Fiestin to Clear Senescent Cells

Following studies with mice that showed significant senolytic clearance of senescent cells following large doses of the readily available flavenoid supplement Fisetin,  my wife and I (ages 79 and 84) decided to try it.  We have just completed two sets of massive Fisetin doses.

We had Life Extension blood-work done in October before the start, and we will have more again next week to observe any changes.  The first set of Fisetin doses was on October 22-25 with 800 mg/day for three days followed by 600 mg on the fourth day, for a total of 4 g.  I didn't notice much in the way of effects.  Perhaps some reduction of small aches and pains and some increase in energy and mental acuity.

For the second set of doses done November 22-26, since we experienced no negative side effects in the first set we decided to increase the dosage a bit and to add 10 mg of BioPerine, a supplement that is reputed to magnify the effects and potency of flavenoids.  For five days starting on Thanksgiving we took 500 mg of Fisetin and 10 mg of BioPerine twice per day, for a total of 5 g of Fisetin.

This time. I did experience one negative side effect.  A few months ago, about 2 AM in the morning I awoke from a deep sleep and experienced a severe episode of vertigo.   I turned over in bed, and the the whole room seemed to tilt.  Suddenly, I didn't know which way was up.  I staggered to the bathroom and vomited.  The symptoms tapered off and disappeared in a few days, but it was a very distributing experience.

On the 2nd day of our 2nd Fisetin series, I experience a recurrence of that vertigo in the middle of the night, not as bad as my initial experience but still rather disturbing.  I tolerated this mild vertigo and continued the treatment.  My wife had no similar symptoms, and after my last dose I experienced no further vertigo symptoms.

On the positive side, following the second set of dosages I did feel very well, and very sharp and alert.  This past weekend I ran my Shetland Sheepdog Taliesin in an AKC Canine Agility Trial in Mt. Vernon, WA, and we did very well, qualifying in 7 runs out of 15 and getting various colored placement ribbons.  I was feeling quite sharp, and I even invented a new dog-handling technique that fixed an ongoing problem we were having.

Next week we will do the blood-work again, and I'll report any changes.

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  • Thank you for the info. My understanding is the Fisetin should be taken with quercetin? 

    I have been taking only 100mg Fisetin + 500mg quercitin daily for about 2 weeks. Can't say I have noticed any changes. Except, I did have a short duration vagus nerve zinger that included a hot flash, dizziness, nausea, near faint, and SURPRISE! Lasted only 30 seconds or so but scared the heck out of me. It occurred on the 3rd day of my 5 day fast.

    Would like to read more on dosage, duration, and results from others?

    Reply Like
      • JGC
      • JGC
      • 10 mths ago
      • Reported - view

      nealfg 

      It's Dasatinib that is supposed to be taken with Quercetin, not, to my knowledge, Fisetin.  The mouse studies involved large doses of Fisetin administered alone.  However, it has been pointed out that taking a small amount (10 mg) of BioPerine along with Fisetin tends to magnify the effect, since Ficetinis a flavenoid.  Therefore, in our last session my wife and I took 10 rounds of 500 mg of Fisetin with 10 mg of BioPerine over five days.  Note that the mouse study indicates that the most effective clearance of senescent cells is accomplished with a few massive doses of Fisetin, not with smaller amounts taken every day.

      Reply Like
      • Iðunn
      • Iunn
      • 9 mths ago
      • Reported - view

      JGC I don't think there's any evidence that piperine/BioPerine enhances absorption of flavonoids generally — just curcumin. Or do you know of any? And the mechanism isn't really understood, so it's hard to make strong predictions.

      Reply Like
      • JGC
      • JGC
      • 9 mths ago
      • 2
      • Reported - view

      Iðunn 

      I refer you to https://www.isotrope.com/bioperine/ .  It says that: "P-glycoprotein is a protein the body uses to break down exogenous compounds found in the body. This protein inhibits the action of many medications, and also regulates the degree to which certain nutrients are absorbed by the body. This protein actively controls the permeability of the blood-brain barrier, which directly impacts the overall effects seen by many compounds such as curcumin—the active compound found in Turmeric. Piperine inhibits the action of this protein."

      Reply Like 2
    • Dan Nave BobM nealfg deahello again;  Dan your wisdom and response to my questions,  is very useful. after 3 consecutive days of aggressive fesitin (? Spelling)  and quercetin and black tea ( help w assimilation)  I've been experiencing high energy,  more and then much less arthritis discomfort some euphoria,  I've discontinued weekly," le senolytic activator" and will do another intense fisetin, quercetin, ( probably black pepper)  and hot black tea in 30 days from now and will report on my, "experiences"  thankyou all and thankyou Dan.

      Reply Like 1
  • Bloodwork Results of Two Fisetin Sessions

      As I stated in my first post on this topic, in the past two months my wife and I have taken two massive doses of Fisetin in an effort to clear our senescent cells.  We did bloodwork arranged by Life Extension on October 22 before the first session and again on December 17 after the second session.  Our goal was to determine if the Fisetin sessions had a measurable effect on our fitness, as measured by the bloodwork results.  We analyzed our result values in three ways: (1) using the Aging AI website, (2) using the Young.AI website, and (3) using a calculation of Levine Phenotypic Age done with a spreadsheet that I have posted elsewhere on this site.  I note that the Levine age is always close to the calendar age because the latter is one of its most important input factors.  The table below summarizes the results:

     

    Interestingly, following the Fisetin sessions my Aging AI age dropped by 8 years and my Young.AI age dropped by 3 years, but my Levine Phenotypic Age actually increased  by 3 years.  I think that this is because at the time of the second bloodwork I had a big bruise on my left leg from a collision with a chair in the dark a few days earlier.  The inflammation from this bruise probably somewhat increased my c-reactive protein, my white blood cell count, and the blood geometry factors, all of which will increase the Levine age.

    Therefore, my wife's numbers are probably more relevant. Her aging AI age dropped by 5 years, her Young.AI age dropped by 11 years, and her Levine age dropped by 1.4 years. My conclusion that the Fisetin sessions did have an observable (but not large) effect on our overall fitness, as reflected by the bloodwork.

      Soon we will undertake two similar sessions with D+Q, and we will report any bloodwork changes after those.

    Reply Like 10
    • JGC This is awesome data, JGC!  Thank you!

      Reply Like
  • JGC said:
    ...The table below summarizes the results: ..

     Thank you for sharing your results and also look forward to the D+Q tests!

    In my case I have noticed large variations in the aging.ai results in time (~10 years) and always wondered how I can disentangle the effect from the error. v1.0 and v3.0 have also resp. an intrinsic MAE of 5.5 and 5.9 years. To understand a bit more I did try an ANOVA test which might show a little effect (only with v1.0) in lowering the aging.ai in recent years and I (would like to :-)) associate this to a regular use of metformin. Coincidence or not, I am also looking at senolytics and might try the new LEF formulation.

    Good luck for your tests!

    Reply Like
  • Fisetin vs. D+Q

    My wife and I have been starting our new senolytic doses on the 22nd of the month.  In October and November, we took large doses of Fisetin, as reported above.

    Today at 10 AM on empty stomachs, we took 200 mg of Dasatinib, 2,400 mg of Quercetin, and 10 mg of BioPerine.  I'll report any side effects that we observe.

    We plan to repeat this in a week, on the 29th.  After that, we'll do bloodwork yet again and report any changes.

    Reply Like 4
    • JGC 

      Reply Like
    • JGC Have you ever try the Senolytic activator by Life extension? I am into this forum trying to find answer because I got some side effect with my first two pills.

      Reply Like
      • JGC
      • JGC
      • 9 mths ago
      • 2
      • Reported - view

      LISBETH Prieto 

        I have not tried LifeExtension's Senolytic Activator.  Its main senolytic ingredient is the flavenoid Quercetin.  I have taken Quercetin along with Dasatinib and Bioperine (a pepper-derived supplement that greatly extends the half-life of flavenoids in the bloodstream).

        The research paper that first tested and suggested Quercetin as a senolytic drug showed that (a) it tends to act on senolytic cells in the lining of blood vessels, and (b) it is far more effective when combined with the expensive anti-cancer drug Dasatinib, which goes after senolytic fat cells.  The D+Q combination is a highly regarded senolytic.

        LifeExtension cannot sell a D+Q pill because Dasatinib is a prescription-only drug and is prohibitively expensive ($2K for 4 pills).  Therefore, they do what they presumably consider the next best thing by adding Theaflavins fron black tea as a Dasatinib substitute.  However, there is no research of which I am aware indicating that Theaflavins are an effective substitute for Dasatinib.

      Reply Like 2
      • JGC
      • JGC
      • 9 mths ago
      • Reported - view

      LISBETH Prieto 

      Correction: "senescent cells", not "senolytic cells".

      JGC

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      • Antonia Gauer
      • Medical Writer working on age reversal for over 20 yrs
      • Antonia_Gauer
      • 4 mths ago
      • 3
      • Reported - view

      JGC  I read somewhere that tocotrienols and quercetin (both proteasome inhibitors in combo is a substitute of sorts for the dasatinib and quercetin. I have been taking these in monthly cycles using Grace tocotrienols (no tocopherol).  I can't seem to find my reference for that but it is likely to be Anti-aging Firewalls or Aging Matters. I've been doing biohacking for over 20 years now and am 67. I can't say that I look any younger, but I certainly feel better at this age than at 50. No arthritis, stiffness, obesity, dark pigmentation etc. I am very interested in your experiences with fisetin. I drink many cups of black tea in a day, but add a little grass-fed milk, which may block the action of the theaflavin.

      ETA (From Life Extension): 

      Tocotrienols, the less well-known members of the vitamin E family, are emerging as the ideal senolytic nutrient. Studies show that tocotrienols have dual and complementary actions:

      • In cancer cells, tocotrienols can stimulate cellular senescence, shutting down their malignant potential.6
      • In healthy tissue, tocotrienols can slow aging changes, promote normal cell division and specialization, and prevent cells from reaching their damaging final aging state.10-14

      Studies have shown the benefits of combining tocotrienols with quercetin, a flavonol found in many fruits and vegetables. Quercetin also has dual and complementary actions with regards to aging cells. Like tocotrienols, quercetin can induce senescence and promote cell death in numerous types of cancer cells.6,15 And, like tocotrienols, quercetin has the opposite effect in healthy cells, delaying senescence in younger cells and rejuvenating older cells to rid them of their abnormal, age-promoting function.1,6

      Together, these two nutrients sweep the body clear of aging cells, while promoting natural termination of cancer cells.

      Reply Like 3
    • Antonia Gauer  Maybe these links can help you to find useful references about tocotrienols?

       

      https://www.ncbi.nlm.nih.gov/pubmed/26343116

       

      https://www.ncbi.nlm.nih.gov/pubmed/30479579

      Reply Like 1
      • Iðunn
      • Iunn
      • 4 mths ago
      • Reported - view

      Staffan Olsson Yes, but there are no data supporting that tocotrienols have senolytic activity, even in cells in a dish.

      Reply Like
      • Iðunn
      • Iunn
      • 4 mths ago
      • 1
      • Reported - view

      Antonia Gauer Note that this is a conclusion that in no way follows from what they've laid out. Tocotrienols delay senescence (in cells in a dish, for reasons that have nothing to do with why cells senesce in the body), and kill cancer cells (in a dish), but they then say they "sweep the body clear of aging cells," for which they have provided zero evidence (since zero evidence existrs).

      Reply Like 1
      • Antonia Gauer
      • Medical Writer working on age reversal for over 20 yrs
      • Antonia_Gauer
      • 4 mths ago
      • Reported - view

      Staffan Olsson  Thank you Staffan. The first ref is likely the one I read. It was a ref for the Life Extension article as I recall. Hard to say if it is working or not, although I always get into a "discussion" with the ferry people who want to see proof of age for free rides midweek :) A server also referred to my nephew as my father one day, which was amusing  for me, but not for him (he is 58). I also do NAD+ or Niagen, with TMG for methylation, and resveratrol. But this is another discussion.

      Reply Like
      • Antonia Gauer
      • Medical Writer working on age reversal for over 20 yrs
      • Antonia_Gauer
      • 4 mths ago
      • Reported - view

      Iðunn Yes, a lot of evidence exists in Petri dishes. Absent of testing, all I go on is how I feel on the inside and appear on the outside.

      Reply Like
    • Antonia Gauer Iðunn Tocotrienols show, like many other substances, potential for reducing risk for various diseases. I look forward to see what the future will hold for tocotrienols. 

       

      https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2956867/

      Reply Like 1
  • Do you feel that the fiestin was more effective taken on an empty stomach?  I've been on the life extension " version of the synolitic therapy,  for over one month, and have noticed subtle yet profound changes. ( without the potential added benefit of taking on empty stomach)  from now moving forward...... 

    Reply Like 1
    • karl kuffner 

      Reply Like
    • karl kuffner         I find," writing in this forum "  to be a little challenging. , " continuing"   I feel more adventurous,  energetic,  healthier and less body/ joint pain, and am encouraged to continue once weekly lof.senolytic. Therapy.   What subjective changes have you and/or wife noticed that correlate with, " testing 8 yrs younger" wow! That's actually amazing. 

      Reply Like 1
      • JGC
      • JGC
      • 9 mths ago
      • 1
      • Reported - view

      karl kuffner 

      The 2018 RAADFest Age Reversal Update document advised administering D+Q on an empty stomach, so we did ours before breakfast yesterday.

      The senolytic research on mice seems to favor periodic large doses of senolytic drugs rather than smaller daily doses.  The idea, I think, is to hit the senescent cells hard with an infrequent big dose.  Also, the worry is that daily doses of senolytics might produce cumulative side effects.

      Reply Like 1
  • D+Q+P Side Effects?

    I do seem to notice some side effects from our D+Q+P (Dasatinib+Quercetin+Piperine) senolytic dose, taken about 24 hours ago.  I had early morning stomach cramps and a mild headache, along with a mild feeling of unwellness (as if I was coming down with the flu).  My temperature, however, is normal.

    I take this as an indication that the D+Q+P treatment is dealing with some senescent cells in my lower digestive system and also has penetrated the blood-brain barrier.  My wife has not experienced any similar symptoms.

    Reply Like 1
  • Thanks for that information.    Karl         ps: do you, " feel" any different,  being "8 yrs younger?

    Reply Like
      • JGC
      • JGC
      • 9 mths ago
      • Reported - view

      karl kuffner 

      Two days after D+Q+P, no cramps, no headache, no feeling of unwellness.  In fact, I feel very good.  Further, I do dog agility on weekends with my 5 year old Shetland Sheepdog Taliesin at the Master's level.  This involves a lot of running and careful timing to keep up with the dog and to guide him over the designated jumps and contact obstacles.  In the past few weeks we have done very well at Seattle-area agility trials, getting qualifying scores (Qs) in more than half  of our runs on each weekend.

      We will do another D+Q+P in a week (Dec. 29), and then we will have another blood test to see if there are any changes.

      Reply Like
      • JGC
      • JGC
      • 9 mths ago
      • 2
      • Reported - view

      My wife and I did our second D+Q+P session yesterday (Dec. 29, 2018).  This time I experienced mild diarrhea in the morning, a mild headache for most of the day and evening, and a mild feeling of unwellness during the day.  The latter was similar to my experience with the first D+Q+P session. I took two 90 minute naps during the day.  My wife, obviously more robust than me, reported no such symptoms.  Today I feel well and energetic.

      We had planned to do another blood test after these two D+Q+P sessions, but we have decided to wait a week and do a Dasatinib (200 mg)  + Fisetin (2,000 mg) + Piperine (10 mg) session on January 5 before the next blood test.  I'll report test results after that.

      Reply Like 2
  • You might know about already, I did not: clinical trial to follow at Mayo. I might start with Fisetin after the first results appear, will see ...

    https://clinicaltrials.gov/ct2/show/NCT03430037?cond=fisetin&cntry=US&rank=2

    Reply Like 2
      • BobM
      • BobM
      • 9 mths ago
      • Reported - view

      albedo 

      Dose is of interest: 20mg / kg (of your weight I assume. For 2 days. This is double what I did (600mg/day). 

      Reply Like
      • BobM
      • BobM
      • 9 mths ago
      • Reported - view

      albedo 

      Looking at the previous test #1 in the series (see the link there) the elegibilty requirements and exclusions are of interest. For example, they want you to be off statins and caffeine before and during dosing. And a long list of other things. I did not on my first dosing. Before jumping to the next round of very high dosing (1200 mg/day, 2 days), I want to get my blood tests back from the previous, and study this further. Any comments on the details of these studies as outlined? 

      Reply Like
  • What are the by all of you on using a high dose of fisetin (600mg?), together with a 24-30 hour water fast. Taking only the fisetin/water throughout the fast?

    Could this combo speed up the purge of senescent cells? 

    Reply Like 1
      • Danmoderator
      • skipping my funeral
      • dantheman
      • 9 mths ago
      • 1
      • Reported - view

      BobM Pretty sure this hasn't been studied so nobody knows. A 5 day water fast is what really kicks in the autophagy - more powerful than fisetin by itself FWIW. 

      Reply Like 1
      • JGC
      • JGC
      • 9 mths ago
      • Reported - view

      BobM 

      For high doses, as far as I can tell, the largest Fisetin capsules available are 100 mg (which means that you have to take a lot of them).  In contrast, one can get Quercetin in 1,200 mg capsules (which I use).  I have also seen old ads for Fisetin in powder form promoting a bottle containing 50 g of powdered Fisetin and a 100 mg scoop.  However, these don't seem to be available any longer.

      Reply Like
      • BobM
      • BobM
      • 9 mths ago
      • 1
      • Reported - view

      JGC Just FYI, caps are little (bottom one here). Taking 4 at each meal is not hard. And these are cheap. $16.26/bottle delivered. 😎. 

      Reply Like 1
      • JGC
      • JGC
      • 9 mths ago
      • 2
      • Reported - view

      BobM 

      Yes, that capsule looks just like the 100 mg fisetin capsules that I have bought from Swanson and from Doctor's Best/Amazon.  However, my point was that for senolytic doses one needs to take on the order of 2,000 mg or 20 capsules.  It would be nice if someone would produce fisetin capsules that contained 500 mg or 1,000 mg, so that one would not have to take so any pills.  This is done for quercetin, but for some reason, not for fisetin, although both are similar flavenoids.

      Reply Like 2
  • Hello team😉       can someone share where I can buy high dose fiestin?

    Reply Like 1
      • BobM
      • BobM
      • 9 mths ago
      • 1
      • Reported - view

      karl kuffner 

      i bought Regular dose (100 mg) from Lucky Vitamin. Took two 3x/ day. These are branded as Doctors Best. They were out of stock for quite a while. 

      Reply Like 1
  • Thanks, how do you compare the fiestin w the synolytics prod. From life extention?

    Reply Like 1
      • BobM
      • BobM
      • 9 mths ago
      • 1
      • Reported - view

      karl kuffner I take both. Really can perceive a gain from either. 

      Reply Like 1
      • BobM
      • BobM
      • 8 mths ago
      • Reported - view

      BobM 

      this should have said “can’t” 

      sorry for any confusion!

      Reply Like
      • JGC
      • JGC
      • 8 mths ago
      • 2
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      karl kuffner 

      Fisetin by itself has been shown in a publication in a refereed journal to cause senescent cells to go in to aptosis and disappear.  Further Fisetin is relatively cheap ($12.99 for 30x100 mg caps from Swanson's).

      LifeExtension's Senolytic Activator costs about $1 per cap for 74 mg of Quercetin + 275 mg of Theaflavins.  Quercetin has been shown to have mild senolytic action, particularly on senscent cells in the linings of blood vessels, but it works much better when combined with the very expensive anti-cancer drug Dasatinib (D+Q).  Dasatininb is prescription-only, so LifeExtension can't market a D+Q product.  They have apparently therefore decided to generate a marketable senolytic product by substituting Theaflavins from black tea for the Dasatinib.  There has been no research, to my knowledge, indicating that Theaflavins enhance the senolytic action of Quercetin or have any senolytic action alone.  It's apparently a guess at best.

      Further, the research shows that for known senolytics the action comes from taking LARGE doses of the senolytic drug separated by sizable time intervals (~1-6 months).  On the other hand, one is supposed to take 2 caps of LifeExtension's Senolytic Activator every week, i.e., a relatively small dose at weekly intervals.  That looks to me like a dosage schedule that is unlikely to produce much senolytic action.

      Reply Like 2
    • karl kuffner I am generally a fan of LEF supplements but since the Senolytic Activator is just quercitin plus some theaflavins, you're probably better off buying the quercitin by itself from a cheaper vendor.

      Reply Like 2
  • JGC  stomach upset is likely just side effect of the pills, you need better biomarkers to test for senolytic effects. I'm putting a list up in a WIKI here in the near future. Clearing senescent cells involves a lot of recycling (e.g. the Golgi apparatus) which isn't something you generally feel, but there surely are parts that are discarded in your urine. I hypothesize that testing your urines specific gravity is a way to check - however during ad libitum feeding you need a baseline, and it might well be lost in that baseline level (lost in the noise). 

    For example during a fast, at day 5 is when it's clinically been measured that heavy senolytic activity occurs. Indeed during my last fast at day 4.5 my urine turned from clear to dark yellow and the specific gravity went from negligible to more than my test stick could measure (> 1.03) - in both cases the only other measured value was high ketone bodies (of course)*. I take this as significant senolytic activity, and is the only non invasive way of testing senolytic effects I can think of and I'm fairly confident of it, but this is just a hypothesis. 

    Note also this has to be calibrated to a given amount of hydration. I carefully measure my daily intake of steam-distilled water at 170 oz, and have that same level of hydration during a fast. Being dehydrated will also drive up your specific gravity. 

     

    * it also had a peculiar odor. Normally my urine smells 'green and spicy' from the vegan diet and supplements I take. During a fast in the early part it becomes clear as water with no odor, until day 4-5. Also to be clear my hypothesis is that the specific gravity is measuring the presence of discarded senolytic junk, which is why it's important (for measuring) to separate from the normal feeding activity. 

    Reply Like 1
  • My Fisetin experiment:

    First day 500 mg; no side effects. 2nd day 1000mg; no effects. 3rd day 1200mg; no effects. 4th day 1200mg with 20mg BioPerine; no side effects.

    Following week noted increased energy, less lower back discomfort, and less/no arthritis in hand. 

    Will repeat Fisetin after 3~4 week interval. Certainly easier than 5 day water only fast.

    This week will start Metagenics' SPM Active pills for 3 weeks. Pill is supposed to provide "resolvins" to help reduce my chronic inflammation.

    And then back to 5 day water fast again.

    Reply Like 1
    • nealfg   hello, how did you break up dosing your fisetin daily? Did you have a normal diet during that time? Do you also do a senolytics. LE program, during or before.?     Thanks

      Reply Like
      • BobM
      • BobM
      • 9 mths ago
      • 1
      • Reported - view

      karl kuffner 

      jumping in here: my recent was 1200mg/day for 2 days. Divided daily into 200mg every 2-3 hours. Some with food, some not. No adverse signs. Extra energy and alertness throughout the day with no afternoon fade, which I usually get. 

      How soon are all of you thinking to repeat dosing? I’m thinking one month.... comments??

      Reply Like 1
      • nealfg
      • nealfg
      • 9 mths ago
      • Reported - view

      karl kuffner ........full dose 1 time in the morning on an empty stomach. No change in diet. Only other "senolytic" is 5-day, water only fast, every ~6 weeks.

      Reply Like
  • Senolytic Bloodwork Results from 2 Fisetin and 3 D+Q+... Sessions

    A while back I reported on the bloodwork results for my wife (PBC) and I (JGC) taken before and after two large-dose sessions of Fisetin.   After that we had rwo sessions of 100 mg Dasatinib + 1000 mg Quercerin + 10 mg Bioperine a week apart, followed in a week with 100 mg Dasatinib + 1000 mg Quercerin + 1000 mg Fisetin + 10 mg Bioperine.   In each of these sessions, the Bioperine, which is supposed to suppress the action of P-glycoprotein that normally gives drugs a short half-life in the bloodstream, an hour before the other items to give it a chance to do its work.  After the last of these sessions we had more bloodwork to observe ant effects of the treatments.  The spreadsheet image belowshows the results, and analyzed using three methods of estimating "blood age".

    The bottom line seems to be that (a) there is a certain amount of "noise" in bloodwork (not surprising) and small difference are probably fluctuations, and (b)  the D+Q sessions didn't do much that the Fisetin Sessions had not already accomplished.  For the December bloodwork I had a big bruise on my leg that I speculated had increased my Levine age.  That seems to have been borne out, in that it dropped by 3 years in the new bloodwork.

    Reply Like 3
  • I have Osteoarthritis around my knees. I started taking D+Q three months ago (70mg of D and 1,000mg of Q for three consecutive days / month). For the first two months, I felt fever around the knees a few days after the dosage. Actually, the knee temperature got 1.5 degrees celsius higher than that of thigh. It means that the inflammation around the knees got higher. I guess my immune system attacked the senescent cells.

    However, my knees are much improved now. I feel no pain anymore when I go down the stairs. I am very impressed by the result.

    I am wondering if your blood age would be younger if you had the blood work weeks after you took the senolytics.

     

    Cheers,

    Reply Like 3
  • Have you considered doing a purity analysis of the Fisetin supplements that have been mentioned in the Forum like Doctor's Best, Swanson, Rejuvenation Therapeutics. Maybe we could fund a comparative analysis to the Fisetin used in the Fisetin article :

    Reply Like 1
      • JGC
      • JGC
      • 7 mths ago
      • 3
      • Reported - view

      JPA 

        The purity issues are (a) does the product actually contain the molecule of interest and (b) does the product contain contaminants that might have negative effects.  The Selleck  Chemicals product you mention claims to have 99.1% purity, but it is rather expensive ($70 for 500 mg of Fisetin powder).  The Swanson Fisetin costs $12.34 for 30 x 100 mg capsules (i.e., $2.06 for 500 mg in 5 caps).  It does not specify purity but lists other ingredients as: microcrystalline cellulose (plant fiber), hypromellose (vegetable capsule), and may contain one or both of the following: magnesium stearate and silica.  (I don't think any of those should be problems.)

        I would say that the Swanson product is very likely to contain Fisetin as claimed and that the impurities are likely to be irrelevant.  Therefore, I doubt that an independent purity analysis would be needed or would contribute much information.

        If there is an important difference between the mouse Fisetin experiment and our own self-experimentation adventures with Fisetin, it is perhaps the difference in drug delivery.   In the mouse work, the Fisetin (which is insoluble in water) was dissolved in 60% Phosal 50 PG: 30% PEG400: 10% ethanol for delivery to the mice.  On the other hand, we self-experimenting humans simply swallow the capsules of Fisetin powder and hope for the best.  It isn't clear to me whether swallowing a water-insoluble compound like Fisetin will actually deliver it to the bloodstream with any efficiency.

        Since Fisetin is soluble in ethyl alcohol at 3 mg/ml, one might consider breaking open the Swanson  capsules and dissolving the Fisetin powder in a good singe-malt Scotch before administration. 🙂

      Reply Like 3
      • Don
      • Don
      • 7 mths ago
      • Reported - view

      JGC Ah, but would it change the flavor of a decent wine?

      Reply Like
      • BobM
      • BobM
      • 7 mths ago
      • 1
      • Reported - view

      JGC JGC 

      I’m definitely changing my delivery method! 

      I have now completed 3 “dosings”. Each dosing was 1200 mg/ Day for 3 days. First 2 doses were a week apart. The 3rd a month later. I’m going to do that dosing once/month from here out. My delivery will be with good whiskey, except morning portion which might have to be a good Bloody Mary 👍

      Gotta Love us self experimenters...

      Reply Like 1
      • Iðunn
      • Iunn
      • 7 mths ago
      • Reported - view

      JPA On quality, both Swanson and Doctor's Best use Bioriginals' branded Novusetin raw material: this is a well-established company with a reliable quality reputation.

      Reply Like
      • BobM
      • BobM
      • 7 mths ago
      • Reported - view

      JGC 

      What are the opinions about taking Fisetin with Grapefruit juice?

      Its been known to increase availability of many things.

      Reply Like
    • BobM Alcohol is the opposite of an anti-aging supplement.  I'd cut it back close to zero if you're actually trying to live longer.  There's some data showing that alcohol may have a very mild hormetic effect, but only at very low doses -- on the order of a few drinks a week.

      Reply Like
  •      That's an interesting point.  I found an article HERE that discusses the effect of grapefruit juice.   It says:  "Compounds in grapefruit called furanocoumarin chemicals are the cause of the increased medication potency. These chemicals interact with the cytochrome P450 3A4 (CYP3A4) enzyme, found in the small intestine and liver, which partially inactivates many medications under normal circumstances."  One can click at the bottom of the document to get a document entitled "Appendix 1: Grapefruit Interacting Drugs and Associated Oral Bioavailability, Adverse Event(s), Risk Ranking and Potential Alternative Medications".  It lists the reaction risk of combining grapefruit juice with Dasatinib as "High".  I don't see any flavenoids on the list.

         On that basis, I would say that combining D+Q with grapefruit juice is risky.

    Reply Like 2
      • Iðunn
      • Iunn
      • 5 mths ago
      • 1
      • Reported - view

      JGC But he was asking about combining grapefruit juice with fisetin, not dasatinib. To my understanding of the metabolic pathways involved, there is no known interaction on that front.

      Reply Like 1
      • JGC
      • JGC
      • 5 mths ago
      • 1
      • Reported - view

      Iðunn 

      The digestive enzyme CYP3A4 in the small intestine is what is normally limiting the bioactivity of Dasatinib and the other drugs.  From the web searches I have done, I have not found any information on whether CYP3A4 interacts with flavenoids like Fisetin and Quercetin and limits their bioactivity.  Do you have any information on that?

      Reply Like 1
      • Dan Nave
      • Dan_Nave
      • 5 mths ago
      • 1
      • Reported - view

      JGC 
      I took 1/4 teaspoon of ground black pepper along with 1g fisetin and ~1g quercetin dissolved in oil, for 3 consecutive days (on an empty stomach).  From the effects I felt on the days taking it, and several days afterwards, I feel that it was well absorbed and was effective.  I actually feel better than usual now after a couple of weeks. 

      Reply Like 1
    • Dan Nave     good evening ; I took 2,800 mgs of fiestin and 1000 mg quercitin w black tea for 3 days ( on day 3 I added le senolytics activator)  without any side affects ( I'm a heavyweight)  and first positive effects was tonight "evening walking" felt younger and. Felt like running/ jogging for first time in a long time. Questions: do I go back to once weekly senolytics aactivator? Question: when can I optimally do 3 day first in treatment again?  Thankyou

      Reply Like 1
      • Dan Nave
      • Dan_Nave
      • 5 mths ago
      • Reported - view

      karl kuffner 

      I'm not sure that anyone can advise you of that at this time.  The large doses of substances to function as synolytics should be done intermittently because they kill off senile cells and then the body needs time to recuperate.  Also, if the senile cells are killed off, what is the point to continue the senolytic until there are more senile cells to kill off?  There are some potential drawbacks of using senolytics constantly. 

      I think that some of the confusion arises in that some of these substances act differently when given in high or low doses.  (Although, I would presume that Dasatinib, for example, is always toxic...)

      I am basing my strategy based on several of the lab tests and proposed trials. 

      My understanding is that the D+Q is given for 2 consecutive days, and then again in a week.  I think they may repeat in 1 month, but it is not to be taken continuously.

      The Mayo Clinic is giving the Fisetin for 2 consecutive days and repeating in 1 month.

      I am doing F+Q, (dissolved in oil), +piperine (black pepper) for 3 consecutive days, and repeating in 1 month.

      I would consider repeating at 6 month or yearly intervals.

      Low doses of these substances (except dasatinib) with low bioavailability may be taken continuously as a supplement with good results, as far as I know.

      Reply Like
      • BobM
      • BobM
      • 5 mths ago
      • Reported - view

      Dan Nave 

      excellent summary!

      thank you!

      Reply Like
    • Dan Nave 

      Reply Like
      • Iðunn
      • Iunn
      • 5 mths ago
      • Reported - view

      JGC "To my understanding of the metabolic pathways involved, there is no known interaction on that front."

      Reply Like
      • Iðunn
      • Iunn
      • 5 mths ago
      • Reported - view

      Dan Nave I'll note again that "I don't think there's any evidence that piperine/BioPerine enhances absorption of flavonoids generally — just curcumin."

      Reply Like
      • Dan Nave
      • Dan_Nave
      • 5 mths ago
      • 1
      • Reported - view

      Iðunn 

      I based my use of piperine based on a reference I saw that stated that piperine from black pepper inhibited the liver's ability to break down certain drugs, thereby ensuring that the substance remained in the bloodstream for a longer time.  

      I am having a hard time finding articles that speak to this, but I found a patent application that discusses it with references that you can look up yourself.  It states:

      "There are two plausible explanations of the role that piperine may have in drug bioavailability: a) non-specific mechanisms promoting rapid absorption of drugs and nutrients, e.g., increased blood supply to the gastrointestinal tract, decreased hydrochloric acid secretion which prevents breakdown of some drugs, increased emulsifying content of the gut, increased enzymes like gamma-glutamyl transpeptidase which participate in active and passive transport of nutrients to the intestinal cells, and b) non-specific mechanisms inhibiting enzymes participating in biotransformation of drugs, preventing their inactivation and elimination."


      "Most drugs co-administered with piperine are probably more bioavailable as a result of both of the mechanisms, i.e., increased absorption from the gut and the slow down of biotransformation, inactivation and elimination from the system. The latter mechanism is probably the most important in sustaining the elevated blood levels of the drug, and making it more bioavailable to the tissue. Although a rapid absorption to the blood stream may account for increased blood levels of the drug, it is the inhibition of drug biotransforming enzymes with piperine that makes a drug stay in the body longer, in higher quantities, which makes it more effective."

      https://patents.google.com/patent/US5972382A/en

      Reply Like 1
      • Iðunn
      • Iunn
      • 5 mths ago
      • Reported - view

      Dan Nave Sure, but that's generic information on how compounds can affect drug metabolism. The question is whether the specific effects of piperine can increase the bioavailable levels of fisetin based on its specific metabolic pathways. I know of no evidence for this.

      Reply Like
      • Dan Nave
      • Dan_Nave
      • 5 mths ago
      • Reported - view

      JGC  @Iðunn

      https://www.hindawi.com/journals/omcl/2015/854015/

      Interactions between CYP3A4 and Dietary Polyphenols

      https://www.ncbi.nlm.nih.gov/pubmed/12130727

      Piperine, a major constituent of black pepper, inhibits human P-glycoprotein and CYP3A4

      Reply Like
      • JGC
      • JGC
      • 5 mths ago
      • 1
      • Reported - view

      Dan Nave 

      Thanks for the references, particularly "Interactions between CYP3A4 and Dietary Polyphenols".  Just to drop the other shoe, I note that Fisetin and Quercetin are both classifiable as polyphenols.

      Reply Like 1
      • Dan Nave
      • Dan_Nave
      • 5 mths ago
      • 1
      • Reported - view

      JGC 

      Yes, the structure of Fisetin is said to be very close to that of Quercetin.  That's one reason that I initially decided to add Quercetin to the Fisetin for the protocol.  I figured that whatever process was working to denature and remove the Fisiten would also have to deal with the Quercetin and therefore possibly maintain a higher dose of the Fisetin for a longer time.  Hard to say.  Perhaps the Quercetin provides its own effects. 

      Reply Like 1
  • I'm sort of surprised that everyone seems to be just swallowing these capsules (fisetin and quercetin) presumably with water.  Since these substances aren't very water soluble it would seem that they aren't being fully absorbed.  The research papers that I have seen dissolve them in Phosal which is phosphatidylcholine with propylene glycol.  It does seem that they dissolve in oil as well.  I emptied my capsules into a bowl and mixed the powders with 1 tablespoon of olive oil.  It seemed to dissolve quite well.  I also feel that it absorbed well as I experienced definite effects when drinking caffeinated beverages (tea) and also some joint and bone pain and general discomfort or malaise for a few days after the doses.

    Reply Like 2
    • Dan Nave As long as they make it into your intestines, they should work fine.

      The alternative is to do what Dave Asprey and Joe Mercola discussed on the Bulletproof podcast, and put them into a suppository.  Which is gross.  But it seems to work.

      Reply Like 1
  • FYI, Drs Best Fisetin is now available next day from Amazon. About $14.15 or so.  

    My previous source, Lucky Vitamin, stopped working. Site would not take an order for weeks. I called and emailed, then gave up on them.

    I’ve now completed my 5th dosing. Once a month schedule. 1200mg (for my 135lb weight). I will continue this for now. 

    Reply Like 2
      • JGC
      • JGC
      • 5 mths ago
      • 2
      • Reported - view

      BobM 

      I notice that Amazon also has Trillium powder-form Fisetin for $59.88 for 50 grams.  That's about $0.12 for 100 mg, as compared to $0.47 per 100 mg from Drs Best.  Further, if you are going to dissolve it in olive oil (see above), having it already in powder form is an advantage, provided you have a good digital scale to measure the dose.

      Reply Like 2
      • Dan Nave
      • Dan_Nave
      • 5 mths ago
      • 2
      • Reported - view

      JGC 

      It is not clear how much fisetin is in this product.  They do not rate it or guarantee it. It may be better to buy from Alibaba if you want bulk fisetin.

      Reply Like 2
      • JGC
      • JGC
      • 5 mths ago
      • Reported - view

      Dan Nave 

      Have you bought supplements from Alibaba?  How does the payment arrangement work?

      Reply Like
      • Dan Nave
      • Dan_Nave
      • 5 mths ago
      • 1
      • Reported - view

      JGC 

      I bought my fisetin from Swansonvitamins.com. It cost $11 to $12 something for 30 100mg capsules. I have been happy with purchases from swanson.

      I have never purchased from Alibaba.  I don't really know but I would try to make sure I was purchasing from a reputable manufacturer with a physical presence, and I would also be prepared to lose my payment.  

      Reply Like 1
      • JGC
      • JGC
      • 5 mths ago
      • 1
      • Reported - view

      Dan Nave 

      I just ordered 100 gm of >98% pure powdered Fisetin from VitaSpace for $190 plus $6 shipping.  That's $0.19 for 100 mg, still a lot better than $0.47 per 100 mg from Drs Best.  Further, it's already in powder form, removing the need for breaking open capsules before dissolving in olive oil.

      The Trillium-brand Fisetin powder from Amazon is cheaper by about a factor of 2, but the purity is not specified.

      Reply Like 1
  • https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6197652/ 

     

    The original study bring forward some ideas. The reserchers show that curcumin is one of the few substances (besides fisetin) that have a proven but smaller senolytic effect.  I can only speculate if curcumin, in combination with fisetin,  Bioperine and quercetin, could bring some extra benefit. Maybe curcumin can complement fisetin by penetrating tissues  where fisetin is less effective?  This is a very  speculative question but I will test it. 

    Reply Like 1
      • Don
      • Don
      • 5 mths ago
      • Reported - view

      Staffan Olsson Do you plan to take the circumin with water or dissolve it in oil as some have recommended for fisetin-bioperine?

      Reply Like
      • Iðunn
      • Iunn
      • 5 mths ago
      • Reported - view

      Staffan Olsson Don It's important to note that curcumin has only been shown to be senolytic in cell culture models: there is no evidence at all that taking it as a supplement kills senescent cells in vivo.

      Reply Like
      • Dan Nave
      • Dan_Nave
      • 5 mths ago
      • Reported - view

      Staffan Olsson 

      I decided to add curcumin to my fisetin+quercetin+black pepper dissolved in olive oil for my second trial (one month after the first one).  I decided to add it based on the paper:

      https://www.mdpi.com/2077-0383/8/4/433/htm

      Curcumin and o-Vanillin Exhibit Evidence of Senolytic Activity in Human IVD Cells In Vitro

      o-Vanillin, apparently, is a metabolite of Curcumin.

      This combo is kicking my *ss...  It may be because I was just coming off a cold that I caught from my grandson last weekend, but I had major joint pain as well as a piercing pain in my left eye and sinus all night, etc...  Feeling reasonably good at present though, but still feel a bit "off" like I did with the original formulation.  With my original dose I felt a reasonable amount of joint and bone pain mostly about the third and fourth day after starting the dosage. (I took approx. 1 gram of each substance dissolved in oil with 1/4 tsp of freshly ground black pepper, on an empty stomach, for three consecutive days.  The first time the pain was mostly in and around the joints of the knees, femurs, backbone, shoulders and elbows.

      Interestingly, this time I only have the joint and bone pain in the knees and lower legs and ankles, particularly the left knee which always had the worst arthritic tendency.

      I was really feeling pretty good, very good actually, just before catching the cold, so I think the initial dose had a really beneficial effect on my joints.  I still get around normally, but seem to have arthritic or rheumatic tendencies, and it runs in the family as well.  I'm hoping this protocol will reduce those tendencies, and from the way I was feeling a few weeks after the first dose, I think it has.

      Reply Like
    • Don I plan to dissolve it with oil. Avaocado oil is my first choice. I try to incorporate more avacado oil in my lifestyle (mostly on salads) so it might just as well be used as a dissolvent to. 

       

      https://www.lifeextension.com/Magazine/2015/10/Avocados-Super-Enhanced-Carotenoid-Absorption/Page-01

       

      https://www.ncbi.nlm.nih.gov/pubmed/15735074

      Reply Like
    • Iðunn Thank you for the reminder. We are in uncharterd territory here, but that the territorry where selfexperimentation usually is. 

      Reply Like
      • Iðunn
      • Iunn
      • 5 mths ago
      • Reported - view

      Staffan Olsson Sure, but you want to be experimenting based on plausible preliminary data 😉. It's one thing to see something like fisetin — which has substantial senolytic effects and low toxicity in mice — and gamble that it may have similar effects in humans; it's quite another to make a similar gamble based on cells in a test tube, with none of the complex metabolism to which curcumin is subject (leading to its extremely low bioavailability). For all we know, something about curcumin or its in vivo metabolites might block the senolytic effects of fisetin — for instance, by competing for access to cellular transporters, altering membrane characteristics necessary for its uptake, or by affecting its metabolism or disposition.

      Reply Like
    • Iðunn if, like its said in this thread, the structure of fisetin and quercetin is very close to each other they might just as well end up competing for transporters.

       

      I see that Dan Nave already have tried the combo with interesting reactions. 

       

      Curcumin in a dose of 400 mg  BCM-95 is a part of my daily program. it has wonderful effects on my body and on my mind. After 15 years of selfexperimentation I think I have  found a few substances that have a robust and excellent effect (Both short term and long term) on me. Curcumin is one of them and that might lead me into a wishful thinking that curcumin not only might be taken with fisetin but that curcumin also might increase the senolytic effect.  

       

      I will use two protocolls. First without curcumin and then with curcumin.  

      Reply Like 1
    • Dan Nave 

       

      Hi Dan! How are you doing?

       

      Regarding curcumin and its role as anti-ageing agent. Senolytic or not?

       

      I read this article and I like to share it. There are groups promoting curcumin as a senolytic agent. But here curcumin is not seen as a primary senolytic agent but as a geroprotector. Quite a lot of in vivo studies and the salk institute chose curcumin and fisetin as the two most promising natural geroneuroprotectors. 

       

      https://www.researchgate.net/publication/328925429_Geroneuroprotectors_Effective_Geroprotectors_for_the_Brain

       

      https://www.genengnews.com/news/life-extending-alzheimers-disease-candidates-identified-from-diet-supplements/

       

      Curcumin is fascinating. I read  another article and it made me think about the importance of optimum dosing. Under the section "6 conclusion" they illustrate the  importance to find the optimal dose of curcumin. To much curcumin could be detrimental. 

       

      https://www.mdpi.com/1422-0067/20/5/1239/htm

       

      They also write that curcumin, as anti-ageing intervention, might work through AMPK induction. 

       

      "it is possible that positive effects of curcumin supplementation, observed on the organismal level, can be attributed to sirtuin and AMPK induction rather than the inhibition of cellular senescence"

       

      https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4991376/

       

      Bottomline: Is curcumin a senolytic substance?  we don't know. But there is a growing amount of indications that it is a promising anti-ageing agent. 

       

      Best Regards. 

      Reply Like 1
  • The F + Q + C (at approx. 1 gm each, in oil) + black pepper (approx. 1/2 tsp) seemed to be a little extreme for me, possibly because of the 50% increase of the quantity of senolytics taken with the addition of the 1 gm of curcumin.  Lots of aches and pains for up to 2 weeks and taking longer to return to normal than the first time last month with just F + Q + black pepper.  I also noticed lack of healing for a couple of small issues during the protocol.  I wouldn't want to do this again for perhaps 6 months.  I feel I got very good absorption and duration doing it this way.  Joints seem good and there is a definite reduction of spider veins.  Who knows if the benefits are deeper than that, time will tell...

    Reply Like
    • Dan Nave Hi Dave!

      I am doing this step by step. 

       

      First, I took senility activator double dose on two consecutive days. I felt good during those two days and I also felt good a few days after.


      After two weeks I tried a double dose of senolytic activator again and then I also added more quercetin. That made me feel even better during the two days as well as during a few days after. 
       

      Then after a few weeks I tried double dose senolytic activator with extra quercetin and I also added tocotrienols and curcumin and mixed it all in avocado oil, Then I added crushed piper longum fruits which was soaked in alcohol (piper longum has piperine as well as piperlongumines). That coktail  made feel unwell.

       

      I don’t know if feeling unwell was good or bad. Proof of strong reaction? Or maybe I did somehting to which my body answered ”this is to much”?

       

      Now I am aiming for fisetin experiments.

       

      As I have read in the now famous paper, They used both chronic feeding with Fisetin as well as intermeittent and acute short term use of larger doses of Fisetin. All experiments produced positive antiaging results.

       

      Later on I will add Fisetin to my daily supplements. But now I go for the larger senolytic doses. 

      Reply Like 1
      • BobM
      • BobM
      • 3 mths ago
      • Reported - view

      Staffan Olsson 

      Hi Staffan, can you kindly share your previous dosing of each item (F, C, SA) , and your body weight?

      Reply Like
      • BobM
      • BobM
      • 3 mths ago
      • Reported - view

      BobM 

      sorry F+ Q + C and the piperine

      Reply Like
    • BobM 

      Hi Bob! My body weight is 77-78 kg. 

       

       I have gradually incresed the dosing and along the way I have added more substances. (curcumin, tocotrienols and piperlongum)

       

      During my most recent senolytic experiment I used:

      - Double dose of senolytic activator.  That is 4 capsules. That should equal up to 2500 mg regular Quercetin. 

       

      - 3 capsules of Quercetin. The Quercetin I use is Life extension. Bio quercetin. (the same quercetin that's in the senolytic activator). That should equal up to 1500 mg regular quercetin. 

      https://www.lifeextension.com/Vitamins-Supplements/item02302/Bio-Quercetin

       

      - 1 capsule of Life extensions Super Bio-Curcumin® Turmeric Extract. (BCM-95®)

      https://www.lifeextension.com/Vitamins-Supplements/item00407/Super-Bio-Curcumin-Turmeric-Extract

       

      - Piperine. I have no exact dosing for the piperine. This since I used three crushed piper longum fruits which was soaked in alcohol after they were crushed.  

       

      The best experiement so far was double dose senolytic activator + 3 capsules of Bio-quercetin. 

       

      For my next experiment I will not use piperlongum and I will not use tocotrienols.  

       

       I have not yet started with Fisetin. I want to go through the selfexperimentation with the other substances first. 

      Reply Like
      • BobM
      • BobM
      • 2 mths ago
      • Reported - view

      Staffan Olsson 

      Hi Staffan

      Thank you so much for sharing all the details!

      Excellent data!

      Reply Like
  • When doing Fisetin and Quercetin senolytic doses consider dissolving the powders in oil before taking.  You could try with or without black pepper or piperine, etc. to see if that makes a difference.  F + Q are not water soluble and I think dissolving them in oil increases their uptake massively.  I don't think one absorbs much of the F + Q without dissolving it in oil.  

    For daily supplementation, you might be fine just taking a pill without the oil.

    Piperine is supposed to increase absorption massively (2,000% for Curcumin) and keep the liver from quickly metabolizing them.  F + Q + Curcumin are all substances that are affected by piperine according to my reading.  

    My advice is not to massively increase the dosages of these substances if you are going to use these mechanisms to increase their absorption and action.  I used only 1 gram of each for 3 days, seeing definite effects. (Weight of approx. 77kg)  I saw more effect when adding the Curcumin to the F + Q.

    Mechanism of piperine action:

    "In general, it inhibits drug metabolizing enzymes, stimulates absorption by stimulating gut amino acid transporters, inhibits the cell pump responsible for drug elimination from cells and inhibits intestinal production of glucuronic acid.

    It may increase the absorption of drug in the GIT, or inhibit enzymes responsible for drug metabolism, especially in the liver when the drug passes through the liver after absorption from GIT. Oral administration of piperine in rats strongly inhibited the hepatic arylhydrocarbon hydroxylase and UDP-glucuronyltransferase activities[30].

    Another study demonstrates that piperine modifies the rate of glucuronidation by lowering the endogenous UDP-glucuronic acid content and also by inhibiting the transferase activity[31].

    Piperine inhibits human P-glycoprotein and cytochrome P450 3A4 (CYP3A4)[32]. Both the proteins contribute to a major extent to first-pass elimination of many drugs.

    Some of the metabolizing enzymes inhibited or induced by piperine include CYP1A1, CYP1B1, CYP1B2, CYP2E1, CYP3A4 etc. Most of the drugs metabolized by these enzymes will therefore be influenced by bioenhancers."

    Reply Like
    • Dan Nave 

       

      So far I have learned that I get a rather strong feel good effect from senolytic activator. Especially when I take it with extra quercetin. An effect that lasts 2-3 days.

       

      I also tend to get a minor feel good effect of a senolytic dose of fisetin. But that effect (if it’s not placebo) is definitely smaller that the effect I get from quercetin.

       

      - Last weekend I took my first senolytic dose of Fisetin disolved in a 60% Phosalmix 50 PG, 30% PEG400. I took the same dose of fisetin on two consecutive days. I stayed at the dose used by the El Mayo researchers in their ongoing human trial, 20 mg Fisetin per kg. I was very inclined to use 35 mg/kg the second day but I  decided to stay at 20mg/kg.

       

      Any acute feel good effect is, of course, not a sign of a working senolytic therapy. But it is a pleasant surprise. There are plenty of harmful substances that produce acute feel good effects (Refined sugar is one out of many).

       

      So it’s wrong of me to assume a strong correlation between acute feel good effects and improved long term health. Feel good effcts are very wellcome, at least when they arise from improved health or reduced disease or inhibited ageing.

       

      I tend to experience some negative effects when I combine fisetin, curcumin, quercetin, and tocotrienols. Even if the dose for each substance is lower than what should be used in a serious senolytic approach. And even if they are taken without piperine containing compounds.

       

      At this stage I can only guess which substance that cause the unpleasant experience  My first wild guess is that it might be some interaction between the tocotrienols some of the other substances. This since curcumin and quercetin, when taken alone or when they are taken together give me a feel good effect.

       

      I also have in mind that the unpleasant feeling and the reduced wellbeing that I experience from to above mentioned combination might be a pure coincidence and is not an effect of any of the substances.

      Reply Like 1
      • BobM
      • BobM
      • 2 mths ago
      • Reported - view

      Staffan Olsson 

      Reply Like
      • BobM
      • BobM
      • 2 mths ago
      • Reported - view

      BobM 

      Great post. Thanks!

      Reply Like
      • JGC
      • JGC
      • 2 mths ago
      • 3
      • Reported - view

      Staffan Olsson 

           It seems to me that if a senolytic session is actually working, is should produce a transitory feeling of unwellness that might last up to a day or so.  The expectation of senolytics is that an accumulation of senescent cells is being driven to aptosis, damaged cells are disassembled, and aptosis-derived component proteins and compounds are being released into the bloodstream.  That seems likely to produce a mild fever and a feeling of unwellness.

           However, after the senescent cells are cleared, toxins in the bloodstream associated with SASP should be significantly reduced, and one might then expect a feeling of improved health and wellness.  That matches my own experience with fisetin and D+Q.

           Of course, this is all theoretical, because we don't have a way of actually measuring and verifying the predicted clearance of senescent cells.  But if quercetin does produce an immediate feeling of wellness, I doubt that it comes from senolytics.

      Reply Like 3
    • JGC that is a reasonable theory.  For now my reasoning is that high doses of quercetin reduces whole body inflammation or reduce organspecific inflammation. And might have minor senolytic effects on some tissues. My brother has morbus bechterew and since 2 years he has a very bad case of sarcoidosis in his lungs. He responds in a favourable way to high doses of quercetin. Especially when I give him senolytic activator + quercetin. A few years ago quercetin got some attention when they did some sarcoidosis research (in England I think). Only 500 mg per day. 

       

      When my brother take large doses of quercetin he reports an immidiate and dramatic reduction in symtoms from his sarcoidosis. Now he has done three sessions and during every session he reports the same immidate and dramatic effect. I know that they have tried D+Q on idiopatisk fibrosis of the lungs. And for the first time  the results showed that it was possible to increase of the functional capacity among the researched subjects (humans). Since qualified researchers in the field of senolytic therapy chose to specifically target a lungdisease as their first human deasease it might indicate that Q theoretically has a favourable organspecific effects on lungtissue. 

       

      Bottomline is that I think these observations is in line with what we know about Quercetin. That Q has minor senolytic effects but that Q Also has know antiinflammatory effects. And if my brother continue to report dramatic effects then I create a sarcoidosis thread here. this since he reports dramatic effects exceeding any medication. 

      Reply Like 2
      • JGC
      • JGC
      • 2 mths ago
      • 1
      • Reported - view

      Staffan Olsson 

           Your thoughts about quercetin and inflammation are interesting.

           I think it's important to measure as much as possible the effects of self-administered senolytic treatments.  The only available measure of inflammation that I have available is the c-reactive protein (CRP) test.  My CRP has almost always been rather low (<1.0 mg/L) in all the tests I've done before and after senolytic sessions.  The exception was a test when I had a large bruise on my leg and the CRP gave 3.7 mg/L.  It was back to the low value the next time I was tested when the bruise was gone.

        Have you had any CRP tests while you were taking the large doses of quercetin? 

      Reply Like 1
    • JGC No, I have not taken CRP test before the senolytic experiments. 

      Reply Like
  • Do u have any preference on ,"oil"  ?   Thanks  karl

    Reply Like
    • karl kuffner I used avocado oil. When I take senolytic doses of fisetin I will use the same mix as in the original research. " 100 mg/kg of fisetin in 60% Phosal 50 PG:30% PEG400:10% ethanol". Now I have recieved the substances. (From amazon). When it comes to creating a formula that increase the bioavailability of fisetin, the researchers doing the research must be  more competent than myself.

      Reply Like
  • I like olive oil, but I have used other oil such as you would have in your kitchen for baking etc.  Surprisingly, with the Fisiten and Quercetin it wasn't bad tasting and none of that unpleasantness you might get from just eating a tablespoon of oil...

    Personally, I am somewhat leery of ingesting PG and PEG.

    Reply Like
    • Dan Nave 

      I am also a bit reluctant to use PG, PEG. But will go for it when I start my fisetin experiment. 

       

      By the way I want to inform you about a research I read the other day. If you take Quercetin It might be a good idea to not drinkgreen tea before, during and after a senolytic session. 

       

      When Quercetin is co-administrated with Green tea polyphenols it increase the tissue absorption of Green tea polyphenols in some tissues. Lung and kidney.

      (But I have read somewhere else that Prostate tissues might have the same tendencies, that Q increase the absorption of Green tea polyphenols).

       

      https://europepmc.org/articles/pmc3590855

       

      "We observed a 2 to 3-fold increase of total and non-methylated EGCG in lung and kidney and a trend to increase in liver. In summary, combining quercetin with GT (Green Tea) provides a promising approach to enhance the chemo prevention of GT.

      Responses of different cancers to the combination may vary by tissue depending on the intrinsic COMT and MRP activity."

       

      "When mice were treated with quercetin alone, about 95 percent of quercetin was found in methylated form (isorhamnetin) in lung, kidney and liver tissues (Figure 5B). The combination of quercetin with GT decreased the tissue concentrations of total quercetin by 20-50% along with a decrease in isorhamnetin ratio to quercetin by 90%, 81% and 61% in lung, kidney and liver, respectively "

       

      This indicate that when you are aiming for senolytic effects, it is reasonable to be careful with ingesting Green Tea. It looks like it takes large doses to achieve a Senolytic effects and Green tea might hold back the maximal tissue concentrations of Quercetin in some tissues. 

      Reply Like
    • Dan Nave

      I have to correct myself. The study that I had in mind before is not about tissue concentrations. It is about synergies, it's about how quercetin synergizes with epigallocathechin gallate (EGCG) to inhibit prostate cancer stem cells.

       

      https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2933702/

       

      "Our data indicate that human prostate cancer cell lines contain a small population of CD44+CD133+ cancer stem cells and their self-renewal capacity is inhibited by EGCG. Furthermore, EGCG inhibits the self-renewal capacity of CD44+α2β1+CD133+ CSCs isolated from human primary prostate tumors, as measured by spheroid formation in suspension. EGCG induces apoptosis by activating capase-3/7 and inhibiting the expression of Bcl-2, survivin and XIAP in CSCs. Furthermore, EGCG inhibits epithelial-mesenchymal transition by inhibiting the expression of vimentin, slug, snail and nuclear β-catenin, and the activity of LEF-1/TCF responsive reporter, and also retards CSC's migration and invasion, suggesting the blockade of signaling involved in early metastasis. Interestingly, quercetin synergizes with EGCG in inhibiting the self-renewal properties of prostate CSCs, inducing apoptosis, and blocking CSC's migration and invasion. These data suggest that EGCG either alone or in combination with quercetin can eliminate cancer stem cell-characteristics."

      Reply Like 1
      • BobM
      • BobM
      • 2 mths ago
      • Reported - view

      Staffan Olsson 

      This article (Linked) is very interesting. It was published in 2010. Darn it takes a long time for good data to get to the public! 

      It is a tough read for non-medical folks like me. 

      Has anyone figured out dosing suggested from this? 

      Reply Like
    • BobM Yes this kind of articles are tough reads, Indeed very tough. 

      regarding human dosing of EGCG and cancerprevention/treatment I have found this article.

       

      https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5824026/

       

      "When the amount of EGCG necessary for the complete elimination of tumors in mice is converted to that for humans, it would be 6 – 9 Japanese-size-cups of green tea, i.e., 1.37 – 2.05 g EGCG/day/person." (2 g EGCG is a lot and might not be tolerated well)

       

      https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4384709/

       

      "The 10-year prospective cohort study by Drs. K. Nakachi and K. Imai revealed that drinking 10 Japanese-size cups (120 mL/cup) of green tea per day delayed cancer onset in humans by 7.3 years among females and by 3.2 years among males. "

       

      At least 1.2 liters of green tea. But keep in mind that different green tea has different amount of EGCG. So it's difficult to give specific recommendations. 

       

      When it comes to EGCG and green tea extracts there is an issue with absorbtion.

      To increase absorption of EGCG the recommendation is to drink green tea (or take supplements) on empty stomach and to have your tea with some vitamin C. Piperine, quercetin is also promoting absorption of EGCG. Most important is to avoid have green tea after a meal. At least if you want maximal absorption of EGCG. 

       

      yes its difficult to understand and to draw conclusions from the plentyful in vitro research that is done on green tea and EGCG.

       

      Thats why I rather trust the research made on green tea that humans actually drink. Like the 10 year prospective study mentioned above. I am not a big fan of pure EGCG supplements. Green tea is more than EGCG, For instance there is an indication that the small amount of coffein in green tea increase the absorbtion of EGCG and that the other substances in Green tea make EGCG more effective in preventing disease.  

       

      A guess made by using the  above reasoning could be to drink 1.2 liter of green tea  on empty stomach and before meals + quercetin + c-vitamin and maybe with piperine or black pepper. (One way to reach therapeutic level in vivo in the human body could be to take a dose of green tea extracts together with the real tea )

      Reply Like
      • BobM
      • BobM
      • 2 mths ago
      • Reported - view

      Staffan Olsson 

      very good!

      thank you!

      Reply Like
    • BobM  I like to give this link to you. it explains the issues surrounding green tea research. And it explains why I put more value on forwardlooking research done by tracking real people over time, drinking real tea. That reasearch indicates meaningful benefits from drinking real tea (and coffee)

       

      https://www.nature.com/articles/d41586-019-00397-2

       

      EGCG supplements taken on their own is more questionable. Green tea looks great for creating synergies with other substances. One example of this is the Pomi-T study. "A double-blind, placebo-controlled randomised trial evaluating the effect of a polyphenol-rich whole food supplement on PSA progression in men with prostate cancer" 

       

      https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4020278/

       

      A small amount of polyphenol rich whole food showed great benefit. Green tea was a part of the polyphenol-cocktail. 

       

      The subject in this thread is fisetin. I am sorry if I fell out of line. 

      Reply Like
      • BobM
      • BobM
      • 2 mths ago
      • Reported - view

      Staffan Olsson 

      excellent!

      thank you Staffan!

      Reply Like
    • BobM 

       

      Hi!

       

      Since I have written a bit about green tea extracts poor availability I would like to share this link to Life extensions new product.

      Claiming to be 10 – 12 times mora bioavailable than regular green tea extract and has 125 mg of green tea extract.

       

      https://www.lifeextension.com/vitamins-supplements/item02305/green-t-max

       

      The substance is called Origene 8 Liposome and is produced by coyne healthcare.

      https://coyne-healthcare.com/origine8-green-tea-extract/

       

       https://origine8.com/quality-science/

       

      They claim that 125 gr extract is equal to 10-12 cups of tea. (And 250 gr origene 8 extract equals 20-24 cups of green tea).

       

      But then again it is unspecific to talk about “cups” of tea. Serious researchers should talk about specific volumes measured in liters. A cup is sometimes referred to as 125 ml and other refer a cup of tea to  250 ml.

       

      When it comes to EGCG content in green tea I read in that it can vary from 50 mg/cup to 125 mg/100 ml. And sometimes I see other figures as well. One statement I have seen is that a cup of tea contains a total amount of 150 – 300 mg catechins. The discussion needs to be more specific.

       

      The bottom line is that a highly bioavailable green tea extract is very welcome. What we have to find out is if one capsule of life extensions new product is equal to the catechins in approx 1 liter of Japanese green tea.  Because that is the amount of green tea that seems to be required to receive the hoped for benefits.

       

      And hopefully this extract is easier for the liver to handle than other extracts.

      Reply Like
      • BobM
      • BobM
      • 1 mth ago
      • Reported - view

      Staffan Olsson Staffan Olsson 

      Reply Like
      • BobM
      • BobM
      • 1 mth ago
      • Reported - view

      Staffan Olsson 

      Hi Staffan

      ive been taking the new Like Extensions green tea supplement for a couple months now. I like it. One (or two tabs) a day. They are very small tabs, which is very welcome. And green tea colored ( most of what I see in supplements are brown).

      Reply Like
  •     Staffan,   If your weight is 100 kilos, what do you feel is an optimum dosage of fistiven, (spelled  wrong?) in milligrams, assuming  we take 500 mg capsules? (from a Brittish source)    thankyou       karl

    Reply Like
    • karl kuffner Karl, The clinical trial that is directed by James Kirkland at the Mayo Clinic uses 20 mg/kg on two consecutive days. That brings us to 2000 mg for a 100 kg person. that is four 5 mg capsules per day. 

       

      https://clinicaltrials.gov/ct2/show/NCT03675724

      (Alleviation by fisetin of frailty, inflammation and related messures in order Adults).

       

      Since we are at the beginning of fisetin human trials nobody can be sure what the optimum human dose is. My own speculation is that an optimum dose is above 20 mg/kg. In my next experiment I will increase my dose to 30 - 35 mg/kg. 

       

      How much fisetin that is actually absorbed is a crucial question. And I am very curious about how they handle the issues with absorption in the above mentioned human study. If we, in this forum, could get that information it would be of great help. 

       

      Since we, in this forum, use different approachens when it comes to the issue of absorption it is a hard for us to be very specific when we discuss optimum doses. What we can do is to be transparent about what we do to handle the absorption issue. 

       

      May I ask where you got the 500 mg capsules from? I have used 100 mg capsules and 500 mg capsules would be easier to work with.

       

      Reply Like
    • karl kuffner  Sir, thankyou for clarification on fisetin usage.   This mayo clinic study appears to be only for 2 days total, and there posted results seem to be " only" reduction in inflammation markers. How does that relate to "frailty syndrome"?   With your knowledge and experience, would you do this treatment protocol, monthly?   What would you sum up are the most definitive benefits of your self experimentation.?  THANKYOU      karl

      Reply Like
    • karl kuffner 

       

      The dosing regimen regarding fisetin is in its infancy. There have been research done using fisetin on two consecetuive days. And then the same treatment was repeated again after 4 weeks. 

       

      There has been senolytic research done with dasatinib och quercetin with doses taken three days consecutively then 4 days without treatment. and then another three days treatment followed by 4 day without treatment. And then they had another three days of treatment. The same substances have also been used on a biannual protocoll. 

       

      As far as I can read from the fisetin mouse study they showed a senolytic effect also from chronic feeding with a lower dose and not only from the intermittent treatment. 

       

      I am not a person to give recommendations based my fisetin experiments. I have recently started with fisetin. But I decided to start with a intermittent protocoll.

       

      Senescent cells are a driver of pathologies. Senescent cells ellicit an inflammatory respons and if a senolytic experiment reduce inflammation then that can be sen as an indication of a sucessful experiment.  

      Reply Like
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