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 Extension, with 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.
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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?
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I think piperine only effects flavonoid input.
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- 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 ...
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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.
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Why do you attribute your symptoms to senescence rather than to side effects of the substances you took?
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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.
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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.
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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.
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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.
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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.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.
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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?
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JGC if the prostate is causing discomfort from BPH/prostatitis PL might (anecdotally) reduce the discomfort.
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Staffan Olsson
Fortunately, my prostate is normal size and has not yet been a problem.
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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
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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.
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JGC Thank you
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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.
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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.
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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.
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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.
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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?
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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?
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JGC dropshipmd.com
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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
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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.
