D+Q+F+P+L+G+GLA: A New Senolytic Cocktail

     For my May 15-18 senolytic session I tried something new.  In a recent Foresight Institute talk available on YouTube, James Kirkland identified the flavonoid Luteolin as a senolytic.  There have also been reports that GLA and Gingerenone have strong senolytic properties.  Therefore, on the theory that in a senolytic session the more different senolytics the merrier, I decided to combine these three with the D+Q+F+P senolytics that I has already been using.  It is not clear how much of the new items one should take, so I had to guess.  And so, in late mornings of this past Sunday, Monday, and Wednesday I took the following senolytic cocktail:

1 x 50 mg  Dasatinib  (From India; I usually take 100-200 mg, but only 3 tabs left)
4 x 475 mg Quercetin (Swanson)
10 x 44.5 mg Bio-Fisetin (Life Extension protected caps with x25 bioavailability)
1 x 10 mg Bioperine (Swanson)
8 x 165 mg Luteolin (Geroprotect Autophagy Renew)
10 x 200 mg Ginger Root Extract (Swanson, Gingerenone amount unknown)
5 x 400 mg Mega GLA (Life Extensionwith 10 mg Sesame Lignans)

     That’s a dismayingly large number of tablets and capsules, but for these three sessions I took them with water all in one sitting.  On Sunday evening following the first session I experienced a mild headache, mild intestinal cramps, and a feeling of unwellness.  On Monday evening I experienced stronger versions of these symptoms, plus frequent bowel movements and a mild fever.  On Tuesday I was scheduled for a 12:15 PM dog-agility training class, and I felt unwell enough that I almost skipped it.  My performance at class was sub-par.  When I returned home from it, I decided to defer the final Tuesday senolytic session by a day.  I went directly to bed and took a long nap.  On Wednesday I felt better, and I did the final senolytic session at about 11 AM.  This time the side-effects were not as strong, but I had a bowel movement that included a rather strong burning sensation, which I suspect was due to the exit of the Ginger Root Extract.  While I was sleeping last night from 3-7 AM I experienced mild intestinal cramps.  On Thursday (today) all the negative symptoms are gone, and I feel very well and energetic, with no bodily aches and pains at all.

    I attribute the negative side effects described above to (a) the residue of cleared senescent cells in my bloodstream and (b) the presence in my digestive system of molecules that are usually not present and are temporarily producing intestinal inflammation and cramping (and clearing senescent intestinal cells).  The observed effects were quite a bit stronger than I had experienced with D+Q+F+P sessions in October and in February, and I think the three added ingredients are achieving increased senolytic action and perhaps are clearing senescent cells of more diverse cell types.  I take the mild headaches as an indication that senolytic molecules are getting past the blood-brain barrier.

    All in all, I think my experiment was a success.  I plan to repeat the use of this cocktail for my next sessions in August.

33replies Oldest first
  • Oldest first
  • Newest first
  • Active threads
  • Popular
  • Thanks for the detailed report. In the future do you plan to continue the same cocktail, or will you make modifications based on this experience? Have you calculated the effective dosages based on interactions with piperine? What do you believe to be the effect of piperine on dasatinib? 

    Like
  • I think piperine only effects flavonoid input.

    Like
      1. JGC I'm not sure.

      I am confused by the following publications I found:
       

      Piperine, a major constituent of black pepper, inhibits human ...

      https://pubmed.ncbi.nlm.nih.gov › ...

      by RK Bhardwaj · 2002 · Cited by 579 — In summary, we showed that piperine inhibits both the drug transporter P-glycoprotein and the major drug-metabolizing enzyme CYP3A

       

      and this:
       

      Characterization of dasatinib and its structural analogs as ...

      https://pubmed.ncbi.nlm.nih.gov › ...

       

      by X Li · 2009 · Cited by 118 — Dasatinib is extensively metabolized in humans by CYP3A4. In this study, we report that the bioactivation of dasatinib by CYP3A4 proceeds through a reactive ...

      Like
      • JGC
      • Retired Professor of Physics
      • JGC
      • 6 mths ago
      • 1
      • Reported - view

      chuck stanley 

          On the basis of your references, piperine probably does boost the bioavailability of Dasatinib, which like flavonoids does have low solubility in water.  Perhaps it is a good thing that I took only 50 mg of Dasatinib per session (instead of the recommended 200 mg) because I was running out.

      Like 1
  • Why do you attribute your symptoms to senescence rather than to side effects of the substances you took?

    Like
      • JGC
      • Retired Professor of Physics
      • JGC
      • 6 mths ago
      • Reported - view

      Karl 

          All of the individual supplements (except the anti-cancer drug Dasatinib) are considered safe and are not known to produce intestinal cramps or mild fever).  The Dasatinib dose is very small and should have minimum negative effects (unless Chuck is right in suggesting possible enhancement by Piperine).

          On the other hand, when one is coming down with the flu (and having symptoms similar to what I experienced) the fever, headache, intestinal distress, and feeling of unwellness are because the virus is destroying cells and dumping their residue into the bloodstream in the process of reproducing itself.  Therefore, destruction of senescent cells is the likely cause of what I experienced.  Admittedly, some of the intestinal distress is likely the result of overburdening my digestive system, but my system is accustomed to something similar from my taking a stack of supplements every night before bedtime.

      Like
      • Karl
      • Karl.1
      • 6 mths ago
      • Reported - view

      JGC you may very well be right, and it would be hard to find any “standard” symptoms of senescent cell death.

      I do get gastro symptoms from one time doses of ginger and dasatinib. And I had severe fever, chills from Dasatinib.

      Like
  • I think you need to do more frequent sessions.

    Dr Green takes dasatinib and fisetin every 2 weeks.

    I think that is a bit too frequent, but people report return of inflammation that the senolytics alleviated after about 3-4 weeks.

    So I think monthly sessions are more optimal versus a few times per year.

    Like
      • JGC
      • Retired Professor of Physics
      • JGC
      • 6 mths ago
      • Reported - view

      Fred Cloud 

          You may be right, Fred, but until we can do real senolytic-effectiveness tests (maybe by using Judy Campisi's killed-senescent-cell detection technique)  there is no way of really knowing.  Even at age 87, I don't seem to be experiencing perceptible inflammation, so I'm not being pushed by that.  Further, the senolytic sessions I do are sufficiently unpleasant and disruptive that I wouldn't welcome doing them more often, so I've settled on every 3 months.  On the other hand, perhaps they would be less unpleasant and disruptive if I did them more often.

          I've run out of Dasatinib, and my former supplier in India, BonHoa, does not seem to be in business any more.  I hope that by August I will have been able to find an alternative supplier and replenish my supply.

      Like
  • Geroprotect Autophagy Renew is an interesting product. This since it is one of the few products that contain piperlongumine.

     

    I think it is a substance that could use at lot more attention since it has many interesting properties. One that comes to my mind is the effect on prostate tissues. It blocks the androgen receptor as well as induce apoptosis in many cancerous cell lines. Another nice property is its good bioavailability and the low threshold to reach therapeutic levels.  

    https://www.urotoday.com/recent-abstracts/urologic-oncology/investigative-urology/52516-piperlongumine-induces-rapid-depletion-of-the-androgen-receptor-in-human-prostate-cancer-cells-abstract.htm

     

    https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6087492/

    ”PL appears to be very safe, and its maximum tolerated oral dose in mice is >1 g/kg, while the effective therapeutic doses for cancer can be as low as 2.4 mg/kg by oral dosing."  If 2,4 mg/kg is translated to the human the equivalent, then 2,4 mg/kg in mice will be 2,4/12,3=0,195 mg/kg for a human. For a 80 kg person this means 80*0,195 mg =15,6 mg. to reach a therapeutic threshold for cancer treatment. So if you take 8 geroprotect autophagy renew then you take a dose of 80 mg piperlongumines.  

     

    80 mg looks like a massive dose! Have you noticed any change in urodynamics?

     

    https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5191878/#!po=53.0303

    "Another potential use of PL and its derivatives is in combination with ABT-263, or other inhibitors of Bcl-2 family proteins, for a synergistic senolytic effect. Although ABT-263 is a highly specific senolytic agent, it causes transient thrombocytopenia and neutropenia in patients this results from its inhibitory effect on Bcl-xL, which is important for platelet survival. We showed that PL had a strong synergistic effect on the senolytic activity of ABT-263 in vitro, potentially reducing the dose of ABT-263 needed to effectively deplete SCs. We expect this therapeutic approach would significantly reduce ABT-263-induced thrombocytopenia, making senolytic treatment with ABT-263 safer.”

     

    My personal exepience is from me taking at the most 3-4 geroprotect autophagy renew = 30 - 40 mg piperlongumine. I have taken the Geroprotect with theflavines (which are thought to be an inhibitor of BCL-2 ) which I bought from life extension. I also take it woth quercetin from thorne.  My anecdotal experience is that PL works well for me.

     

    One thing to keep in mind is that PL works in many ways. In ROS dependent ways as well as in ROS independent ways In some cancer research the positive effect of PL has been eradicated by n- Acetyl cysteine.

    Like
      • JGC
      • Retired Professor of Physics
      • JGC
      • 6 mths ago
      • Reported - view

      Staffan Olsson 

          I'm bit vague about the difference between piperine and piperlongumine.  I took 10 mg of the former and 80 mg of the latter in my three senolytic sessions.  In answer to your question, I did not experience any notable changes in urodynamics.  What changes might one expect?

      Like
    • JGC if the prostate is causing discomfort from BPH/prostatitis PL might (anecdotally) reduce the discomfort. 

      Like
      • JGC
      • Retired Professor of Physics
      • JGC
      • 6 mths ago
      • Reported - view

      Staffan Olsson 

          Fortunately, my prostate is normal size and has not yet been a problem.

      Like
  • JGC I'm just trying to understand. So you believe that the discomfort you experienced was clearing of senescent cells? Also, is this process normally regarded as something that happens so quickly?  Thank you

    Like
      • JGC
      • Retired Professor of Physics
      • JGC
      • 6 mths ago
      • Reported - view

      Michael 

          See my reply to Karl above.  Yes, I think the flu-like symptoms are the body's response to having the debris resulting from cell disassembly (apoptosis) dumped into the bloodstream.  It has been experienced by many of us who have done senolytics, and it tends to appear briefly on the first or second day of a senolytic sessions and stop soon after.  The symptoms I experienced were stronger than usual.

          Admittedly, there could be no senolytic action at all, and we could be just experiencing side effects of the flavonoids or Dasatinib, but the dose of the latter is small and flavonoids are not supposed to produce such effects.

          To put it another way, if senescent cells are indeed being killed, one would expect a body reaction similar to that when a virus is doing something similar.

      Like
      • Michael
      • Michael.1
      • 6 mths ago
      • Reported - view

      JGC Thank you

      Like
      • UB
      • U_Bednarzik
      • 6 mths ago
      • 1
      • Reported - view

      JGC After reading and benefiting from so many of your contributions to this forum, am trying to think of an effective analogy that might persuade for more frequent dosing. Waiting to accumulate enough deleterious senescent cells (and SASP) before a senolytic treatment seems like one would slowly lose ground to senescent associated illnesses and ageing...kind of like waiting too long between oil changes? Yeah, crappy analogy, but a healthier strategy may lie with the senomorphic benefit of quieting existing senescent cells with more frequent dosing. You maybe can't get totally rid of the senescent cells that you have, but you can at least quiet them (to a quiescent state, so no harm no foul) and not let them produce more zombie cells (as with infrequent senolytic treatments) that will eventually be producing their own SASP...like whack a mole.

      Like 1
      • JGC
      • Retired Professor of Physics
      • JGC
      • 6 mths ago
      • 1
      • Reported - view

      UB 

          As I understand it, Dasatinib and the flavonoids induce senescent cells to finish the job started by halting cell division by going into apoptosis.  However, these molecules have not been singled out of the vast spectrum of candidate molecules because they are senomorphic, i.e. they tame senescent cells by suppressing SASP.  It's my impression that senomorphic action is optimally done by different molecules.

          I don't have much enthusiasm for senomorphics, because I think bad molecules should be cleared and replaced rather than tamed, because even tamed they are too damaged to perform their intended functions.  Therefore, my approach is to lie in the weeds for three months waiting for suitable targets to accumulate and then hit them hard with a spectrum of senolytics.

      Like 1
  • That makes sense, but what would happen if you increased your treatment frequency to, say, once a month?...roughly the amount of time it takes for a senescent cell to start secreting SASP (and affecting adjacent cells). Think you would help break (or substantially slow down) the senescent cell production cycle associated with SASP exposure from adjacent senescent cells. Do you think this might, also, be physically verified by less fever-like reactions (and headaches?) from the more frequent interventions?...would be interesting to find out.

    Like
      • JGC
      • Retired Professor of Physics
      • JGC
      • 6 mths ago
      • 4
      • Reported - view

      UB 

          You said: "once a month?...roughly the amount of time it takes for a senescent cell to start secreting SASP, ..."   Where does that time estimate come from?

          Clearly cells all over the body are going senescent continuously, at some unknown rate that differs for each cell type.  And the time required for a given damaged cell to go senescent, to start producing SASP, and to induce senescence in neighboring cells is also unknown and likely different for each cell type.  Therefore, since we presently cannot test senolytic effectiveness, it's all a guess.

          My arrival at a 3-month senolytic cycle is based on several considerations: (a) each senolytic session seems to be doing something  in the form of short-term symptoms and longer-term feelings of health, (b) the three days of taking a lot of pills and  making flu-like symptoms are disruptive enough to my other activities that I don't want to endure them more often, and (c) I'm suspicious that if one does senolytics too often, it diminishes the effectiveness.  Of course, your suggestion that if done once a month the flu-like symptoms might be less severe is a good point.  However, I doubt that the intestinal discomfort from taking all those pills at once would be diminished.

      Like 4
  • Remember reading that on Dr. Green's senescence-related website (https://senolyticstreatment.com/) regarding the time-line from senescence to SASP. It's too bad about the discomfort at your present rate/schedule though. Quality of life is important too.

    Am guessing you don't subscribe to inhibiting your mTORC1 (e.g. taking Rapamycin) which reduces senescence rate ~ 3-fold?

    Like
      • JGC
      • Retired Professor of Physics
      • JGC
      • 6 mths ago
      • Reported - view

      UB 

          I was taking RapaPro once a week obtained from The Antiaging Store until I ran out and encountered supply problems and Chinese scam artists.  Do you know of a reliable supplier?

      Like
    • Like 1
  • A reliable (and relatively well reviewed) supplier is Towada Products via Indiamart--Ravinder Gandhi is the contact there. They offer several manufacturers, but recommend Biocon (Rapacan1) since they are better known than the rest. Remember buying 400 x 1mg for a little over $440 including shipping last year, so it's also very reasonable...but you'll have to wait roughly 3 weeks or so for delivery.

    Here's the link: https://www.indiamart.com/towadaproducts/search.html?ss=sirolimus

    Like 1
  • Hi, team. It's Dr. Mark McGovern, an Australian plastic surgeon interested in anti-ageing (yes, that is how it is spelt in English) medicine. I can vouch for the apparent reliability and efficacy of an Indian brand of dasatinib, being Dasakast-70 by manufacturer Aprazer Healthcare in New Delhi. I am 90 kg and took 4 x 70 mg tablets initially, with somewhat incapacitating GI symptomatology initially. At a dose of 210mg, I just get mild diahorrea for a couple of days. As for rapamycin, in Australia I can write myself a script for 100 tablets of 1 mg Rapamune (Pfizer) for A$41.30, i.e. about US $30. I am using 2,500 mg quercetin with my 3 monthly 210mg dasatinib and 100mg fisetin, the latter from Life Extension. Is there data supporting a higher fisetin dose? Cheers, Mark.

    Like 2
  • Is there any way of measuring senescent cells in the human body?  I am afraid we may be poisoning ourselves without a proper way to measure to see what is happening to our bodies.  Feelings can be deceptive as many feel great after recovering from major illness, but it is doubtful if the illness was beneficial.  The best forms of proof for me would be hair regrowth or spot removal (i.e. liver spots) or some other physiological change that can be measured.  Is there anything out there to prove senescent cell removal in vivo?  Thanks...

    Like 1
      • JGC
      • Retired Professor of Physics
      • JGC
      • 5 mths ago
      • 1
      • Reported - view

      Chris M 

          There are methods of measuring senescent cells, but no really cheap and satisfactory way:

      (1) The senescent cells in a tissue sample can be stained to indicate the presence of beta-galactose (SABG, a signal of senescence)  and counted with a microscope.  That requires an autopsy or a biopsy, however.

      (2)  In April-2021 Judy Campisi reported that the molecule dihomo-15d-PGJ2 was a unique indicator of the destruction of senescent cells.  It should be present in blood and urine after senolytics, and would come from the whole body, not just the blood.  In principle, it could be detected with an ELISA test, but I'm not aware that anyone is offering one.

      (3) The firm Jininiti offers an assay in cells from SABG in a blood sample.  That indicates immunosenescence, but doesn't say much about the rest of the cells in the body.

      (4) Dr. She of Jinfiniti has constructed a Senescence Panel (Jinfiniti Precision Medicine).  This includes SABG, 4 SASP (IL6, IL8, IL1b and TNFa) and a proprietary and unique NAD test.  That would cover a good fraction of body cells and use multiple ways of assessing senescence.  However, it is sufficiently expensive that doing before-and-after senescence panels along with a D+Q+... senolytic session would be out of my price range.   Someone with deep pockets should do it and report the results for the rest of us.

      Like 1
    • Chris M   I think CRP is useful as it depends in part on IL-6 and is not particularly expensive to test for.

      There can be problems when CRP goes too low for the sensitivity of the test, but I think it is helpful.

      Like
      • Chris M
      • Chris_M
      • 5 mths ago
      • Reported - view

      John Hemming Thanks.  I think that is probably the best thing to go on.  It also seems that inflammation is a key component of a lot of epigenetic age tests as well.  Sometimes I wonder if they should call them inflammation tests that compare inflammation levels at various ages.

      Like
    • Chris M 

      My view is that it is in fact the IL-10 levels in groups of cells that drives this.  IL-10 is part of SASP and is in theory anti-inflammatory.   Because it drives down NF Kappa B, the citrate carrier is down rated in the mitochondria and cells fail to differentiate.

      However, IL-10 is hard to measure and although CRP is affected by more things than IL-6 it is a workable proxy.  

      My own view is that cell differentiation (via acetylation) is the key to this rather than methylation patterns.

      Like 2
      • JGC
      • Retired Professor of Physics
      • JGC
      • 5 mths ago
      • Reported - view

      John Hemming 

          Yes, CRP tests are cheap.  At the moment, Life Extension does their CRP tests for $31.50.  I have tested and noticed some decrease in the CRP level following a senolytic session.

          However, the CRP level also depends on other things.  A few years ago I stumbled over a chair in the dark and received rather spectacular bruises on my right leg.  My CRP level shot up until the bruising went away.  Also, I note that the Levine Phenotypic Age calculation used the logarithm-base-10 of the CRP value to take into account the large variations it may have.

      Like
    • JGC IL-6 has a similar problem. CRP is a good compromise people need to be aware of its limitations.

      Like
  • I've long been fond of CRP testing, and short of more accurate & inexpensive tests to measure senolytic activity, it may be best.  However, almost all medicine & even holistic drug recommendations are based on weight.  Far more accurate, & useful, would be to include age, health conditions, etc.  For instance, CRP is mostly to catch over-all inflammation, which is likely root of all disease & aging, but shouldn't individuals with cancer, take more -- and/or more frequent -- dosing?

     

    Separately, maybe 30 years ago, as an LEF member, I did blood work through them, and despite checking the appropriate boxes, LEF used my blood results in a study (I found out through another error by LEF.)  And with LEF, publishing my results -- even without my ID -- is with purpose of selling various LEF products.  That & other experiences, have resulted in my not trusting LEF, although I still use some of their products, although buying from AMZN is same price as being an LEF member

    Like
Like4 Follow
  • 4 Likes
  • 2 mths agoLast active
  • 33Replies
  • 597Views
  • 15 Following