Monitoring Senescent Cell Clearance with Cytokine Levels

Many of us have been attempting to clear our senescent cells with large senolytic doses of Fisetin and/or Dasatinib plus Quercetin.  There have been many anecdotal reports of "feeling better" or "more energy" or "reduced arthritic pain" following such treatments, but there is always the worry that we are seeing the placebo effect in action.  Some of us have attempted to monitor the results using "blood age" algorithms, but the results have been mixed and rather inconclusive.  What is needed is a semi-quantitative way of determining whether and to what degree our senescent cells are actually being cleared.

SASP (Senescence-Associated Secretory Phenotype) is the acronym for the negative effects of the bad molecules released into local organs and into the bloodstream by senescent cells.  I found a review entitled "SASPects of Radiation Induced Senescence" and a paper entitled "Senescence-Associated Secretory Phenotypes Reveal Cell-Nonautonomous Functions of Oncogenic RAS and the p53 Tumor Suppressor", both of which give lists of these SASP-related bad molecules.  The two most prominent bad actors on these lists are the cytokine molecules Interleukin-6 (IL-6) and Interleukin-8 (IL-8).  Therefore, monitoring the concentrations of these cytokines in the bloodstream should be a good way of monitoring whether and to what degree senescent cells are being cleared by senolytic treatments.

I note that LifeExtension offers an Interleukin-6 (IL-6) test for $75, an Interleukin-8 (IL-8) test for $199, and a Cytokine Panel test that includes Interleukin-1 beta (IL-1β), Interleukin-6 (IL-6), Interleukin-8 (IL-8), and Tumor necrosis factor alpha (TNF-α) for $399.  It seems to me that it would be an excellent idea to do at least the IL-6 test (and perhaps the more expensive ones) before and after taking  large senolytic doses of Fisetin and/or Dasatinib plus Quercetin.  I wish I had done this before my recent senolytic adventures.

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  • I saw today that Unity is adding 24 people to it's phase 1 trial because of the apparent  positive results in clinical 1 trials of UBX0101

    " This expansion is intended to provide supplemental data for the trial, allowing the company’s researchers to analyze the fluid in the knee joints of patients in order to measure the harmful chemicals (known as the SASP) secreted by senescent cells. Low SASP levels in this fluid suggest that the drug was effective in destroying these harmful cells and may be more likely to be successful in future trials."

    I hope to find something long before they will get through FDA but at least it's good that multiple companies are working on the issue.

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      • JGC
      • JGC
      • 3 yrs ago
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      murray 

      This is dismayingly off the topic here, but in my opinion Unity Bio  has distinguished themselves mainly by extracting large contributions from aging billionaires.  Their senescent cell knee treatments have failed in aging subjects, mainly because SASP from untreated senescent cells near the knee has blocked replacement of the senescent knee joint cells that their toxic UBX0101 drug has zapped.

      Like 2
    • JGC  Thank you for the quick reply. I do not know anything about Unity so I appreciate any information such as what you provided. My mother is 86 and still living at home on her own. Because of her age I am hoping to find something that will clear the cells in the next year. I know Bill had mentioned hoping to find a source soon for the chemo drug and quercetin combination. I was surprised to read your thread because I thought it was almost certain that the combo you are using works well and the main issue was just obtaining it. Should you learn of something else very promising over the next few months , I would appreciate any advice.

      Thanks again for your info.

       

      Murray Flewelling

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      • JGC
      • JGC
      • 3 yrs ago
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      murray flewelling 

        I think that it would be good for you to give a senolytic like Fisetin (or D+Q if you can obtain the Dasatinib) to your mother, but there are no guarantees.  The journal publications indicating that these senolytics can clear some sizable fraction of senescent cells have been done only on cell cultures and on mice.  We think that they should also work on humans, but there are no documented  trials indicating that.  Based on experience, we think that there are no negative effects in humans.

        In my view, this is why it is important to combine senolytic  self experiments with some monitoring that can indicate that senescent cells are actually being cleared.  This is why I suggested the IL-6 blood test as a bio-marker that has the potential for providing such an indication, as described above.

        As for the Unity Bio work, their approach is to use the fairly toxic UBX0101 senolytic drug to repair degenerated knees, by injecting that drug directly into the knee capsule.  They cannot inject the drug into the bloodstream because of the toxicity.  Their results, so far as I am aware, are that the procedure works well on young subjects but not on older ones.  The difference seems to be that in older subjects the senescent knee-joint cells are cleared but not replaced, leading to incomplete repair.  In my opinion, the lack of cell replacement in the older subjects arises from SASP, because the procedure is not clearing the senescent cells outside the knee area.

      Like 1
  • Hi JGC

    Thank you for the information. I was in no way promoting Unity if that is how it came off. I watch pretty much anything related to Aging and therefore I see Aubrery De Grey and Mr Faloon talk about the various studies that are taking place and then make a note of it whenever I see anything new.

    Has there been any animal tests with Fisetin? I am skeptical of that working because I would have thought anything naturally occurring would have been discovered if it had a big impact on the zombie cells. However it is cheap and worth a try.

    I was wondering if you might know anything about the Rapamycin info that is here. I tried using the "research" code but it is not working.

     

    I really appreciate the information you have provided.

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    • murray flewelling Update - Forget the question about the code as I was just keeping the quotation marks when I should have dropped them . Thanks for the advise.

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      • JGC
      • JGC
      • 3 yrs ago
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      murray flewelling 

        The journal publication describing the senolytic tests of Fisetin on mice is available HERE.  The difference between taking small doses of Fisetin regularly as a health supplement and the senolytic treatment of mice (and humans) is in the size and scheduling of the dose.  Instead of taking 50 milligrams once a day, the senolytic treatment involves taking 2,000 to 5,000 milligrams (i.e., 2-5 grams) all at once, and then no more for 6 months.  There seems to be a threshold effect in clearing senescent cells, and small regular doses seemingly never get over that barrier.

        I'm scared of Rapamycin because it suppresses the immune system.  In my opinion, Metformin (which we take) does more or less the same thing and is much safer.

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      • Dan Nave
      • Dan_Nave
      • 3 yrs ago
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      murray flewelling wrote: "Has there been any animal tests with Fisetin? I am skeptical of that working because I would have thought anything naturally occurring would have been discovered if it had a big impact on the zombie cells. " 

      It is being discovered now..

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    • Dan Nave 

      Hi Dan. I have been thinking of ordering fisetin from amazon for a week and ironically did not get around top it today as intended. Which study or personal stories are you referring to ?

      Thank you very much for getting back to me.

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      • Dan Nave
      • Dan_Nave
      • 3 yrs ago
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      murray flewelling 

      There are many scholarly articles that show up if you search for 'Fisetin and Senolytic' for instance.  You can modify your search with 'Quercetin' or 'Dasatinib' etc for even more.  Here is one that may be helpful:

      https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6197652/

      Fisetin is a senotherapeutic that extends health and lifespan

       

       

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    • Dan Nave 

      Thanks Dan. I know Dasatinib will work for certain but I doubt I can get it in Canada where things seem to be a little more strict so I have been hoping Fisetin would prove effective as well.

      I appreciate you taking the time to let me know. There is an NAD booster coming in May from the UK company Nuchino that has shown to be 4x as effective as what we have in North America to date. Just thought I would point that out in case you or anyone else is interested in NAD.

      Cheers!

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    • murray flewelling - I should clarify that it is more effective as an oral supplement vs the great results with IV that I have heard of. I am sure anyone in this forum would know that anyway.

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    • Dan Nave 

      I have looked at the one you sent the link for and it is the one that made me decide to give it a try. There are a few listed on Amazon that I am looking at. Do you have any personal experience or is there any Fisetin product that you have heard to be one of the best ?

      Thanks.

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      • BobM
      • BobM
      • 3 yrs ago
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      murray flewelling 

      Hi Murry, when you talk about the booster from UK being 4x better, are your referring to the LE supplement, or the compounded product delivered via electric skin patches?

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      • BobM
      • BobM
      • 3 yrs ago
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      Dan Nave 

      Hi Dan, this was an excellent reference!

      They talk about chronic and acute use of Fisetin several times. What do you think this means to our dosing schedules? 

      How does the mouse dosing of 500ppm compare to dosings most of us are taking ? 

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      • JGC
      • JGC
      • 3 yrs ago
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      murray flewelling asked "is there any Fisetin product that you have heard to be one of the best ?"

      Most of the capsules available on the Internet come from the same source.  Most recently we have purchased Fisetin from Swanson's, because they have good prices ($12.99 for 30 x 100 mg capsules) with free shipping for orders over $50.. 

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      • Dan Nave
      • Dan_Nave
      • 3 yrs ago
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      BobM 

      I can only refer you to this link:

      https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4804402/

      A simple practice guide for dose conversion between animals and human

      Like 1
  • Thank you again for your time.

    Rapamycin is a wild card for sure. I have watched every video on it that I could find and the proponents such as Peter Attia and Matt Kaeberlain say that Rapamycin is the only thing that has universally extended life in all animal models , yeast etc. When mentioning the immune system , there seems to be no measurable instances of mortality from animals dying as a result of diseases that one would expect if our systems were weaker. I should go back and refresh but I believe it had to do with the very limited amounts one would take vs larger amounts in transplant patients. That said , Doctor Attia of course pointed out that it is not approved and he would not advise anyone until we know more. 

    When I was looking for a source , I did find a forum with people taking it , and a very positive write up by a Canadian doctor who had used it for two years. He did make sure to point out that it was his experience and that he was in no way promoting people taking it.

    There was an approved study on a small group of seniors , some of which were in middle stages of alezhemirs . One senior that was around 90 had regained his faculty's and was back doing lawn care etc. The study was mainly for safety , but there was suppose to be follow ups. The family was very upset that at the end of three months , their father was no longer able to get any ( as the study ended)  and soon he reverted back to the foggy state he had been in at the start.

    JGC I am on the same page with the Rapamycin especially when my mom is 86. However one thing that has been consistent in the studies is that Rapamycin appears to reverse some aspects of heart disease and the last study found a 25% increase in refraction ( I think that's the word) allowing more oxygen to the blood stream as the heart was much less strained. 

    IF anyone is interested and we decide to ease in to it  , I will people know how things progress or any issues causing us to stop. I see a source for dasitinab and will try the Fisetin before a decision on Rapamycin. My mom still looks after herself well and I would just like to see her have more energy etc.

    Thanks Again

    Like 1
  • JGC said:
    I note that LifeExtension offers an Interleukin-6 (IL-6) test for $75, an Interleukin-8 (IL-8) test for $199, and a Cytokine Panel test that includes Interleukin-1 beta (IL-1β), Interleukin-6 (IL-6), Interleukin-8 (IL-8), and Tumor necrosis factor alpha (TNF-α) for $399.  It seems to me that it would be an excellent idea to do at least the IL-6 test (and perhaps the more expensive ones) before and after taking  large senolytic doses of Fisetin and/or Dasatinib plus Quercetin.  I wish I had done this before my recent senolytic adventures.

    Quite happy of my last inflammation panel results which included: hr-CRP, ferritin, leucocytes, fibrinogen, ESR, IL-6 and TNF-alpha.

    IL-6 tested at < 1.5 pg/ml (ref. < 7.0) and TNF-alpha at < 4.0 pg/ml (ref. < 8.1). Any data from your side?

    Specifically for senolytics we should look maybe more at matrix metalloproteinase Mmp12 vs. IL-6 and p16Ink4a. But that is a bit far from the clinic. Please refer to Aubrey de Grey book (Ending Aging, Chapter 10) and also this paper (at least for mice):

    "...Nevertheless, the matrix metalloproteinase Mmp12 represents a robust SASP factor that showed consistent age-dependent increases in expression across all tissues analyzed in this study..."

    "... In this study, we did not observe significant age-dependent upregulation of the prominent SASP cytokine Il6 in any tissue, although an upward trend was observed that was consistent in magnitude with previous observations in the heart and kidney (Baker et al., 2016). This modest agerelated upward trend could be explained by a previous report which demonstrated that senescent cell-secreted IL-6 acts in an autocrine manner, reinforcing the senescent state, rather than inducing senescence or promoting dysfunction in neighboring cells (Kuilman et al., 2008)..."

    "...Thus, utilizing p16Ink4a-expressing cells as a biomarker of tissue aging and a target of senolytic therapies could prove to be an effective strategy in the future treatment of age-related diseases in humans..."

    Hudgins AD, Tazearslan C, Tare A, Zhu Y, Huffman D, Suh Y. Age- and Tissue-Specific Expression of Senescence Biomarkers in Mice. Front Genet. 2018;9:59.

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