Fisetin: Antioxidant and Senolytic

Aging brings 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. We’ll probe the evidence for using fisetin as a longevity compound and explore 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.

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: Natural supplement for longevity and healthspan

Fisetin is a natural flavonol found in several types of fruits and vegetables. It is being studied for various health benefits, including preventing complications from diabetes to heart disease and as a longevity compound.

In several recent studies, fisetin clears out senescent cells holding a lot of promise for healthy aging.

First, let me give you a little background science, and then I’ll go into the research studies on fisetin…

Why is cellular senescence important?

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 it gives off are pro-inflammatory cytokines, which become a source of low-level inflammation. Senescent cells sometimes are called ‘zombie cells‘. They aren’t quite dead but no longer function as a cell.

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

Cellular senescence is triggered by many circumstances, including[ref]:

  • Telomeres are 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

Senescent cells increase with age:

Younger people with a good immune system have no problem clearing out senescent cells. The process of cell-cycle arrest and clearing out cellular insults works well, just as it should.

Senescent cells increase with age. Older people often have a problem clearing out all of the senescent cells, which relates directly to some aging-related diseases.

I mentioned above that cells hang out a flag when they become senescent. The senescent cells’ ‘flag’ waves when they need to be killed off and recycled. This flag is a chemical signal of inflammatory cytokines.

When senescent cells aren’t cleared out quickly, local inflammation can occur due to the increased inflammatory cytokines, causing neighboring cells also to become senescent. The secretion of inflammatory cytokines by senescent cells is known as the ‘senescence-associated secretory phenotype’ (SASP).[ref] Stopping this low-grade inflammation is one goal of longevity science.

Clearing out senescent cells prevents the onset of age-related diseases in animal studies. It increases healthspan (number of years of healthy living), as well as increases lifespan (in animals).[ref]

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

The animal studies on removing senescent cells 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 take a lot of money and a much longer time (of course).

Two pathways exist by 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 calling for the cell to stop dividing and be destroyed through apoptosis, senescent cells also upregulate 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. The concept of being able to clear out senescent cells in aging has prompted a lot of interest, and there have been many studies 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. It 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 acts as a senolytic in several promising new studies.

Research studies on fisetin:

 The rest of this article is for Genetic Lifehacks members only.  Consider joining today to see the rest of this article.

Member Content:

An active subscription is required to access this content.

Join Here for full access to this article, genotype reports, and much more!


Already a member? Log in below.


Related Articles and Topics:

Alzheimer’s and APOE genotype
One very important gene that has been extremely well researched for Alzheimer’s disease is the APOE gene. This gene is involved in carrying cholesterol and other fats in your bloodstream, and a common variant of the gene is linked to a higher risk of Alzheimer’s.

Mast cells: MCAS, genetics, and solutions
Mast Cell Activation Syndrome, or MCAS, is a recently recognized disease involving mast cells that are misbehaving in various ways. Symptoms of MCAS can include abdominal pain, nausea, itching, flushing, hives, headaches, heart palpitations, anxiety, brain fog, and anaphylaxis.

Intermittent Fasting: Benefits from changing Gene Expression
The intermittent fasting concept has gained traction in health circles. Learn more about the importance of when you eat and its effects on gene expression.

Inflammation: Causes and Natural Solutions
Take a deep dive into the causes of chronic inflammation and learn how to target specific inflammatory pathways to reverse or prevent chronic disease.

 

References:

Aarabi, Mohammad Hossein, and Seyyed Mehdi Mirhashemi. “To Estimate Effective Antiamyloidogenic Property of Melatonin and Fisetin and Their Actions to Destabilize Amyloid Fibrils.” Pakistan Journal of Pharmaceutical Sciences, vol. 30, no. 5, Sept. 2017, pp. 1589–93.

Che, Denis Nchang, et al. “Fisetin Inhibits IL-31 Production in Stimulated Human Mast Cells: Possibilities of Fisetin Being Exploited to Treat Histamine-Independent Pruritus.” Life Sciences, vol. 201, May 2018, pp. 121–29. PubMed, https://doi.org/10.1016/j.lfs.2018.03.056.

Chen, Tong, et al. “Randomized Phase II Trial of Lyophilized Strawberries in Patients with Dysplastic Precancerous Lesions of the Esophagus.” Cancer Prevention Research (Philadelphia, Pa.), vol. 5, no. 1, Jan. 2012, pp. 41–50. PubMed, https://doi.org/10.1158/1940-6207.CAPR-11-0469.

Fan, Qingling, et al. “Fisetin Suppresses 1,2-Dimethylhydrazine-Induced Colon Tumorigenesis in Wistar Rats via Enhancing the Apoptotic Signaling Pathway.” Journal of King Saud University – Science, vol. 32, no. 3, Apr. 2020, pp. 1959–64. ScienceDirect, https://doi.org/10.1016/j.jksus.2020.01.042.

He, Shenghui, and Norman E. Sharpless. “Senescence in Health and Disease.” Cell, vol. 169, no. 6, June 2017, pp. 1000–11. PubMed Central, https://doi.org/10.1016/j.cell.2017.05.015.

Hickson, LaTonya J. Frailty, Inflammation, and Stem Cell Functionality in Chronic Kidney Disease. Clinical trial registration, NCT03325322, clinicaltrials.gov, 13 Sept. 2021. clinicaltrials.gov, https://clinicaltrials.gov/ct2/show/NCT03325322.

Jasso-Miranda, Carolina, et al. “Antiviral and Immunomodulatory Effects of Polyphenols on Macrophages Infected with Dengue Virus Serotypes 2 and 3 Enhanced or Not with Antibodies.” Infection and Drug Resistance, vol. 12, July 2019, pp. 1833–52. PubMed Central, https://doi.org/10.2147/IDR.S210890.

Kang, Chanhee. “Senolytics and Senostatics: A Two-Pronged Approach to Target Cellular Senescence for Delaying Aging and Age-Related Diseases.” Molecules and Cells, vol. 42, no. 12, Dec. 2019, pp. 821–27. PubMed Central, https://doi.org/10.14348/molcells.2019.0298.

Khan, Naghma, et al. “Fisetin: A Dietary Antioxidant for Health Promotion.” Antioxidants & Redox Signaling, vol. 19, no. 2, July 2013, pp. 151–62. PubMed Central, https://doi.org/10.1089/ars.2012.4901.

Kirkland, James L., et al. “The Clinical Potential of Senolytic Drugs.” Journal of the American Geriatrics Society, vol. 65, no. 10, Oct. 2017, pp. 2297–301. PubMed Central, https://doi.org/10.1111/jgs.14969.

Klimaszewska-Wiśniewska, Anna, et al. “Cellular and Molecular Alterations Induced by Low-Dose Fisetin in Human Chronic Myeloid Leukemia Cells.” International Journal of Oncology, vol. 55, no. 6, Oct. 2019, pp. 1261–74. PubMed Central, https://doi.org/10.3892/ijo.2019.4889.

Liu, Xiang-Feng, et al. “Fisetin Inhibits Liver Cancer Growth in a Mouse Model: Relation to Dopamine Receptor.” Oncology Reports, vol. 38, no. 1, July 2017, pp. 53–62. PubMed Central, https://doi.org/10.3892/or.2017.5676.

Maher, Pamela. “Fisetin Acts on Multiple Pathways to Reduce the Impact of Age and Disease on CNS Function.” Frontiers in Bioscience (Scholar Edition), vol. 7, June 2015, pp. 58–82. PubMed Central, https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5527824/.

Nagai, K., et al. “The Hydroxyflavone, Fisetin, Suppresses Mast Cell Activation Induced by Interaction with Activated T Cell Membranes.” British Journal of Pharmacology, vol. 158, no. 3, Oct. 2009, pp. 907–19. PubMed, https://doi.org/10.1111/j.1476-5381.2009.00365.x.

Park, Hyo-Hyun, Soyoung Lee, Jae-Min Oh, et al. “Anti-Inflammatory Activity of Fisetin in Human Mast Cells (HMC-1).” Pharmacological Research, vol. 55, no. 1, Jan. 2007, pp. 31–37. PubMed, https://doi.org/10.1016/j.phrs.2006.10.002.

Park, Hyo-Hyun, Soyoung Lee, Hee-Young Son, et al. “Flavonoids Inhibit Histamine Release and Expression of Proinflammatory Cytokines in Mast Cells.” Archives of Pharmacal Research, vol. 31, no. 10, Oct. 2008, pp. 1303–11. PubMed, https://doi.org/10.1007/s12272-001-2110-5.

PhD, James L. Kirkland, MD. AFFIRM-LITE: A Phase 2 Randomized, Placebo-Controlled Study of Alleviation by Fisetin of Frailty, Inflammation, and Related Measures in Older Adults. Clinical trial registration, NCT03675724, clinicaltrials.gov, 7 Jan. 2022. clinicaltrials.gov, https://clinicaltrials.gov/ct2/show/NCT03675724.

Prasath, Gopalan Sriram, et al. “Fisetin Improves Glucose Homeostasis through the Inhibition of Gluconeogenic Enzymes in Hepatic Tissues of Streptozotocin Induced Diabetic Rats.” European Journal of Pharmacology, vol. 740, Oct. 2014, pp. 248–54. PubMed, https://doi.org/10.1016/j.ejphar.2014.06.065.

Ravichandran, Nagaiya, et al. “Fisetin Modulates Mitochondrial Enzymes and Apoptotic Signals in Benzo(a)Pyrene-Induced Lung Cancer.” Molecular and Cellular Biochemistry, vol. 390, no. 1–2, May 2014, pp. 225–34. PubMed, https://doi.org/10.1007/s11010-014-1973-y.

Rodius, Sophie, et al. “Fisetin Protects against Cardiac Cell Death through Reduction of ROS Production and Caspases Activity.” Scientific Reports, vol. 10, Feb. 2020, p. 2896. PubMed Central, https://doi.org/10.1038/s41598-020-59894-4.

Sandireddy, Reddemma, et al. “Fisetin Imparts Neuroprotection in Experimental Diabetic Neuropathy by Modulating Nrf2 and NF-ΚB Pathways.” Cellular and Molecular Neurobiology, vol. 36, no. 6, Aug. 2016, pp. 883–92. PubMed, https://doi.org/10.1007/s10571-015-0272-9.

Yang, Pei-Ming, et al. “Dietary Flavonoid Fisetin Targets Caspase-3-Deficient Human Breast Cancer MCF-7 Cells by Induction of Caspase-7-Associated Apoptosis and Inhibition of Autophagy.” International Journal of Oncology, vol. 40, no. 2, Feb. 2012, pp. 469–78. PubMed, https://doi.org/10.3892/ijo.2011.1203.

Yi, Canhui, et al. “Melatonin Enhances the Anti-Tumor Effect of Fisetin by Inhibiting COX-2/INOS and NF-ΚB/P300 Signaling Pathways.” PLoS ONE, vol. 9, no. 7, July 2014, p. e99943. PubMed Central, https://doi.org/10.1371/journal.pone.0099943.

Yousefzadeh, Matthew J., et al. “Fisetin Is a Senotherapeutic That Extends Health and Lifespan.” EBioMedicine, vol. 36, Oct. 2018, pp. 18–28. www.thelancet.com, https://doi.org/10.1016/j.ebiom.2018.09.015.

Zhao, Xin, Xin-Lin Li, et al. “Antinociceptive Effects of Fisetin against Diabetic Neuropathic Pain in Mice: Engagement of Antioxidant Mechanisms and Spinal GABAA Receptors.” Pharmacological Research, vol. 102, Dec. 2015, pp. 286–97. PubMed, https://doi.org/10.1016/j.phrs.2015.10.007.

Zhao, Xin, Chuang Wang, et al. “Fisetin Exerts Antihyperalgesic Effect in a Mouse Model of Neuropathic Pain: Engagement of Spinal Serotonergic System.” Scientific Reports, vol. 5, Mar. 2015, p. 9043. PubMed Central, https://doi.org/10.1038/srep09043.

Zhu, Yi, et al. “The Achilles’ Heel of Senescent Cells: From Transcriptome to Senolytic Drugs.” Aging Cell, vol. 14, no. 4, Aug. 2015, pp. 644–58. PubMed, https://doi.org/10.1111/acel.12344.


About the Author:
Debbie Moon is the founder of Genetic Lifehacks. Fascinated by the connections between genes, diet, and health, her goal is to help you understand how to apply genetics to your diet and lifestyle decisions. Debbie has a BS in engineering and also an MSc in biological sciences from Clemson University. Debbie combines an engineering mindset with a biological systems approach to help you understand how genetic differences impact your optimal health.