Cell Death Mechanisms Behind D+Q and Fisetin Senolytics

     After having done about 9 months of self-experimentation with the effects of D+Q and Fisetin senolytic burst-treatments, I and others in my family have noticed that senolytics with D+Q tends to induce transient flu-like symptoms and a half-day or so feeling of un-wellness, while Fisetin, even taken in 2,000 gram/day doses, does not.

     The research on mice indicates that the two senolytic treatments have roughly the same level of senolytic effectiveness.  Therefore, I speculate that in the D+Q treatment the immune system is going autophagous, destroying the senescent cells while leaving behind considerable symptom-producing molecular debris, while the Fisetin treatment is triggering aptosis, the natural dismantling of cells that is relatively clean, with little leftover molecular debris.

  Comments on this speculation?

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  • I don't seem to get as much reaction to D+Q as others.  While I've gotten a mild reaction several times, other times simply nothing.  Since I frequently take 3 grams of Lyposomal C, perhaps the C is clearing the reaction enough that I don't even notice.  So the question for me is whether the C is preventing symptoms, or preventing the senolytic action.  Next time I take D+Q I think I'll specifically avoid the C for a few days.

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  • I only got a mild headache the day after D&Q and nothing from Fisetin. 

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  • I have not tried D+Q yet. When I do Fisetin as single treatment I don’t feel any negative effects. But when I have tried Fisetin in combination with other substances I have felt unwell and had Headache and pain in muscles. (Different ombinations with Piperine/piperlongumines/tocotrienols/quercetin).

     

    Yes it could be that fisetin starts a “cleaner” process. But I also speculate that the fluelike symptoms that is reported by D+Q users are a sign of effectiveness. And that kind of effect is also a common side effect of many anticancer treatments, (when an hopefully effective substance attacks unwanted cells).

    Like 1
  • If using D+Q etc, we have some substantial old cell death and removal going on, shouldn’t we be able to test urine for something to tell a level of increase? What test? Any data on this?

    Any at home testing possible?

    Thanks for your thoughts. 

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      • Danmoderator
      • skipping my funeral
      • dantheman
      • 2 yrs ago
      • Reported - view

      BobM inflammation might go down which can be tested via a common homocysteine blood test. General health affects that number too. 

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  • Correction:  2,000 mg/day (not 2,000 gram/day)

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  • The immune system cleans up the dead cells anyway no matter what senolytics you use. 

    I get flu-like symptoms about 12 hours after taking D+Q, but I have no symptoms after taking fisetin. My guess is that D+Q kills more zombie cells than fisetin in my case.

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  • <pure handwaving speculation from non experts disclaimer> 

     Let's trace out getting the flu. We're inundated with viruses and bacteria continually, we only get sick when they get the upper hand and proliferate 'too much'. For example you can eat a 'certain amount' of bacteria without getting sick, but if you eat too much they overwhelm your immune system. It takes a while for a killer T cell to destroy an invader, on the order of a half hour I think. So, just like in ancient wars, it's a matter of numbers. 

    OK here's a popular article on what causes actual flu symptoms from a professor of immunology.

    most of the symptoms of the flu are actually caused by the immune response to the virus. The initial immune response involves cells of the body’s innate immune system, such as macrophages and neutrophils. These cells express receptors that are able to sense the presence of the virus. They then sound the alarm by producing small hormone-like molecules called cytokines and chemokines. These alert the body that an infection has been established.

    OK, inflammatory cytokines are produced. I believe this also occurs during, for example, heavy exercise (memory could be faulty, I recall Dr Rhonda talking about these a lot). But it's an immune response. Continuing

    While the influenza virus is wholly contained in the lungs under normal circumstances, several symptoms of influenza are systemic, including fever, headache, fatigue and muscle aches. In order to properly combat influenza infection, the cytokines and chemokines produced by the innate immune cells in the lungs become systemic—that is, they enter the bloodstream, and contribute to these systemic symptoms. When this happens, a cascade of complicating biological events occur.

    and

    One of the things that happens is that Interleukin-1, an inflammatory type of cytokine, is activated. Interleukin-1 is important for developing the killer T cell response against the virus, but it also affects the part of the brain in the hypothalamus that regulates body temperature, resulting in fever and headaches.

    So on to your mild flu like symptoms. Dasatinib is an immune system moderator, so it appears that the affected immune system thinks it is experiencing an infection whereas you simply tricked it. So the drug turns on some immune switches which have the effect of macro flu symptoms.  

    From this I don't think we can say whether anything is actually happening. The hypothesis is that this immune response is attacking senescent cells, instead of an infection, but we don't know. The question is, why would the activated immune system go after these cells? Perhaps because it's looking for invaders and 'trouble spots'? Intuitively that makes sense but is not otherwise clear. But continuing the intuitive thinking, the natural state with the flu is to fast (animals do this when they get sick). Fasting gives the body a chance to repair the illness. So ... it seems to fit together somehow but really is handwaving. 

    During an extended fast we know autophagy occurs but there the mechanism is clear, it is because the energy freed up from digestion goes into repair as fasting is a switch which tells the body to repair itself. 

    Like 1
  • My senolytic therapy is a bit more complex but from what I've experienced, D is a cancer drug and you're going to feel like shit taking something like that. The worst of the side effects are mitigated by splitting dosage throughout the day as much as possible, especially the headache. I don't know why but 3 hrs apart with dosing is a life saver. Cardio works well to mitigate other bad feelings. Again, not sure why but it works.

    IMHO one day or dose doesn't work well and that's why you see a lot of mixed or non results. Q needs fat to absorb, plan on that. Only a therapy with D kills cancer like growths on your body. That's enough for me to know that Fisetin is not going to give you what you want by itself. Raised moles, some skin lesions and pigmented areas are 'cured' with D in there. That's all the evidence I needed. 

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    • To add. WBC went from 6600 to 4400 after 72 hours of higher dose (240/day) D. No worries there at all for immune system. I did skip Rapa that week as precaution. Side note, Rapa at 10mg is not negatively affecting my blood work/immune system. Bro science meter says immune system is actually stronger.

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      • BobM
      • BobM
      • 2 yrs ago
      • Reported - view

      uzoma iwuagwu 

      Hi Uzoma,

      Question- were these results you reported your actual experience?

      ” Raised moles, some skin lesions and pigmented areas are 'cured' with D in there”

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  • My own personal experience. I'm 47. My close friend is 65, same results but she was lesions more than moles. I had one mole I was going to get cut off that I no longer have to. 

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      • BobM
      • BobM
      • 2 yrs ago
      • Reported - view

      uzoma iwuagwu 

      thanks again for sharing....these effects on the skin are very interesting and certainly a measurable result. 

      Tou mention 1day D treatment did not seem effective. 

      Are you doing 2 consecutive days? Or what’s your (suggested) dosing schedule?

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  • I'm not a doctor, don't want to get in trouble. Consider this non-professional observation and guesswork. 

    I researched for many months digging through studies and trying to understand mechanisms of action. I came to personal conclusions  and theories.

    Dasa is a targeted cancer therapy and when used, you're trying to kill bad actors. Generally when trying to kill off a cell or organism it needs exposure to the poison for extended periods. Cells don't die immediately. If they did cancer treatments would be single dose. They are often a year. So the longer you're on, the better chance you kill the bad cells off. Having said that, there are side effects you want to mitigate. Changes in immune system, blood cell count, etc. From what I read blood begins to be affected on Dasa at 5 days so I chose a 3 day protocol. After testing my blood, I'd be comfortable going 4 as the changes after 3 days were very small and both of us 'felt' back to normal in less than 24hrs after drug cessation. Not sure 4 is needed because the results we got were very good after 3. I completely disagree with the protocol of one dose and another 2 weeks later but I admit, I have no expertise.

    I did not expect to see results for 2-3 months if at all. We were shocked in that I saw the results after 3 weeks, she saw them at 5 weeks. I consider them dramatic. 

    My protocol consisted of D&Q Fisetin Met Vit C, no sugar, raised fat diet. Any cell you want to kill dies quicker with a lack of fuel and metformin has synergistic affects in 2 known pathways. The problem She ran into was diarrhea. Bad. I suspect this was the flavonoids and C in someone not used to them and her not adhering to the higher fat diet required to bind to F&Q for absorption. You must eat and this therapy kills appetite. For future I will start Q C and F earlier to get the digestive system used to it. Same goes for Metformin which I believe should be run as high as safely possible. I was very conservative with it at 850/eve 500/morn. The blood sugar affects are immediate but other components linger in the system for many days. For this reason met should be started a week before therapy. It will help with stomach to ramp up dose too. 

    My dasa was 60mg/pill and I swallowed 4 pills before bed. I didn't sleep. My head felt like it was going to crack open. I assumed that with an 18hr half life it didn't matter and I wanted drug in my system quickly. Rookie mistake. Day two I was a mess so I just took 1 pill afternoon. Sides were mild so I took another 3 hours later. I learned if you split the doses, it stays in the system the same but sides (esp headache) is vastly reduced. She started before me and didn't know this, my 2nd two days were better than the first 24 hrs.

    Many people think Q or F are amazing senolytics and the Q combines with D for a double whammy. They may be helpful but largely the Q is added to the D because your body immediately adjusts to D and it's effectiveness starts diminishing immediately. The Q stops this. Q and F may be helpful but no one is going to reverse aging with them alone IMHO. 

     

    In my next protocol I have adjusted many things and will have what I think is a much stronger cocktail with lower side effects. I've added coconut oil pills, another leukemia drug and reduced D dose. I'll report when I have data from myself and a group of people who saw what happened and may be following my lead. I don't sell anything and won't share details that could be legally gray. I don't provide anyone with meds just share what I'm doing and recommend no one copy me or take anything I say as advice of any kind. 

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  • I tried High dose Fisetin first and felt nothing. It had no effect on my cycling power output or post-ride fatigue. I tried D&Q about 4 months later and had a mild headache (which is rare for me) and no other negative symptoms.   Two days after D&Q I did a hard ride and felt strong and felt very low post-ride fatigue. I was not expecting that. Ever since then I've gotten better power numbers and I fell great. I am almost certain it's the D&Q. I don't think fisetin does anything. Poor availability? 

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  • Here is a blog on a self-experimenter in Mexico. He uses Tasigna instead of Dasatinib.   http://www.rajeun.net/Senolytics.html

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      • RobH
      • RobH
      • 2 yrs ago
      • Reported - view

      Larry I couldn't find the Senolytics topic, but there is a long page at http://www.rajeun.net/rejuvenation.html . Ellis Toussier has been taking HGH, EPO, and insulin (he's not diabetic) for decades and it appears to work.

      EDIT:  Tried again and the link worked. The entire website would be interesting for anyone interested in healthy aging supported by off-label use of drugs.

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  • I'm on day 4 of a 5 day x 1200mg fisetin regimen (planned for every 2 months per my doc), and both yesterday and today added 100mg 7,8 Benzoflavone, 100mg resveratrol + 10mg black pepper + 240mg r-lipoic acid + 290mg PS to the 1200mg fisetin.  Detox reaction / headache & vertigo for the last 3 hours, although yesterday wasn't as much of a headache.  Also consider the deep tissue massage received shortly after today's dose.  Also on 6mg rapamycin / week + 500mg Metformin ER x 2.

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  • I got plenty of symptoms with 1 gram Fisetin and 1 gram of Quercetin mixed in 1 Tablespoon olive oil with 1/2 teaspoon of ground black pepper, taken on an empty stomach for three day.  The symptoms were similar to those of a 4 day water fast, without the gastro-intestinal discomfort.  I think the effects on mTOR etc of the combination was similar to that of the water fast.

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    • Dan Nave 

       

      Hi!

       

      It’s an interesting experience you share. There are quite a few people in this forum that report very little, if any, noticeable effect from fisetin alone.  

       

      I am one of these people. To me this is an indication that Fisetin might need to be co-administrated with other substances. Some here have used co-administration with piperine + curcumin + quercetin.

       

      Myself I have tried a few combinations. The last one I did about  two weeks ago (not previously reported here) with day one Fisetin (30 mh/kg) being co-administrated with only piperlongum extract (which contains quite a lot of piperine as well piperlongumines). That made me have the now familiar unwell feeling. Not as strong as I have previously felt.

       

      Day two only 30mg/kg Fisetin. That single dose of Fistein alone gave me only a tiny (if any) experience of being unwell. It could be placebo, this since I after a dose of potential senolytics I tend to bring a lot of attention to how I feel.   

       

      I don’t want to overdo senolytic treatments so I have to wait quite some time until next treatment.  

       

      Next time I will most likely pursue this course of co-administration of Fisetin with quercetin and curcumin and piperlongum or black pepper.

       

      I find it very interesting to hear about the fisetin experiments from the rest of the people in here. And also to hear if you have any more or less vague theories about which is the best fisetin combination.

       

      Just like dasatinib needs quercetin I find it logical that fisetin might need other substances to give the sought for senolytic effect.

      Like 1
      • Dan Nave
      • Dan_Nave
      • 2 yrs ago
      • Reported - view

      Staffan Olsson 

      I concur with your insights here.

      I like 1 gram each of F + C mixed in 1 Tablespoon olive oil with 1/2 teaspoon of freshly ground black pepper, taken immediately.  Take on very empty stomach (2 or 3 hours after eating or 1 hour before).

      I also like the above with the addition of 1 gram Curcumin.  This seemed a bit harsher (more symptoms).  I added the Curcumin based on an article I read that indicated it removed senescent cells from intervertebral discs.

      I'm about 77 kg and 67 yrs old.  I felt quite good both times about a week or so after taking, like you might say about old age related issues, it feels good when it stops...

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    • Dan Nave 

      Hi!

       

      I have also felt a distinct vitalizing effect a few days (3-5 days ) after the end of the senolytic treatment,  then it fades away. I am 57 years old (in 4 weeks time) and at 74 kg right after waking up in the morning and after urination.

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      • Dan Nave
      • Dan_Nave
      • 2 yrs ago
      • 1
      • Reported - view

      I forgot to mention in the post above that I took these for three days in a row.

      Other considerations (in my opinion):

      Take away from other medications.

      Stop other supplements for this time.

      Reduce your caffeine intake, per Mayo Clinic.

      Don’t do any strenuous exercise for a week or two after taking.

      Don’t take while sick or healing.

       

      If you are under 45 years old or so you might just want to take this once or twice a year as a prophylactic and not worry too much about symptoms... 

      Like 1
  • I've just started the fisetin mayo protocol and after day 1, I'm feeling like shit. I took 20mg/kg (1800mg) with MCT oil, spreading the dose out into 3 administration's throughout the day. I woke up this morning feeling terrible. Headache, sore muscles etc. I'm only 41 but suffer from multiple auto-immune conditions so feel that the protocol would benefit me. I'll update after a few weeks as there aren't many folks in my age group sharing their stories of self-experimentation. 

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    • Katy Weston What do do expect? You are supposed to feel terrible

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    • Andrew P K Yap ???? Both wife ( 75 yo)and I (80 yo) have been following Mayo protocol for a year and neither of us have had anything but positive results. A number of others on this forum also reported only positive effects. You can check the numerous postings in the fisetin topic  section. 

      We take the 20 mg/kg dose on two consecutive days/ month on an empty stomach first thing in the am and do not eat for ~ 4 hours. Every other month I follow the protocol 2X that month. 

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    • Katy Weston  Katy see my comment to Mr. Yap's comment on your reaction to fisetin. It "may"  be that you had a reaction to the MCT. I tried MCT  it several years ago and had an extreme reaction in that I  broke out in hives over most of my body.  This response to MCT has been  noted by other if you check google. 

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    • Katy Weston did you buy low quality 10% fisetin?

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    • Peter H. Howe MCT oil is something I routinely supplement with and experience no adverse reactions to so I don't think it's that. I'm definitely experiencing an inflammatory reaction, similar to what I would experience when eating gluten or another food I'm sensitive to. Muscle aches, headache, stiff neck etc... I used this product: https://ca.iherb.com/pr/california-gold-nutrition-fisetin-with-novusetin-100-mg-180-veggie-capsules/101509?rcode=ABO0110

      Perhaps it's not as good quality as I thought.

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    • Katy Weston  Katy, am sorry to hear that as I think fisetin is perhaps a wonder supplement for someone my age. I use Swanson's  fisetin and consume 1.5 grams  (20mg/kg) on two consecutive days on empty stomach when I first get up. I do not eat for ~ 4 hrs afterward. I note that several on this forum also includes some type of oil or black pepper combination.

      Hope it works out for you. Sorry about inflammation and autoimmune disease. 

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    • Katy Weston It seems that this particular senolytic protocol might not be beneficial for you. In a PubMed document it is suggested that increasing autophagy could in fact be harmful for some conditions.

      "Alterations of autophagy contribute to the progression of various autoimmune diseases, including systemic lupus erythematosus (SLE), inflammatory bowel disease (IBD), rheumatoid arthritis (RA), and systemic sclerosis (SSc). In patients with SLE, autophagy defects result in poor clearance of phagocytic fragments and excessive secretion of inflammatory factors. The disorder of autophagy in IBD patients is closely related to the regulation of inflammatory factors and the clearance of pathogenic pathogens of enteropathy. The increase of autophagy in synovioblasts of RA patients will promote RA-associated synovitis. The autophagy of fibroblasts in SSc patients is dysfunctional, leading to overactive wound healing. Understanding the role of autophagy in the pathogenesis may give us hints on the therapy of autoimmune diseases."

      I believe it was worth a try, but given your reaction it doesn't seem its is something you should continue with.

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    • chuck stanley can you tell me the source of this quote? Id like to further explore this connection. I do quite a few protocols to promote autophagy including fasting and always feel amazing while doing them. It's possible that I need to have some sauna sessions to clear out the debris from this senolytic protocol. 

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    • Katy Weston 

      Here is the document I quoted from:  https://pubmed.ncbi.nlm.nih.gov/32671763/

      And here is another one of interest:  https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5346336/

      Please keep us posted on your experiments and your progress.

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      • Fred Cloud
      • Fred_Cloud
      • 2 mths ago
      • Reported - view

      chuck stanley autophagy? That is not what senolytics do. Senolytics trigger apoptosis or cell death in senescent cells not autophagy.

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      • Fred Cloud
      • Fred_Cloud
      • 2 mths ago
      • 2
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      Katy Weston You took too high of a starting dose. I have autoimmune problems too and small doses like 500mg of fisetin wrecked me. I felt horrible for a couple of days and then I felt better. But I took more rounds with smaller doses and worked my way up to higher doses and can tolerate 1,000mg+ now. You just need to start small, find a dose that you can tolerate and work your way up to mayo clinic doses. I suspect senescent cells are somehow involved or aggravate autoimmune problems, so the good news is you can greatly improve your condition if you purge them, you just have to work your way up to it.

      Like 2
    • Fred Cloud Corrected. Important Distinctions.

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    • Peter H. Howe I'm not saying that it doesn't work over time.

      During treatment, you can expect to feel the effects of the treatment. You don't expect to feel great during treatment. It's the price you pay.

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    • Andrew P K Yap Not "my" and many others experience with fisetin. 

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    • Peter H. Howe 

      My experience is that during treatment I feel terrible.

      After stopping treatment and after the body heals itself, I feel wonderful.

      Because I feel wonderful after treatment  (after the body heals itself), I continue with the next round of treatment even when I feel awful during treatment.

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      • Dan Nave
      • Dan_Nave
      • 2 mths ago
      • 1
      • Reported - view

      Katy Weston The first time I took the protocol I had a much more noticeable reaction than with subsequent doses.  If you initially have a  high number of senescent cells you might expect that.  

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