchers also compared fisetin against other compounds, including resveratrol, luteolin, rutin, epigallocatechin gallate, curcumin, pirfenidone, myricetin, apigenin, and catechin. This study showed that fisetin was the most effective of these compounds.

Since fisetin has a good safety profile, Mayo Clinic followed these mouse studies by launching three trials to see if the compound is effective for humans.

Further fisetin studies

Fisetin has been studied prior to the interest in senolytics and, like many polyphenols, it has anti-inflammatory activity. While not all of the following studies are directly about aging per se, they do explore inflammation, which is a critical component of aging.

A 2018 study by researchers at the Salk Institute tested fisetin, curcumin, and three modified variants of these two compounds and discovered that they all reduced some biomarkers of aging, increased median lifespan in mice and flies, and reduced the signs of dementia [2]. While the modified compounds worked somewhat better, the unmodified fisetin also worked.

Fisetin also appears to have a potent effect on inflammation by blocking the activity of lipoxygenases, thus reducing the level of pro-inflammatory factors [3-4].

There also appears to be some potential for fisetin in addressing high blood sugar in diabetics. In a 2014 study, researchers discovered that fisetin was able to block the inflammatory response to prevent damage to blood vessels and tissue in mice [5]. Similar results were found for human cell lines tested during the same study.

A 2014 study found that fisetin was an effective treatment for eczema in mice, as it was able to reduce the presence of immune cells such as T cells, mast cells, and eosinophils, which are commonly encountered in the skin lesions that eczema causes [7].

There are a considerable number of additional studies involving fisetin:

Currently, the lack of clinical trial data makes it impossible to say if fisetin is a geroprotector in humans, though the signs are positive for animal studies. With Mayo Clinic and other groups conducting human trials, we likely will not have to wait too long before we have the answers. Fisetin has an excellent safety profile and is well tolerated and cheap, so if human trials confirm its effectiveness as a geroprotector, it would be a real low-hanging fruit for people with an interest in combating the effects of aging. We will have to wait and see what such trials say before we jump on the bandwagon.

Disclaimer

This article is only a very brief summary. It is not intended as an exhaustive guide and is based on the interpretation of research data, which is speculative by nature. This article is not a substitute for consulting your physician about which supplements may or may not be right for you. We do not endorse supplement use or any product or supplement vendor, and all discussion here is for scientific interest.

Literature

[1] Yousefzadeh, M. J., Zhu, Y., McGowan, S. J., Angelini, L., Fuhrmann-Stroissnigg, H., Xu, M., … & McGuckian, C. (2018). Fisetin is a senotherapeutic that extends health and lifespan. EBioMedicine, 36, 18-28.

[2] Schubert, D., Currais, A., Goldberg, J., Finley, K., Petrascheck, M., & Maher, P. (2018). Geroneuroprotectors: Effective Geroprotectors for the Brain. Trends in pharmacological sciences, 39(12), 1004-1007.

[3] Sadik, C. D., Sies, H., & Schewe, T. (2003). Inhibition of 15-lipoxygenases by flavonoids: structure–activity relations and mode of action. Biochemical pharmacology, 65(5), 773-781.

[4] Maher, P. (2015). Fisetin Acts on Multiple Pathways to Reduce the Impact of Age and Disease on CNS Function. Frontiers in bioscience (Scholar edition), 7, 58.

[5] Kwak, S., Ku, S. K., & Bae, J. S. (2014). Fisetin inhibits high-glucose-induced vascular inflammation in vitro and in vivo. Inflammation Research, 63(9), 779-787.

[6] Kim, G. D., Lee, S. E., Park, Y. S., Shin, D. H., Park, G. G., & Park, C. S. (2014). Immunosuppressive effects of fisetin against dinitrofluorobenzene-induced atopic dermatitis-like symptoms in NC/Nga mice. Food and Chemical Toxicology, 66, 341-349.

[7] Kim, G. D., Lee, S. E., Park, Y. S., Shin, D. H., Park, G. G., & Park, C. S. (2014). Immunosuppressive effects of fisetin against dinitrofluorobenzene-induced atopic dermatitis-like symptoms in NC/Nga mice. Food and Chemical Toxicology, 66, 341-349.