Fisetin

2021-06-29T05:05:15Z

Aycoble: No content changes - just edited for accessibility/readability.

Fisetin is a potent, plant-based polyphenol compound that has been found to reduce senescence markers (signs of cellular aging) in human and animal tissues.<ref name=":0">[https://pubmed.ncbi.nlm.nih.gov/30279143/ Yousefzadeh, M. J., Zhu, Y., McGowan, S. J., Angelini, L., Fuhrmann-Stroissnigg, H., Xu, M., Ling, Y. Y., Melos, K. I., Pirtskhalava, T., Inman, C. L., McGuckian, C., Wade, E. A., Kato, J. I., Grassi, D., Wentworth, M., Burd, C. E., Arriaga, E. A., Ladiges, W. L., Tchkonia, T., Kirkland, J. L., … Niedernhofer, L. J. (2018). Fisetin is a senotherapeutic that extends health and lifespan. ''EBioMedicine'', ''36'', 18–28. https://doi.org/10.1016/j.ebiom.2018.09.015]</ref> It can be extracted from most vegetables and fruits, such as strawberries, onions, and cucumbers.<ref>Kim, H. J., Kim, S. H., & Yun, J. M. (2012). Fisetin inhibits hyperglycemia-induced proinflammatory cytokine production by epigenetic mechanisms. ''Evidence-based complementary and alternative medicine : eCAM'', ''2012'', 639469. https://doi.org/10.1155/2012/639469.</ref> Fisetin has many therapeutic benefits, including anti-inflammatory, cardioprotective, and neuroprotective properties. It is also an antiangiogenic, meaning it can reduce the growth of unwanted blood vessels.<ref>Mehta, P., Pawar, A., Mahadik, K., & Bothiraja C. (2018). Emerging novel drug delivery strategies for bioactive flavonol fisetin in biomedicine. ''Biomedicine & Pharmacotherapy'', ''106'', 1282-1291. https://doi.org/10.1016/j.biopha.2018.07.079</ref>

== Evidence of lifespan extension ==
The primary advantage of fisetin treatment is that it targets senescent cells (SCs).

SCs are cells that have accumulated DNA damage or other stressors, which leads to changes in two types of cellular proteins: chromatin, the protein that chromosomes, including RNA and DNA, are made of; and secretome, a general name for proteins secreted by human cells. These changes lead to apoptosis (programmed cell death) which prevents the cell from replicating.<ref name=":0" /> This mechanism is designed to prevent the cell from becoming a cancer cell.

However, SCs can instead develop senescence-associated secretory phenotypes (SASPs) which induce inflammatory immune responses via cytokines, chemokines, and extracellular degrading proteins. Even at low levels, SASPs have been shown to contribute to tissue dysfunction.<ref name=":0" />

SCs are closely linked to age since they usually increase with age in several tissues, including adipose (fat) tissue, skeletal muscle, kidney tissue, and skin.<ref>Herbig, U., Ferreira, M., Condel, L., Carey, D., & Sedivy, J. M. (2006). Cellular senescence in aging primates. ''Science'', ''311''(5765), 1257-1257. ''science.sciencemag.org'', [https://science.sciencemag.org/content/311/5765/1257 doi:10.1126/science.1122446].</ref>

Fisetin well-suited treatment to destroy such cells and this has thus been investigated in mice and in humans.

=== Mice ===
[[File:Yousefzadeh et al. (2018) results.jpg|thumb|MEFs and IMR90 comparison in flovanoid polyphenols in Yousefzadeh et al. (2018)'s study. |351x351px]]
[[File:FisetinDietAdvantage.jpg|thumb|Fisetin diet advantages in Ercc1−/∆ mice with the p16Ink4a-luciferase transgene. |375x375px]]
Yousefzadeh et al. (2018) found that fisetin was the most effective [[Senolytics|senolytic]] out of 10 different flavonoids (a class of plant-based polyphenol compound).<ref name=":0" /> In vitro, the defective DNA repair gene Ercc1−/− in the embryonic stem cell line was targeted to induce senescence. The mutant Ercc1−/− mice cells had the greatest improvement when treated with fisetin.

In vitro, they used Ercc1−/∆ mice with the p16Ink4a-luciferase transgene to accelerate accumulation of senscent cells. The mice were then fed a diet from 6-8 to 10-12 weeks of age that included fisetin supplements administered every 500 mg/kg.

They found that luciferase Ercc1−/∆;p16Ink4a signal was significantly suppressed following the diet. They also found that, in the following weeks, the fisetin-treated mice had lower p16Ink4a expression levels when they did not receive more fisetin.

Yousefzadeh et al. (2018) argue that this result demonstrates both that fisetin can destroy senescent cells and that fisetin does not have to be continuously present to successfully suppress senescence.<ref name=":0" />

=== Humans ===
In studies on humans, results have indicated that fisetin can be an effective supplement to combat aging. Studies have shown that it can improve lung fibroblast tissues, known as IMR90 cells.<ref name=":0" /> Fibroblast cells normally help with lung architecture, specifically cell scaffolding and injury response. However, when they change in number and phenotype, they can also play a key role in the development of chronic lung conditions like asthma, chronic obstructive pulmonary disease (COPD), and idiopathic pulmonary fibrosis (IPF).

Two days following a fisetin treatment, scientists found that an enzyme only found in senescent cells, SA-β-gal, had decreased by 70 percent.

=== Other vertebrates ===
Fisetin has been found to extend lifespan by 55% in S. ''cerevisiae''<ref>Howitz, K. T., Bitterman, K. J., Cohen, H. Y., Lamming, D. W., Lavu, S., Wood, J. G., ... & Sinclair, D. A. (2003). Small molecule activators of sirtuins extend Saccharomyces cerevisiae lifespan. ''Nature'', ''425''(6954), 191-196.</ref> and 23% in D. ''melanogaster.''<ref>Wood, J. G., Rogina, B., Lavu, S., Howitz, K., Helfand, S. L., Tatar, M., & Sinclair, D. (2004). Sirtuin activators mimic caloric restriction and delay ageing in metazoans. ''Nature'', ''430''(7000), 686-689.</ref>

== Biological mechanism ==

=== Cardioprotective ===
Similar to [[Rapamycin]], Fisetin is believed to inhibit the effects of the glycogen synthase kinase 3''β'' (GSK3''β)'' enzyme by suppressing the signaling pathway and reversing mitochondrial dysfunction.<ref name=":1">Shanmugam, K., Ravindran, S., Kurian, G. A., & Rajesh, M. (2018). Fisetin confers cardioprotection against myocardial ischemia reperfusion injury by suppressing mitochondrial oxidative stress and mitochondrial dysfunction and inhibiting glycogen synthase kinase 3β activity. ''Oxidative medicine and cellular longevity'', ''2018''.</ref>

The GSK3''β'' enzyme plays a key role in ischemia reperfusion injury (IRI). IRI describes tissue damage that occurs when blood flow returns to myocardial (heart) tissue after a period of ischemia (lack of oxygen). during an IRI, the mitochondria of the tissue cells are especially susceptible to damage: GSK3''β'' converges in the mitochondria and affects mitochondrial functions, including the determination of cell outcomes.

By inhibiting GSK3''β'', fisetin regulates the mitochondrial ATP-sensitive K+ channels and protects the cell. Specifically, fisetin has been found to reduce oxidative stress markers in other cell structures, lysosomes and microsomes.<ref name=":1" /> Plus, mitochondrial swelling decreased and K+ channels took less damage from IRI when fisetin was used.

Interestingly, fisetin can also "blunt" IRI-induced apoptosis in damaged myocardial tissues.

=== Cancer ===
Fisetin has been found to inhibit anti-apoptotic Bcl-2 cells and induce pro-apoptotic Caspase-9 and Caspase-3 expression in cancerous colon cells.<ref>Fan, Q., Wang, X., Chinnathambi, A., Alharbi, S. A., & Wang, Q. (2020). Fisetin suppresses 1, 2-dimethylhydrazine-induced colon tumorigenesis in Wistar rats via enhancing the apoptotic signaling pathway. ''Journal of King Saud University-Science'', ''32''(3), 1959-1964.</ref> In other words, fisetin both inhibits the growth of and promotes the death of cancerous colon cells. <references />

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Fisetin