Fisetin

From Longevity Wiki
Molecular structure of fisetin.

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.[1] It can be extracted from most vegetables and fruits, such as strawberries (160 μg/g), apples (26.9 μg/g), persimmons (10.6 μg/g), lotus roots (5.8 μg/g), onions (4.8 μg/g), grapes (3.9 μg/g), kiwi (2.0 μg/g), peaches (0.6 μg/g), and cucumbers (0.1 μg/g).[2][3] 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.[4]

It is important to note that the consequences of eliminating senescent cells in vivo remains unknown, with some studies suggesting that it might be detrimental.[5]

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 the expression profile of proteins secreted by human cells. These changes lead to apoptosis (programmed cell death) which prevents the cell from replicating.[1] This mechanism is designed to prevent the cell from becoming a cancer cell.

However, SCs can instead develop a senescence-associated secretory phenotype (SASPs) to induce inflammatory immune responses via cytokines, chemokines, and extracellular degrading proteins. Even at low levels, SASPs have been shown to contribute to tissue dysfunction.[1]

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.[6]

Fisetin appears to be a well-suited treatment to destroy senescent cells and this has thus been investigated in mice and in humans.

Mice

Longevity graph of mice on fisetin diet and control diet. Retrieved from Yousefzadeh et al. (2018) study.

Yousefzadeh et al. (2018) found that fisetin was the most effective senolytic out of 10 different flavonoids (a class of plant-based polyphenol compound).[1] 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 and inserted the p16Ink4a-luciferase transgene (bioluminescent foreign gene) 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.[1]

Humans

Preliminary studies in human adipose explant tissues, suggested that fisetin can be an effective supplement to clear senescent cells.[1]

Mammals

Animal studies have shown that it can improve the status of lung fibroblast tissues, known as IMR90 cells.[1] 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.

Non-mammals

Fisetin has been found to extend lifespan by 55% in S. cerevisiae[7] and 23% in D. melanogaster.[8]

CMS121

CMS121 is a small molecule and derivative of the flavonoid fisetin, that is 400 times more potent, than fisetin in the ischemia assay and is able to rescue cells from oxytotic/ferroptotic cell death.[9][10]

CMS121 is a direct fatty acid synthase (FASN) inhibitor which, by CMS121-mediated, dose-dependent decrease in fatty acid synthase activity, alleviates cognitive loss, modulates lipid metabolism and reduces inflammation and lipid peroxidation in the brains of transgenic model of Alzheimer's disease mice.[11] Long-term treatments with CMS121 restored a more youthful level of physiological markers and prevent age-associated disease in both brain and kidney.[12][13]

Biological mechanism

Cardioprotective

Illustration from Shanmugam et al. (2018) study showcasing the biological mechanisms of fisetin's cardioprotective qualities against myocardial ischemia reperfusion injury.

Similar to rapamycin, fisetin is believed to inhibit the effects of the glycogen synthase kinase 3β (GSK3β) enzyme by suppressing the signaling pathway and reversing mitochondrial dysfunction.[14]

The GSK3β 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: GSK3β converges in the mitochondria and affects mitochondrial functions, including the determination of cell outcomes.

By inhibiting GSK3β, 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.[14] Plus, decreasing mitochondrial swelling and less damage from IRI on the K+ channels when fisetin was used.

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

Cancer

Fisetin can help inhibit the growth of and expedite the death of cancerous colon cells. It does this in two ways:

  1. Inhibiting anti-apoptotic B-cell lymphoma 2 (BCL-2) cells. B-cell lymphoma 2 proteins prevent cell death (apoptosis) in both healthy and cancerous cells. By targeting BCL-2, fisetin can help ensure that malignant cells undergo normal programmed cell death.
  2. Induce pro-apoptotic Caspase-9 and Caspase-3 gene expression in cancerous colon cells. Caspase-9 and Caspase-3 are proteins expressed by the CASP9 and CASP3 genes respectively; both proteins induce apoptosis (cell death) by destroying critical cell infrastructures.[15]

Fisetin has also been found to be an effective inhibitor of matrix metalloproteinase (MMP)-1 activity. MMP-1 aids in extracellular matrix (ECM) remodelling and degradation which can occur during neoplastic transformation like uncontrolled cell growth or failed apoptosis. More broadly, this can manifest as tumor growth and metastasis of cancerous cells.[3] Since MMP-1 promotes ECM remodelling and fisetin inhibits MMP-1 activity, fisetin thus helps to slow the progression of cancer.

ECM remodelling describes the changes that occur in cells when they undergo neoplastic transformation, i.e. when they grow more rapidly than they should, or do not die when they should. More broadly, this can manifest as tumor growth and metastasis of cancerous cells.[3]

Since MMP-1 promotes ECM remodelling and fisetin inhibits MMP-1 activity, fisetin thus helps to slow the progression of cancer.

  1. ↑ 1.0 1.1 1.2 1.3 1.4 1.5 1.6 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
  2. ↑ 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.
  3. ↑ 3.0 3.1 3.2 Khan, N., Syed, D. N., Ahmad, N., & Mukhtar, H. (2013). Fisetin: a dietary antioxidant fro health promotion. Antioxidants & Redox signaling, 19(2), 151-162. http://doi.org/10.1089/ars.2012.4901
  4. ↑ 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
  5. ↑ Born, E. et al. (2022) “Eliminating senescent cells can promote pulmonary hypertension development and progression,” Circulation [Preprint]. Available at: https://doi.org/10.1161/circulationaha.122.058794.
  6. ↑ 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, doi:10.1126/science.1122446.
  7. ↑ 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.
  8. ↑ 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.
  9. ↑ Chiruta, C., Schubert, D., Dargusch, R., & Maher, P. (2012). Chemical modification of the multitarget neuroprotective compound fisetin. Journal of Medicinal Chemistry, 55(1), 378-389. PMID: 22192055 PMCID: PMC3291199 DOI: 10.1021/jm2012563
  10. ↑ Prior, M., Chiruta, C., Currais, A., Goldberg, J., Ramsey, J., Dargusch, R., ... & Schubert, D. (2014). Back to the future with phenotypic screening. ACS Chemical Neuroscience, 5(7), 503-513. PMID: 24902068 PMCID: PMC4102969 DOI: 10.1021/cn500051h
  11. ↑ Ates, G., Goldberg, J., Currais, A., & Maher, P. (2020). CMS121, a fatty acid synthase inhibitor, protects against excess lipid peroxidation and inflammation and alleviates cognitive loss in a transgenic mouse model of Alzheimer's disease. Redox Biology, 36, 101648. PMID: 32863221 PMC7394765 DOI: 10.1016/j.redox.2020.101648
  12. ↑ Kepchia, D., Currais, A., Dargusch, R., Finley, K., Schubert, D., & Maher, P. (2021). Geroprotective effects of Alzheimer’s disease drug candidates. Aging (Albany NY), 13(3), 3269. PMID: 33550278 PMCID: PMC7906177 DOI: 10.18632/aging.202631
  13. ↑ Zahid, S., Dafre, A. L., Currais, A., Yu, J., Schubert, D., & Maher, P. (2023). The Geroprotective Drug Candidate CMS121 Alleviates Diabetes, Liver Inflammation, and Renal Damage in db/db Leptin Receptor Deficient Mice. International Journal of Molecular Sciences, 24(7), 6828. https://doi.org/10.3390/ijms24076828
  14. ↑ 14.0 14.1 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.
  15. ↑ 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.
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