Fisetin—a new senolytic

Senolytic drugs have been the most promising near-term anti-aging therapy since the ground-breaking paper by van Deursen of Mayo Clinic published in 2011.  The body accumulates senescent cells as we age, damaged cells that send out signal molecules that in turn modify our biochemistry in a toxic, pro-inflammatory direction.  Though the number of such cells is small, the damage they do is great. Van Deursen showed that just getting rid of these cells could increase lifespan of mice by ~25%. But he did it with a trick, using genetically engineered mice in which the senescent cells had a built-in self-destruct switch.  

After that, the race was on to find chemical agents that would do the same thing without the genetically engineered self-destruct.  They must selectively kill senescent cells, while leaving all other cells unharmed. It’s a tall order, because even a little residual toxicity to normal cells can be quite damaging.  Before last week, the two best candidates were FOXO4-DRI and a combination of quercetin with dasatinib.


I’ve written in the past (here and here) that senolytic drugs are our best prospect for a near-term lift on the road to anti-aging medicine.  

Last week, a large research group affiliated with the original May Clinic team published findings about fisetin, the latest and greatest candidate for a senolitic pill, another flavenoid, very close in structure to quercetin. 

They grew senescent and normal cells in a test tube, then tested 11 different plant-derived chemicals for power to kill the one while leaving the other unharmed.  The winner was fisetin.

(MEF stands for Mouse Embryonic Fybroblast, the cells that were cultured in the screening experiment.)

Fisetin is especially interesting because it is cheap, easily available, widely-regarded as safe, but not nearly as well studied as quercetin.

They took the winner, fisetin, and subjected it to a series of tests.  They began with in vitro (cell culture) tests and proceeded to in vivo tests with live animals, culminating with an impressive life span assay in mice.

(The runner-up was curcumin, less interesting perhaps only because it has already been extensively studied.  The curcumin molecule is unrelated to quercetin or fisetin, and is not a flavenoid. I can’t help but wonder if they had subjected curcumin to the same thorough testing that they reserved for fisetin, how would curcumin have fared?)

curcumin

 

The paper’s principal findings were:

  • Fisetin has lower liver toxicity (at equivalent doses for senolytic benefit) than any of the other senolytics tested so far.
  • Fisetin reduces pro-inflammatory signaling in a short course given to mice and in long-term experiments where fisetin was added to the mouse chow.
  • Fisetin reduces number of senescent fat cells in a short course given to mice.
  • Mice fed fisetin for long periods had much more glutathione than control mice.  (Glutathione is one of very few marker molecules that seems to be wholly beneficial.)
  • Most impressively, mice fed fisetin late in life lived 10-15% longer than control mice. This represents a 50% increase in the remaining lifespan after the intervention.


What we know and what we’d really like to know

We’d like to know, do humans who take large doses of fisetin live longer?  Do they have toxic side-effects? These questions require decades to answer.

Does fisetin reduce age markers in humans, especially methylation age?  This is a feasible study, since the test is mature and safety of fisetin is fairly well established for short courses.  Perhaps this experiment is being considered; I’ve written to the corresponding authors of the most recent study, in case they haven’t already thought of it.  This test would not be definitive because we know that methylation age is not perfectly correlated with biological age; but if positive it would confirm both that fisetin is accomplishing epigenetic rejuvenation and that methylation tests were correctly informing us of this; a negative result would be ambiguous.

Episodic Dosing

It makes sense that senolytics should be taken periodically, not continuously.  A high dose can be toxic to existing senescent cells, and then getting out of the way, it can allow normal cells to recover from any damage.  This sounds like good theory, but different dosing regimens have not been tested experimentally. In fact, the new paper reports positive results from both high episodic dosing and lower everyday dosing.

The Mayo group had previously tested fisetin, and found it effective in killing some kinds of human senescent cells but not others.  In previous tests, fisetin was found to be effective in senescent fat cells (pre-adipocyte, white adipose tissue), and that is where it was primarily tested in the new studies.  

Authors’ comments

They note that the episodic treatment and short half-life suggest that the benefits of fisetin come from its senolytic action, rather than other actions as an antioxidant and signal molecule.  They emphasize that clearing senescent white blood cells and making room for new, active white blood cells are activities that enhance the benefits of fisetin, since white blood cells contribute to clearing the remaining senescent cells.  

Fisetin has previously been shown to have anti-cancer activity and to inhibit inflammatory signals directly.  Here is a review of benefits of fisetin from three years ago.  Drugage lists just two previous lifespan studies with fisetin, with encouraging results from yeast and fruitflies.

The Bottom Line

If we choose to take fisetin at this stage in the science, we are early adopters, and our main concern ought to be safety.  There is little doubt that killing senescent cells will be beneficial. But what is the toxic burden of fisetin, and what dosage can we safely take without risk of damage to normal cells?  The current study covers a lot of ground but doesn’t answer this question, apparently because they are convinced that fisetin is quite safe.

Strawberries, apples, grapes, and onions all contain fisetin, but at low levels compared to a senolytic dose.  For example, the highest food concentration, 160 ppm, is found in strawberries.  A half pound of strawberries yields 36 mg of fisetin.  We’re still guessing at the therapeutic dose, based on mouse studies, and the experimental dosage in human trials is about 1,000 to 1,500 mg (based on this clinical trial), the content to 30-40 pounds of strawberries on each of two consecutive days.

In the best cases, fisetin was shown to reduce senescent cell burden by 50% and up to 75% in cell cultures.  This is a good start, and encourages us to think we can do better by combining fisetin with other agents, or perhaps with fasting.


Also reported today,

Clearing Senescent Cells From The Brain In Mice Preserves Cognition

It sounds impressive, but I’m not impressed.  First, mouse models of Alzheimer’s have been discredited repeatedly.  Mice don’t naturally get AD, so they have to be genetically engineered to do so, and the genetically modified mice don’t share the deep causes of human AD.  Time and again, treatments have been found effective in the mouse model that fail to translate to humans. Second, the treatment used in the study to kill senescent brain cells also relied on another genetic modification, and would not be applicable to humans.  

My guess is that effective senolytic agents for humans will be available within a few years, and that they will decrease risk of all age-related disease, including Alzheimer’s.  But this study does little to advance us toward that goal.

49 thoughts on “Fisetin—a new senolytic

    • Thank you once again for sharing the news, Josh! I’m thinking that another thought in considering episodic rather than everyday dosing of fisetin (or many other supplements) is the former protocol’s greater potential to diminish a homeostatic response, which may in turn diminish these supplements’ effectiveness. Any other thoughts on this?

    • Neurons don’t divide, so they don’t go senescent from short telomere length… but senescent cells don’t perform their normal functions correctly anyway. The senescent fibroblasts that I nursed along for a couple of years blew up to 10X the right size… and they spew pro-inflammatory chemicals.

    • You know, they need to sell everything.
      It’s more like you will die sooner.I have found a great excellent senolytic in Russia
      Emoxypine (2-ethyl-6-methyl-3-hydroxypyridine), also known as Mexidol

  1. In case my last post failed because of containing a link. Good coverage of fisetin. Perhaps another ‘natural senolytic’ is piperlongumine (from Indian long pepper). An article on Pubmed describes one mechanism — title is “Oxidation resistance 1 is a novel senolytic target.”

      • You should google before you giggle!
        Melatonin is better than a senolytic ..it rescues cells from senescence.

        Melatonin reverses H2O2-induced premature senescence in …
        http://www.ncbi.nlm.nih.gov › Journal List › HHS Author

        Melatonin suppresses doxorubicin-induced premature …
        https://www.ncbi.nlm.nih.gov/pubmed/22536785
        Together, these results reveal that melatonin has an inhibitory effect of melatonin on premature senescence at the cellular level and that melatonin protects A549 cells from DOX-induced senescence. Thus, melatonin might have the therapeutic potential to prevent the side effects of …

        Melatonin reverses H2O2‐induced premature senescence in …
        onlinelibrary.wiley.com/doi/10.1111/jpi.12250/abstract

        Journal of Pineal Research · 2015

        Melatonin Rescues Mesenchymal Stem Cells from Senescence …
        http://www.biomolther.org/journal/view.html?volume=26&number=4&spage=389&...

        Melatonin reverses H2O2-induced senescence in SH-SY5Y …
        onlinelibrary.wiley.com/doi/10.1111/jpi.12407/abstract
        SH-SY5Y cells were treated with H 2 O 2 to induce the senescent state.

        Melatonin regulates PARP1 to control the senescence …
        https://reference.medscape.com/medline/abstract/2824753

    • in fact it dioes it rescues senescent cells and makes them normal try googling it it iis not that difficult just type in the words and hit the search button

        • Jeff – you provide excellent information and I enjoy reading your posts.
          Thank you for the contribution – I was only joking about your vast over-simplification of Bredesen’s supplement/protocol anti-alzheimer’s regimen (55 items listed) as possibly down to just 1 supplement: melatonin (which is obviously ridiculous).
          I think melatonin is beneficial but certainly not the panacea you make it out to be; but if it helps you sell books, carry on.

  2. Fascinating stuff, and something one can easily do at home.

    I noticed an interesting exclusion criterion in Dr. Kirkland’s clinical trial, i.e. the concomitant use of proton pump inhibitors. I assume that has to do with the ability of these drugs to inhibit the ABC transporters and increase absorption of polyphenols as described in this interesting paper: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2820202/. I suppose that the extent of the effect is imprecisely known thus far, and would therefore muddy the results. Still, this has the potential to facilitate entry of polyphenols to various tissues, such as the brain, so that more types of senescent cells could potentially be targeted. I hope to encounter more research on this. Does anyone know of any, or have thoughts on the matter?

    The second is the

  3. Josh, regarding your idea of testing epigenetic age changes from a senolytic therapy – I think the result would depend on the tissue type. If the cleared cells were then replaced by differentiation from epigenetically younger stem cells then you would expect a positive result. But in some cases cells are turned over very rapidly anyway, and I’m that case I expect an ambiguous result.

    Didn’t they show epigenetic age reversal for allogenic stem cell transplant patients?

  4. My major concern about Fisetin is that it acts as a topoisomerase 1 and 2 inhibitor. Various chemotherapy drugs also work via this mechanism and have to found to damage chromosomes and may lead to leukemia, in particular AML.
    https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3961513/

    It has also been recently demonstrated that this same mechanism may lead to the tendon ruptures seen with certain antibiotics in the fluoroquinolone class.

    The inhibition of topoisomerase 1and 2 is a real concern with Fisetin, especially at high doses.

    • Paul, this is very interesting. I had no idea fisetin had these powerful properties. As for topoisomerase 2 inhibitors like fluoroquinolones, they should not exert a negative effect on human cell lines (at least in theory), because the affected bacterial enzymes have little homology with mammalian DNA gyrase. The tendon rupture issue remains elusive, but the underlying cause seems to be related to fluoroquinolones toxicity to type 1 collagen.

      • Cipro impairs mitochondrial energy production and blocks cellular differentiation most likely leading to most of its side effects including tens rupture. This is most likely due to topoisomerase 2 inhibition. Normal doses of Fisetin are of no concern, but the very high dosing may well be a problem. https://www.sciencedaily.com/releases/2018/10/181001101943.htm

        Not to mention the association of topoisomerase 1 and 2 inhibition with the development of AML.

        Fisetin may be perfectly safe at any dose. We’ll see. But I’m going to wait until we know more.

    • Paul, EGCG and reseveratrol, which many on this site supplement with, is also on the list. I suppose a daily cup of green tea should still be ok?

    • Thanks for the heads up, Paul. So now I’m thinking we should wait for the results of the clinical trials before we start messing around with fisetin.

      On the other hand, I’m not a very patient person, and, at 52, I’m starting to feel the effects of all these goddamned senescent rabble-rousing freeloaders in all my tissues, so I’ll happily spend some energy trying to find a cheat. Some questions that come to mind:

      1) What are the plasma levels at which fisetin has significant senolytic activity, and how do these compare with the levels that mess with topoisomerase?

      2) Are the deleterious effects of topoisomerase inhibition limited to rapidly proliferating cells and, if so, what happens to the proliferation rates of these cell types during a fast? Might we be able to mitigate the consequences by taking fisetin during a fast? (I know that leukocytes multiply quickly on refeeding _after_ a fast (see V. Longo), so presumably that would be a bad time to use fisetin.)

      3) Would a combination of fisetin and curcumin synergize to produce useful senolytic effects while keeping fisetin concentrations low enough to be safe?

      4) Why is it always so goddamned complicated? Where’s my free lunch, dammit?

  5. Hi Josh, everyone,

    Cellular senescence can be terminated via two distinct methods. one by causing the cell to undergo apoptosis and the other is to regress or resque the cell from senescence by reverting or restoring the health of the cell back to a fully functional cell. I am not sure the researchers have said which mechanism or both are at play here?

    I find it interesting that fisetin as researched by Salk institute over the last 10 years is a powerful antioxidant that increases glutathione levels over time. Also they have shown fisetin to have anticancer and antidiabetic effects.

    The question is does fisetins antioxidant effects cause senescent cells to be rescued from senescence to the point that they become apoptosis-competent and then eliminate themselves? Or does the antioxidant effects of fisetin even go further with some senescent cell and allow the cell to repair itself enough to become fully functioning again and not undergo apoptosis?

    Does fisetin sort of resurrect the ( now considered dead ) free radical theory of aging?

    Any thoughts?

    Kevin Brown

  6. Curcumin the other very effective senolytic affects topo 1 and 2 as well….
    Curcumin Induces High Levels of Topoisomerase I− and II−DNA Complexes in K562 Leukemia Cells
    Miguel López-Lázaro†‡, Elaine Willmore†§, Andrew Jobson†⊥, Kathryn L. Gilroy†, Hannah Curtis†, Kay Padget†, and Caroline A. Austin*†
    Institute for Cell and Molecular Biosciences, The Medical School, Newcastle University, Newcastle-upon-Tyne, NE2 4HH, United Kingdom, Department of Pharmacology, Faculty of Pharmacy, University of Seville, 41011, Seville, Spain, Northern Institute for Cancer Research, The Medical School, Newcastle University, Newcastle-upon-Tyne, NE2 4HH, United Kingdom, and Laboratory of Molecular Pharmacology, Centre for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892
    J. Nat. Prod., 2007, 70 (12), pp 1884–1888
    DOI: 10.1021/np070332i
    Publication Date (Web): December 13, 2007
    Copyright © 2007 The American Chemical Society and American Society of Pharmacognosy
    * To whom correspondence should be addressed. Tel: +44 191 222 8864 . Fax: +44 191 222 7424. E-mail: [email protected]., † Institute for Cell and Molecular Biosciences, University of Newcastle., ‡ University of Seville., § Northern Institute for Cancer Research, University of Newcastle., ⊥ National Cancer Institute, Bethesda, MD.
    Cite this:J. Nat. Prod. 2007, 70, 12, 1884-1888

    Abstract
    Abstract Image
    Recent data suggest that curcumin, a phytochemical with cancer chemopreventive potential, might be useful in the treatment of several solid and hematological malignancies. DNA topoisomerases (topos) are the target of several drugs commonly used in cancer chemotherapy. These drugs induce topo−DNA complexes with either topo I or topo II; then cellular processing converts these complexes into permanent DNA strand breaks that trigger cell death. Using the TARDIS in vivo assay, this study shows for the first time that curcumin induces topo I and topo II (α and β)−DNA complexes in K562 leukemia cells. A comparative analysis revealed that the levels of these complexes were higher than those induced by several standard topo I and topo II inhibitors at equitoxic doses. Curcumin-induced topo I and topo II−DNA complexes were prevented by the antioxidant N-acetylcysteine; this suggests that, unlike the standard topo inhibitors, reactive oxygen species may mediate the formation of these complexes. Overall, this work shows that curcumin is capable of inducing topo−DNA complexes in cells with both topo I and topo II and increases the evidence suggesting that this dietary agent has potential to be tested in cancer
    chemotherapy

    and another one

    Antagonism between curcumin and the topoisomerase II inhibitor etoposide
    A study of DNA damage, cell cycle regulation and death pathways
    Ekram M. Saleh, 1 , † * Raafat A El-awady, 2 , 3 , † Nadia A. Eissa, 4 and Wael M. Abdel-Rahman 5
    Author information Copyright and License information Disclaimer
    This article has been cited by other articles in PMC.
    Go to:
    Abstract
    The use of combinations of chemotherapy and natural products has recently emerged as a new method of cancer therapy, relying on the capacity of certain natural compounds to trigger cell death with low doses of chemotherapeutic agents and few side effects. The current study aims to evaluate the modulatory effects of curcumin (CUR), Nigella sativa (NS) and taurine on etoposide (ETP) cytotoxicity in a panel of cancer cell lines and to identify their underlying mechanisms.

    CUR alone showed potent antitumor activity, but surprisingly, its interaction with ETP was antagonistic in four out of five cancer cell lines. Neither taurine nor Nigella sativa affect the sensitivity of cancer cells to ETP. Examination of the DNA damage response machinery (DDR) showed that both ETP and CUR elicited DNA double-strand breaks (DSB) and evoked γ-H2AX foci formation at doses as low as 1 µg/ml. Cell cycle analysis revealed S phase arrest after ETP or CUR application, whereas co-treatment with ETP and CUR led to increased arrest of the cell cycle in S phase (MCF-7 cells) or the accumulation of cells in G2/M phases (HCT116, and HeLa cells). Furthermore, cotreatment with ETP and CUR resulted in modulation of the level of DNA damage induction and repair compared with either agent alone. Electron microscopic examination demonstrated that different modalities of cell death occurred with each treatment. CUR alone induced autophagy, apoptosis and necrosis, whereas ETP alone or in combination with CUR led to apoptosis and necrosis.

    Conclusions: Cotreatment with ETP and CUR resulted in an antagonistic interaction. This antagonism is related, in part, to the enhanced arrest of tumor cells in both S and G2/M phases, which prevents the cells from entering M-phase with damaged DNA and, consequently, prevents cell death from occurring. This arrest allows time for the cells to repair DNA damage so that cell cycle -arrested cells can eventually resume cell cycle progression and continue their physiological program.

  7. I did a pub med search for reverses and senescence in the title and got thes 18 results>>>
    Acquired resistance to BRAFi reverses senescence-like phenotype in mutant BRAF melanoma.

    Krayem M, Najem A, Journe F, Morandini R, Sales F, Awada A, Ghanem GE.

    Oncotarget. 2018 Aug 7;9(61):31888-31903. doi: 10.18632/oncotarget.25879. eCollection 2018 Aug 7.

    PMID: 30159130 Free PMC Article
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    2.
    Effects of Oleo Gum Resin of Ferula assa-foetida L. on Senescence in Human Dermal Fibroblasts: – Asafoetida reverses senescence in fibroblasts.

    Moghadam FH, Mesbah-Ardakani M, Nasr-Esfahani MH.

    J Pharmacopuncture. 2017 Sep;20(3):213-219. doi: 10.3831/KPI.2017.20.025. Epub 2017 Jul 30.

    PMID: 30087798 Free PMC Article
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    Chemical constituents of Asafoetida | Essential Oil
    ayurvedicoils.com/tag/chemical-constituents-of-asafoetida
    Asafoetida was the most prevalent folk remedy for treating flatulence, colic and cold in children and as a contraceptive medicine. The Arabian pharmacists and scientists like Avicenna, Fakhr al-Din al-Razi and Ibn al-Baitar have talked about the positive effects of Asafoetida on …
    Select item 29803744
    3.
    SIRT1 reverses senescence via enhancing autophagy and attenuates oxidative stress-induced apoptosis through promoting p53 degradation.

    Liu T, Ma X, Ouyang T, Chen H, Lin J, Liu J, Xiao Y, Yu J, Huang Y.

    Int J Biol Macromol. 2018 Oct 1;117:225-234. doi: 10.1016/j.ijbiomac.2018.05.174. Epub 2018 May 24.

    PMID: 29803744
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    Select item 28774385
    4.
    Telomerase mRNA Reverses Senescence in Progeria Cells.

    Li Y, Zhou G, Bruno IG, Cooke JP.

    J Am Coll Cardiol. 2017 Aug 8;70(6):804-805. doi: 10.1016/j.jacc.2017.06.017. No abstract available.

    PMID: 28774385 Free Article
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    Select item 28479002
    5.
    Inhibition of Bcl-2/xl With ABT-263 Selectively Kills Senescent Type II Pneumocytes and Reverses Persistent Pulmonary Fibrosis Induced by Ionizing Radiation in Mice.

    Pan J, Li D, Xu Y, Zhang J, Wang Y, Chen M, Lin S, Huang L, Chung EJ, Citrin DE, Wang Y, Hauer-Jensen M, Zhou D, Meng A.

    Int J Radiat Oncol Biol Phys. 2017 Oct 1;99(2):353-361. doi: 10.1016/j.ijrobp.2017.02.216. Epub 2017 Mar 4.

    PMID: 28479002
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    Select item 28295567
    6.
    Melatonin reverses H2 O2 -induced senescence in SH-SY5Y cells by enhancing autophagy via sirtuin 1 deacetylation of the RelA/p65 subunit of NF-κB.

    Nopparat C, Sinjanakhom P, Govitrapong P.

    J Pineal Res. 2017 Aug;63(1). doi: 10.1111/jpi.12407. Epub 2017 Apr 12.

    PMID: 28295567
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    Select item 27660040
    7.
    Dietary rapamycin supplementation reverses age-related vascular dysfunction and oxidative stress, while modulating nutrient-sensing, cell cycle, and senescence pathways.

    Lesniewski LA, Seals DR, Walker AE, Henson GD, Blimline MW, Trott DW, Bosshardt GC, LaRocca TJ, Lawson BR, Zigler MC, Donato AJ.

    Aging Cell. 2017 Feb;16(1):17-26. doi: 10.1111/acel.12524. Epub 2016 Sep 22.

    PMID: 27660040 Free PMC Article
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    Select item 27350449
    8.
    NANOG Reverses the Myogenic Differentiation Potential of Senescent Stem Cells by Restoring ACTIN Filamentous Organization and SRF-Dependent Gene Expression.

    Mistriotis P, Bajpai VK, Wang X, Rong N, Shahini A, Asmani M, Liang MS, Wang J, Lei P, Liu S, Zhao R, Andreadis ST.

    Stem Cells. 2017 Jan;35(1):207-221. doi: 10.1002/stem.2452. Epub 2016 Jul 11.

    PMID: 27350449 Free Article
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    Select item 27048648
    9.
    Rapamycin reverses the senescent phenotype and improves immunoregulation of mesenchymal stem cells from MRL/lpr mice and systemic lupus erythematosus patients through inhibition of the mTOR signaling pathway.

    Gu Z, Tan W, Ji J, Feng G, Meng Y, Da Z, Guo G, Xia Y, Zhu X, Shi G, Cheng C.

    Aging (Albany NY). 2016 May;8(5):1102-14. doi: 10.18632/aging.100925.

    PMID: 27048648 Free PMC Article
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    Select item 25975679
    10.
    Melatonin reverses H2 O2 -induced premature senescence in mesenchymal stem cells via the SIRT1-dependent pathway.

    Zhou L, Chen X, Liu T, Gong Y, Chen S, Pan G, Cui W, Luo ZP, Pei M, Yang H, He F.

    J Pineal Res. 2015 Sep;59(2):190-205. doi: 10.1111/jpi.12250. Epub 2015 Jul 7.

    PMID: 25975679 Free PMC Article
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    Select item 25725291
    11.
    Downregulation of PEA-15 reverses G1 arrest, and nuclear and chromatin changes of senescence phenotype via pErk1/2 translocation to nuclei.

    Lee YY, Kim HS, Lim IK.

    Cell Signal. 2015 Jun;27(6):1102-9. doi: 10.1016/j.cellsig.2015.02.014. Epub 2015 Feb 26.

    PMID: 25725291
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    Select item 23777706
    12.
    Antisense directed against PS-1 gene decreases brain oxidative markers in aged senescence accelerated mice (SAMP8) and reverses learning and memory impairment: a proteomics study.

    Fiorini A, Sultana R, Förster S, Perluigi M, Cenini G, Cini C, Cai J, Klein JB, Farr SA, Niehoff ML, Morley JE, Kumar VB, Butterfield DA.

    Free Radic Biol Med. 2013 Dec;65:1-14. doi: 10.1016/j.freeradbiomed.2013.06.017. Epub 2013 Jun 15.

    PMID: 23777706 Free PMC Article
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    Select item 23518600
    13.
    Repairing DNA damage by XRCC6/KU70 reverses TLR4-deficiency-worsened HCC development via restoring senescence and autophagic flux.

    Wang Z, Lin H, Hua F, Hu ZW.

    Autophagy. 2013 Jun 1;9(6):925-7. doi: 10.4161/auto.24229. Epub 2013 Mar 21.

    PMID: 23518600 Free PMC Article
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    Select item 22030897
    14.
    Ginsenoside Rb1 reverses H2O2-induced senescence in human umbilical endothelial cells: involvement of eNOS pathway.

    Liu DH, Chen YM, Liu Y, Hao BS, Zhou B, Wu L, Wang M, Chen L, Wu WK, Qian XX.

    J Cardiovasc Pharmacol. 2012 Mar;59(3):222-30. doi: 10.1097/FJC.0b013e31823c1d34.

    PMID: 22030897
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    Select item 20351343
    15.
    Relaxin therapy reverses large artery remodeling and improves arterial compliance in senescent spontaneously hypertensive rats.

    Xu Q, Chakravorty A, Bathgate RA, Dart AM, Du XJ.

    Hypertension. 2010 May;55(5):1260-6. doi: 10.1161/HYPERTENSIONAHA.109.149369. Epub 2010 Mar 29.

    PMID: 20351343
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    Select item 18202313
    16.
    Activation of cardiac progenitor cells reverses the failing heart senescent phenotype and prolongs lifespan.

    Gonzalez A, Rota M, Nurzynska D, Misao Y, Tillmanns J, Ojaimi C, Padin-Iruegas ME, Müller P, Esposito G, Bearzi C, Vitale S, Dawn B, Sanganalmath SK, Baker M, Hintze TH, Bolli R, Urbanek K, Hosoda T, Anversa P, Kajstura J, Leri A.

    Circ Res. 2008 Mar 14;102(5):597-606. doi: 10.1161/CIRCRESAHA.107.165464. Epub 2008 Jan 17.

    PMID: 18202313
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    Select item 15165184
    17.
    Senescence-induced expression of cytokinin reverses pistil abortion during maize flower development.

    Young TE, Geisler-Lee J, Gallie DR.

    Plant J. 2004 Jun;38(6):910-22. Erratum in: Plant J. 2014 Apr;78(2):357. Giesler-Lee, Jane [corrected to Geisler-Lee, Jane].

    PMID: 15165184 Free Article
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    Select item 1504830
    18.
    Testosterone reverses a senescent decline in extrahypothalamic vasopressin mRNA.

    Dobie DJ, Miller MA, Raskind MA, Dorsa DM.

    Brain Res. 1992 Jun 26;583(1-2):247-52.

    PMID: 1504830
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  8. I pattern my week with a 4 day protein fasting period followed by a protein feasting period. I try to time my workouts and supplements around this pattern, but I’m still in the process of figuring it out. My 2 strength training weekly workouts bookend each transition, with a HIIT workout during the protein fast. I also plan on a complete fast maybe once a quarter, but have only managed to complete one about 8 months ago. Planning is easy, doing not so much as life happens. My general supplement pattern would be to only take flavonoids and antioxidants on non-workout days or before ed after a workout, and senolytics could be during the complete fasts and possibly during some of the protein fasts. Don’t want too much too often. Maybe once a month?

  9. ok I looked through all 320+ pub med entries that have the word fisetin in the title and cannot present all 141 of them that i saved so ill sned you a truncated list of …just the titles after this brief note….
    Fisetin sounds like a wonder drug! it activites Sirt1 , it is a potent antiinflammatory, it protects all sorts of normal cells, it causes all kinds of cancer cells to self destruct…it is an AMPK pathway regulator, it is antidiabetic, anti depressant , it protects tisxsues against various kinds if injury, it is an antifungal, it prevents amyloid bujild up, it helps to treat parkinsons and als…and its activities are enhanced in conjunciton with mealtonin!>>>
    Selected items
    Items: 141
    Select item 12107653
    1.
    Wogonin and fisetin induction of apoptosis through activation of caspase 3 cascade and alternative expression of p21 protein in hepatocellular carcinoma cells SK-HEP-1.

    Chen YC, Shen SC, Lee WR, Lin HY, Ko CH, Shih CM, Yang LL.

    Arch Toxicol. 2002 Jun;76(5-6):351-9. Epub 2002 Apr 23.

    PMID: 12107653
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    Select item 12789233
    2.
    Fisetin, a flavonol, inhibits TH2-type cytokine production by activated human basophils.

    Higa S, Hirano T, Kotani M, Matsumoto M, Fujita A, Suemura M, Kawase I, Tanaka T.

    J Allergy Clin Immunol. 2003 Jun;111(6):1299-306.

    PMID: 12789233
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    Select item 15153793
    3.
    Flavonoids such as luteolin, fisetin and apigenin are inhibitors of interleukin-4 and interleukin-13 production by activated human basophils.

    Hirano T, Higa S, Arimitsu J, Naka T, Shima Y, Ohshima S, Fujimoto M, Yamadori T, Kawase I, Tanaka T.

    Int Arch Allergy Immunol. 2004 Jun;134(2):135-40. Epub 2004 May 17.

    PMID: 15153793
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    4.
    Chromosomal malsegregation and micronucleus induction in vitro by the DNA topoisomerase II inhibitor fisetin.

    Olaharski AJ, Mondrala ST, Eastmond DA.

    Mutat Res. 2005 Apr 4;582(1-2):79-86.

    PMID: 15781213
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    Neuroprotective properties of the natural phenolic antioxidants curcumin and naringenin but not quercetin and fisetin in a 6-OHDA model of Parkinson’s disease.

    Zbarsky V, Datla KP, Parkar S, Rai DK, Aruoma OI, Dexter DT.

    Free Radic Res. 2005 Oct;39(10):1119-25.

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    Fisetin inhibits the activities of cyclin-dependent kinases leading to cell cycle arrest in HT-29 human colon cancer cells.

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    J Nutr. 2005 Dec;135(12):2884-90.

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    Flavonoid fisetin promotes ERK-dependent long-term potentiation and enhances memory.

    Maher P, Akaishi T, Abe K.

    Proc Natl Acad Sci U S A. 2006 Oct 31;103(44):16568-73. Epub 2006 Oct 18.

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    Anti-inflammatory activity of fisetin in human mast cells (HMC-1).

    Park HH, Lee S, Oh JM, Lee MS, Yoon KH, Park BH, Kim JW, Song H, Kim SH.

    Pharmacol Res. 2007 Jan;55(1):31-7. Epub 2006 Oct 10.

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    Fisetin, an inhibitor of cyclin-dependent kinase 6, down-regulates nuclear factor-kappaB-regulated cell proliferation, antiapoptotic and metastatic gene products through the suppression of TAK-1 and receptor-interacting protein-regulated IkappaBalpha kinase activation.

    Sung B, Pandey MK, Aggarwal BB.

    Mol Pharmacol. 2007 Jun;71(6):1703-14. Epub 2007 Mar 26. Erratum in: Mol Pharmacol. 2012 Jun;81(6):856.

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    Suppressive effects of flavonoid fisetin on lipopolysaccharide-induced microglial activation and neurotoxicity.

    Zheng LT, Ock J, Kwon BM, Suk K.

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    Fisetin, a novel dietary flavonoid, causes apoptosis and cell cycle arrest in human prostate cancer LNCaP cells.

    Khan N, Afaq F, Syed DN, Mukhtar H.

    Carcinogenesis. 2008 May;29(5):1049-56. doi: 10.1093/carcin/bgn078. Epub 2008 Mar 20.

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    The flavonoid fisetin promotes nerve cell survival from trophic factor withdrawal by enhancement of proteasome activity.

    Maher P.

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    Structural requirements for the flavonoid fisetin in inhibiting fibril formation of amyloid beta protein.

    Akaishi T, Morimoto T, Shibao M, Watanabe S, Sakai-Kato K, Utsunomiya-Tate N, Abe K.

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    A novel dietary flavonoid fisetin inhibits androgen receptor signaling and tumor growth in athymic nude mice.

    Khan N, Asim M, Afaq F, Abu Zaid M, Mukhtar H.

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    The flavonoid, fisetin, inhibits UV radiation-induced oxidative stress and the activation of NF-kappaB and MAPK signaling in human lens epithelial cells.

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    21.
    The hydroxyflavone, fisetin, suppresses mast cell activation induced by interaction with activated T cell membranes.

    • That’s all interesting but there is nothing there to convince me that a very large dose of Fisetin is safe in humans.

    • Hi Jeff,

      Do you agree that many of the effects you listed would be due to its direct or indirect antioxidant effects and not due to it functioning as a signaling agent since mammals do not make it and is not always available in food? Do you agree it seem reasonable that it is its antioxidant effects that is rescuing the senescent cells and either setting them up for apoptosis or for full return to functional competence as I described in my previous reply above?

      It seems that the term “senolytic” leaves out the the removal of senescent cells that are truly rescued and return them to functional competence. Isn’t senescent cell rescue better than senescent cell death much of the time? When cells become senescent due to mitochondrial damage it seems that a powerful antioxidant such as fisetin could allow remaining mitochondria to reproduce/fuse and save the cell or if the percentage of good mitochondria is too small at least get enough of them to a level of competence that they can initiate successful apoptosis? Do you agree with this line of thinking or do you feel that fisetin has some direct ability to distinguish and kill senescent cells while leaving normal cells essentially alone?

      Thanks Jeff,

      • Hi Kevin
        I pub med searched “fisetin and signaling” in the title and came up with one study only….here is the abstract>>>

        Int J Dev Neurosci. 2018 Oct;69:88-96. doi: 10.1016/j.ijdevneu.2018.07.002. Epub 2018 Jul 20.
        Fisetin impedes developmental methylmercury neurotoxicity via downregulating apoptotic signalling pathway and upregulating Rho GTPase signalling pathway in hippocampus of F1 generation rats.
        Jacob S1, Thangarajan S2.
        Author information
        Abstract
        Methyl mercury is a teratogenic and neurodevelopmental toxicant in the environment. MeHg affects several biological pathways critical for brain development. The present study validated the effect of Fisetin on developmental MeHg exposure induced alterations in mitochondrial apoptotic pathway and Rho GTPase mRNA expressions in hippocampus of F1 generation rats. Pregnant Wistar rats were grouped as Group I : administered with vehicle control, Group II: MeHg (1.5 mg/kg b.w), Group III: MeHg + Fisetin (10 mg/kg b.w), Group IV: MeHg + Fisetin (30 mg/kg b.w), Group V: MeHg + Fisetin (50 mg/kg b.w), Group VI: MeHg + Fisetin (70 mg/kg b.w), Group VII: Fisetin (30 mg/kg b.w) alone. Fisetin reduced mercury accumulation in offspring brain. In hippocampus, Fisetin preserved mitochondrial total thiol status, glutathione antioxidant system, mitochondrial metabolic integrity and respiratory chain activity. Fisetin ameliorated apoptotic signals by preventing Cytochrome c release, down regulating ERK 1/2 and Caspase 3 gene expression. Fisetin also upregulated mRNA expressions of RhoA/Rac1/Cdc42 in hippocampus. Predominant effect of Fisetin was to reduce mercury accumulation in offspring brain there by diminishing the toxic effect of MeHg. Hence we showed that, gestational intake of Fisetin (30 mg/kg b.w.) impedes developmental MeHg neurotoxicity by regulating mitochondrial apoptotic and Rho GTPase signalling molecules and by reducing the mercury accumulation in hippocampus of F1 generation rats.

        Here\s one I found with bing>>> Fisetin treatment of preadipocytes reduced the phosphorylation of S6K1 and mTORC1 in a time- and concentration-dependent manner. To further our understanding of how fisetin negatively regulates mTORC1 signaling, we analyzed the phosphorylation of S6K1, mTOR and Akt in fisetin-treated TSC2-knockdown cells.

        Here’s one where it protects bones via signalling>>As expected, the RANKL-activated p38 MAPK and JNKs signaling pathways were inhibited by fisetin in “shControl” cells (shCtrl); p38, JNK and c-jun were less phosphorylated in cells cultured in the presence of fisetin . However, fisetin had a lower inhibitory action in “shMKP-1” cells.

        So the bottom line is somehow fisetin seems to activate pathways that protect good tissues and kills of bad actors like cancer cells It’s chemical structure looks very much like a DNA base pair and /or steroid hormone ..kind of like vitmain d3 And with all the OH’s sticking off of it it obvioudly has a lot of antioxidant potential..So my guess is it is causing good things by both ways acting as an antioxidant and a pseudo hormone that affects signalling

  10. Here is an October 15th article by Dr. Mercola on Fisetin.
    https://articles.mercola.com/sites/articles/archive/2018/10/15/fisetin-health-benefits.aspx

    Also, the wikipedia page on Fisetin shows a great number of sources.
    https://en.wikipedia.org/wiki/Fisetin

    To prevent ageing one needs to choose a healthy lifestyle in their 20s or 30s or whenever possible, encompassing periodic fasting, eating small meals of predominantly raw, superfoods which include Fisetins and other phytonutrients, pre and probiotics, enzymes, minerals, and vitamins; a practice of daily aerobic movement where the heart is working against one’s weight–pushing against gravity (or the grave); meditation; projects that challenge the memory; quality, no stress relationships; and freedom to choose a life that is happy, peaceful, thrives in nature, grateful, vibrant and meaningful.

    Taking a drug such as Fisetin to clear ageing cells to enhance autophagy might help, but is not the answer. The answer is to choose “life” every day, which encompasses the above factors over years, and prevents scrambling for the quick cure later. Unfortunately, most people get caught with too many symptoms, that have been ignored–many of which could have been attended to on the onset with natural therapies. Thus, becoming desperate to be fixed is the norm for a great many of people over 50.

  11. I wonder if these senolytic drugs may synergize with short fasts of 3-5 days? I’m thinking here of Valter Longo’s work on the longevity and health benefits of his 5 day fading mimicking diet. Autophagy, apoptosis and stem cells are all upregulated which may make senescent cells more vulnerable?

    However, I’ve looked through all of Valter Longo’s papers and don’t see any mention of senescent cells.Surprised that he hasn’t looked at that aspect yet!

    • Dear Malcolm L. Klien,

      I am no scientist and no doctor but I am almost 70 and have been coaching people on fasting programs with colonic irrigation for around 25 years; and I have to say I have seen people in their 40s, 50s, 60s, and 70s shed a great number of old cells as well as toxic material. This is not the fasting mimicking diet. This is the real thing–no food at all, just mineral water, coconut water and mineral broth. After 7 days and some 10 or 20 days, those who come with inflammatory health conditions leave feeling and looking vibrantly healthy. Autophagy, apoptosis, mitophagy, lymphophagy, you see it all. And what a miraculous privlege it is!.

      Eliminating senscent cells requires a daily practice, a whole lifestyle, a commitment to eliminate that which contributes to ageing and all that sustains, enhances, uplifts and enlightens your existence. This includes intermittent and periodic fasting and list of other practices–I did mention some of them in my last comment post. . . Hillary

  12. Two points here.

    One is that over the past year research is showing a more complex picture of the role of inflammation and senescence. It is now becoming clear that some degree of inflammation and the SASP is necessary for repair and rejuvention, but obviously not to excess, but the goal is careful intervention with senolytics and I don’t feel that we’re at that point yet. Our knowledge is emerging but still very rudimentary.

    This is also true about toxicity. We do not know that fisetin is safe at very high doses. The quinolone antibiotics are given generally over a short course and are associated with spontaneous tendon ruptures. This is almost certainly due to topoisomerase inhibition.

    I’m not ready to jump in just yet.

    • The thing is, even though the SASP is required for regeneration, the persistance of these cells shows that this regeneration has not occurred, otherwise they would have been replaced with healthy tissue. So I’m not concerned about losing the transient benefits of senescent cells. They are useful and used rather than apoptosis in those situations when a chunk of tissue needs to be arrested and replaced – but this situation should not persist.

      Whether they can be removed safely in the very old is a bigger concern for me. As is the long term effect of forcing your remaining cells to replace them (bringing those cells closer to senescence, on average).

      But as there are clinical trials on fisetin in humans going on RIGHT NOW, most of us can surely afford to wait.

  13. I would recommend you research the iodine protocol. Iodine allows apoptosis to occur. People are taking huge doses (many hundreds of times the RDA) and reporting many benefits. At least Google apoptosis and iodine.

  14. I do 3-4 5 day dry fasts during the year to increase autophagy and get rid of sentient cells, I wonder if taking scenolytics would help this process.
    I also do intermittent fasting and thinking of using senolycs with that as well, anyone have any experience with this?

  15. Senolytics have become one of the most hopeful near-term interventions for aging. Not sure it’s much use to me as I’m only 34 and have been doing CR since I was 18, but great for older people. Although, I’m much more excited about companies like Unity, who are working on more powerful senolytics. After following life extension for over 15 years, things are finally starting to pick up momentum. We just a win or two for aging therapies (like senolytics) and it’ll encourage even more investment.

  16. I’m producing 98% pure Fisetin from a novel botanical source and presently have 20 kilos per month capacity. Planning to scale this to 1,000 kilos per month in one year. Im personally going to take 500 Mgs. once per week.

    Piperlonggumine is much easier due to centuries of use in Ayurveda. I manufactured industrial scale quantities of Phytochemicals for 18 years and have zero concerns about safety. Supply is no problem and I’m taking 300 mgs. of this with the Fisetin while research on dose / efficacy continues.

    Luck and logenvity favor the bold.

  17. Why not take the study dose ( being conducted now) ?
    1200 mg for each of 2 days, repeat 1 month later.
    Do annually.
    Or base it on rat data and do 500 mg, for 5 nights, that’s it.
    To enhance effect, water fast on dosing days.
    Maybe add a dose of Life Extensions new bioavailable Quercetin plus black tea Senolyic product.

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