Name: Fisetin
Class: Flavonoid Supplement (senolytic)
Alias(es): CAS# 528-48-3, 5-Desoxyquercetin, Cotinin, Fustel, Viset
Recent/Breaking Articles:
Senolytic elimination of senescent macrophages restores muscle stem cell function in severely dystrophic muscle – use of fisetin… enabled
https://pubmed.ncbi.nlm.nih.gov/36084954/
Background: Fisetin is a flavonoid polyphenol, found naturally in many fruits and vegetables, including strawberries, apples, persimmons, grapes, onions, and cucumbers[1,2]. High doses of fisetin can be obtained via supplements if one is interested in benefiting from its senolytic properties (selectively clears senescent cells) in certain tissue and cell types[2]. In fact, when testing a panel of senolytics, which included apigenin, quercetin, resveratrol, curcumin, and other big names, for their potency in reducing levels of senescent cells (induced by oxidative stress), fisetin was the most potent senolytic compound tested[2]. Fisetin has demonstrated the ability to prevent and improve age-related biomarkers in vitro in human and model organisms’ cells, and has improved health-span and life-span in vivo in model organisms. See preclinical studies section for references and details. Furthermore, no adverse effects have been reported, even with long-term high-dose fisetin administration (orally)[3,4].
Is there evidence it works in humans for aging?
Not yet, but see clinical trials below:
ClinicalTrials.gov ID And Reference | Trial Status | Title | Summary |
NCT03675724 | Recruiting | AFFIRM-LITE: A Phase 2 Randomized, Placebo-Controlled Study of Alleviation by Fisetin of Frailty, Inflammation, and Related Measures in Older Adults | This study is accepting volunteers ≥ 70 years old and suffering with age-associated frailty.
Subjects will take 20mg/kg/day of fisetin or placebo capsules by mouth for 2 consecutive days.
The study will evaluate markers of frailty, inflammation, insulin resistance, and bone resorption with maintenance of bone formation.
Estimated study completion date is 06/30/2023. |
NCT04994561 | Not Yet Recruiting | VIAging Deceleration Trial Using Metformin, Dasatinib, Rapamycin and Nutritional Supplement. Official title: Pilot Study to Test the Safety and Efficacy of Metformin, Dasatinib, Rapamycin and Nutritional Supplements (Bio-quercetin; Bio-fisetin; Glucosamine; Nicotinamide Riboside; Trans-resveratrol) in Reducing Clinical Measures of Aging in Older Adults
| This study will be accepting healthy volunteers ≥ 65 years old. This study will involve first taking metformin and gradually increasing the dose. Then dasatinib, bio-quercetin, and bio-fisetin will be added. Then glucosamine, NR, and resveratrol will be added. And lastly rapamycin will be taken, at which point the subjects will continue on this intervention (taking all of these compounds) for 12 months.
The study will evaluate: adverse effects of treatments, DEXA scans of visceral adipose tissue, systolic blood pressure, senescent cell levels, glucose control, and DNA methylation via GrimAge.
Estimated study completion date is December 2023. |
Is there evidence it works in preclinical studies for aging?
Model | Vivo/Vitro | Outcome | Reference |
S. cerevisiae (yeast) | In vivo | Increased average replicative lifespan of yeast by 55% and extended maximum lifespan | Howitz et al., 2003 |
D. melanogaster (fruit fly) | In vivo | Extended lifespan of fruit flies by 23% | Wood et al., 2004 |
Mice (transgenic AD strain) | In vivo | Oral fisetin prevented learning and memory problems in Alzheimer’s disease (AD) mice. It was also found to reduce oxidative stress and neuroinflammation in both controls and AD mice. | Currais et al., 2013 |
Human | In vitro | Fisetin reduced markers of senescence (induced by radiation) in HUVEC cells, and it induced apoptosis in senescent HUVEC cells. However, it did not affect IMR90 cells, a human lung fibroblast strain, or primary human preadipocytes. | Zhu et al., 2017 |
Mice (SAMP8 rapid-aging model) | In vivo | Senescence-accelerated prone 8 (SAMP8) mice are an accelerated-aging breed of mice that show early brain aging and cognitive deficits as they age similar to Alzheimer’s disease (AD). Fisetin prevented cognitive and locomotor deficits with age in SAMP8 mice. Fisetin significantly improved homeostasis of certain proteins in the brain relevant to neuronal function and stress (closer to younger levels). Fisetin significantly decreased brain inflammation in older mice. Fisetin altered levels of brain and plasma metabolites to more closely match younger levels.
Overall, results indicate that fisetin may be useful in preventing or treating age-related neurodegeneration. | Currais et al., 2017 |
Mice (progeroid (Ercc1-) and naturally aged (C57BL/6)); human tissue | Mice: In vivo & in vitro Human: in vitro, ex vivo | In Vitro: Fisetin reduced oxidative stress-induced senescence markers in both cultured HUVEC cells and IMR90 cells, and in cultured MEF cells from Ercc1-/- mice as measured by SA-ß-gal activity. Fisetin induced apoptosis in HUVEC senescent cells but did not affect proliferating cells, and in MEF cells there was no evidence of cell killing despite lower senescent cell levels. Thus, fisetin appears to selectively target senescent cells without affecting healthy cells. Fisetin was administered to human adipose tissue and resulted in a significant reduction in senescent cell marker SA-ß-gal and in SASP factors IL-6, IL-8, and MCP-1, suggesting the benefits of fisetin should translate to humans.
In Vivo: Fisetin, supplemented at a dosage of 500mg/kg/day intermittently in food to Ercc1−/∆ (progeroid) mice, led to significant decreases in levels of senescence markers p16Ink4a and p21Cip1, and in SASP markers compared to controls. It reduced these levels in fat, spleen, liver, kidneys, and peripheral blood CD3+ cells. Senescent cells were either cleared or senescence was reversed, because senescence levels stayed low in a month-long break from fisetin supplementation. Thus, fisetin does not need to be taken chronically to suppress senescence. Fisetin also showed antioxidant activity in liver cells. A short course of fisetin was given to elderly naturally aged mice, and it reduced markers of senescence and SASP in mesenchymal stem/progenitor, immune, and endothelial cells. It also significantly improved tissue homeostasis, extended both median and max healthspan (reduced age-related pathologies) and lifespan. Oxidative stress in the liver was also reduced.
| Yousefzadeh et al., 2018 |
Mice [progeroid model (Zmpste24-/-)] | Vivo | Weekly dosing of fisetin for weeks starting at 3 months of age (middle-age for Z24−/− mice) significantly attenuated bone density loss in Z24−/− mice as evidenced by micro-CT analysis. | Hambright et al., 2020 |
Mice [utrophin−/−mdx mice] | In Vitro & Vivo | Mouse models of muscular dystrophy, in which there is development of high levels of stem cell exhaustion, immune cell infiltration (which drives inflammation), and cellular senescence, were treated with fisetin. Fisetin treatment effectively reduced levels of senescent macrophages both in vitro and in vivo, and this resulted in improved numbers of stem cells and muscle phenoytypes. | Liu et al., 2022 |
Fisetin Mechanism:
The above diagram depicting pathways that Fisetin acts upon was made by the Clock Foundation and is based on research cited below. Fisetin has been shown to selectively target certain types of senescent cells (poorly functioning cells that can no longer reproduce and accumulate with aging for several reasons) and appears to not affect healthy cells. Aging Pathways affected by fisetin include:
Inhibits the PI3K/AKT/mTOR pathway, causing death of senescent cells via apoptosis and reducing senescence associated secretory phenotype (SASP), which is a known cause of increased levels of inflammation with age[2]
Reduces markers of senescence SA-ß-gal, p16Ink4a and p21Cip1[2]
Has anti-tumor/cancer activity by inhibiting topoisomerase[2] and inhibiting matrix metalloproteinases (MMPs)[5]
Increases hSIRT1 activity, a known longevity gene, which inhibits senescence[2]
Inhibits pro-inflammatory cytokine activity (TNFα, IL-6, IL-8, MCP-1, and NF-κB)[2]
Neutralizes reactive oxygen species and other free radicals, and has been shown to upregulate synthesis of glutathione, an antioxidant[2].
Reduction of senescent cell burden may underlie fisetin’s anti-inflammatory, anti-hyperlipidemic (prevents fat accumulation in blood), anti-hyperglycemic (prevents high blood sugar), and neurotrophic and neuroprotective effects[2]
Are there known safety concerns?
No known safety data for humans, but no reported adverse effects from supplements.
There is no evidence of short or long term toxicity in mice. A mouse study found no acute toxicity of fisetin when mice were fed at doses up to 2 g/kg, and no long-term toxicity (9 months) when supplemented in food at 25mg/kg.
Literature Cited:
1. Khan, N., Syed, D. N., Ahmad, N., & Mukhtar, H. (2013). Fisetin: A Dietary Antioxidant for Health Promotion. Antioxidants & Redox Signaling, 19(2), 151–162. https://doi.org/10.1089/ars.2012.4901
2. 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., … 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
3. Maher, P. (2015). How fisetin reduces the impact of age and disease on CNS function. Frontiers in Bioscience (Scholar Edition), 7(1), 58–82. https://doi.org/10.2741/S425
4. Modulation of p25 and inflammatory pathways by fisetin maintains cognitive function in Alzheimer’s disease transgenic mice—PMC. (n.d.). Retrieved April 1, 2022, from https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3954948/
5. Park, J. H., Jang, Y.-J., Choi, Y. J., Jang, J. W., Kim, J.-H., Rho, Y.-K., Kim, I. J., Kim, H.-J., Leem, M. J., & Lee, S.-T. (2013). Fisetin inhibits matrix metalloproteinases and reduces tumor cell invasiveness and endothelial cell tube formation. Nutrition and Cancer, 65(8), 1192–1199. https://doi.org/10.1080/01635581.2013.828090
