Senolytics
I've just finished my third Senolytic cycle.
Fisetin 1500 mgs on 2 consecutihve days repeated one month later
Dasatinab 180 mgs on 2 consecutive days + Quercitn 2250 mgs on the same days
I also take 4 mgs of Rapamycin once a week and 500 mgs of MetforminER twice a day.
65 years young.
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Results? Side effects?
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Dan Nave
Zero negative side effects so far. Wound healing is better. Slight hair growth on head.
All inflammatory biomarkers optimal.
Have been able to discontinue my thyroid med and testosterone injections.
Will get new blood work next month
Very satisfied
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Charles Grashow
that is fantastic your massage ! First time I find in internet this direct link between androgen dificiency and senolitic therapy. I was diagnosed 3 years ago with age related androgen dificiency. The doctor prescribe me trt . I was using gel patch and now I am near 1-2 year on nebido inj for every 12 weeks. During last 3 months I start only with fisetin Mayo Clinic protocol and made it 2 times. And this really so curiosity for me - that is already pass 16 weeks from the last inj and my testosterone level do not go down. I was doing blood analysis every week in a different labs, think that it might be the mistake. With androgen dificiency right level of testosterone is crucial important for me just to have a normal living and normal work. I depends very much from trt. Before trt my testosterone level was going down bellow then 250 ng/dL if I don’t use trt. Also long time of trt suppressing of my own body production of testosterone.
And now I do not to know what to do - stop trt or to continue any way? Because now my level is not ideal, is suboptimal (near 450 ng/dL). And I feel not enough..Could you clarify little bit more how you could discontinue use of trt. How long you use senolitic to stop trt? How do you stop, immediately or any way continue some time with injection? How much in dynamics your testosterone level change?
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Charles;
you listed 2 different senolytic regimens. How did you separate them?
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As a rapamycin and metformin user, I'm unsure if senolytics will offer additional advantage when combined with mtor inhibition. The main reason for doubt is that in vivo tissue studies of mice (hepatic) and human (skin fibroblast) indicate rapamycin appears to produce a relative "clearance" of sensence as opposed to just inhibition of SASP and slowing senescent conversion. BiogerontologyJune 2019, Volume 20, Issue 3, pp 331–335, GeroScienceDecember 2019, Volume 41, Issue 6, pp 861–869|
Most impressively, the study of human skin showed probable clearance of senescent cells (by biopsy and staining) using a topical .001% rapamycin applied daily or every other day for 8 months. This concentration is like taking one milligram tablet rapamycin, crushing it, and mixing it with about 3.5 ounces (100 grams) of your favorite moisturizer.
It does appear that combining multiple anti-aging therapies can produce additive results such as the fruit fly study combining rapamycin, trimetinib and lithium Proceedings of the National Academy of Sciences, 2019; 201913212 DOI: 10.1073/pnas.1913212116. However, this drug combination affects the nutrient sensing network via three separate pathways which logically could be expected to be additive.
The issue with rapamycin combined with senolytics is: if rapamycin serves to clear senesence, then the addition of a senolytic therapy may not provide that much additional benefit. I have not seen any study which answers this question as it would require a rodent group with rapa, a rodent group with senolytics (and controls) and a combined rapa/senolytic group. Has anyone seen such a study?
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Mark Thimineur I’m no expert but my thinking is that rapamycin decreases the amount of cells that go into SASP therefore your body is able to clear SASP cells somewhat faster then the are created so the overall SASP burden goes down. That doesn’t mean senolytics won’t help IMHO.
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Mark Thimineur I think Josh Mitteldorf is trying to answer that with http://data-beta.net/
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Mark Thimineur by this logic taking metformin and rapamycin together would not be useful since both deregulate mTor.
however, a recent study showed targeting insulin and mTor pathways showed 400% increase in lifespan rather then 30% expected. So it’s possible adding a senolytic treatment will give more than expected
https://www.syfy.com/syfywire/nematode-worms-show-humans-how-to-live-longer
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Mark Thimineur Don't know if this has been answered or not, but here is a study checking many supposed senolytics and Rapamycin is one of the drugs that did not work to clear senscent cells, but Azithromycin did at a certain dosage for 5 days in vitro. Don't know what would be an appropriate dosage of Azithromycin to equal 100uM in petri dish. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6286845/ Ineffective table.
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Metformin is taken along with rapamycin to counteract some of the metabolic effects such as insulin resistance. I have no idea (nor does anyone) if the combo of these two drugs will be synergistic in terms of additive years to human life span.
Yes, genetically modifying the worm genome to manipulate insulin signaling and mtor systems lead to a 500% lifespan increase vs an expected 130%. Both of these pathways are distinct although perhaps somewhat convergent as they are separate parts of a nutrient sensing network. This synergy has also been shown in the fruit fly experiment by combining lithium (insulin signaling), rapamycin (mtor), and a tyrosine kinase inhibitor, all distinct paths of the nutrient sensing network showing a synergistic lifespan extension.
In the case of rapamycin combined with senolytics, they are both doing much of the same thing - decreasing senescent cellular burden. Much of the benefit of each may be acting on exactly the same endpoint and therefore not particularly additive. Study of this could be done as illustrated in a previous post.
For what it is worth, my opinion is that people using rapamycin at an appropriate dose earlier in life (pre-disease) will have markedly less senesence with aging. For those who are already progressed into the disease of aging without treatment, senscent burden will likely be higher. I surmise that people who start treatment later have greater probability of benefit from senolytics while those who have limited senscent burden (earlier treaters) will not benefit as much.
We don't know too much at this time so this seems logical - and this logic affects my personal decisions on my own treatments. Opinions like mine are not worth much until proven or disproven with the scientific method but it is all we can go on sometimes.
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From Dr Greens website
In a 2018 paper Blagosklonny states, "It has been calculated than rapamycin slows geroconversion by approximately 3-fold". This means rapamycin slows formation of senescent cells three-fold. [5]
it seems that if true rapamycin is not getting rid of older senescent cells, just slowing progression of accumulation of new ones.
I would interpret that to indicate another method is needed to rid old cells. I suppose if you start rapamycin young enough then a senolytic treatment is not needed
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Paul Beauchemin More recently and to the point of senescence cell burden, studies of rodents treated with mtor inhibitor showed clearance of hepatic senescence which suggested a probable senolytic action. (The mTORC1-autophagy pathway is a target for senescent cell elimination) Biogerontology June 2019, Volume 20, Issue 3, pp 331–335. The same conclusion was reached in the topical skin study GeroScienceDecember 2019, Volume 41, Issue 6, pp 861–869.
We therefore cannot conclude that the only action of mtor inhibition is to slowdown gero-conversion. This is at least one of the effects in addition to autophagy induction among others. A senolytic action may also be happening over time after multiple exposures as opposed to the rapid clearance with dastinib or fisetin.
Are anti-aging doses of rapamycin enough to get this potential effect - don't know. It seems that 10 micromolar topical for 8 months can achieve it in skin without epidermal drug penetration.
It is all very interesting and further research will certainly be revealing. Would love to see a study combining mtor inhibition and senolytic treatment.
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Mark Thimineur Yes I was wondering how you can get ahold of the 10 micromolar topical solution to apply to the skin? I wonder if it would help with creapy skin?
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garland Easy to make it. allowing 10% wastage it will be made by adding about 1.5mg to 4 ounces of whatever base you choose. Since the best solvent is DMSO I use a 70% DMSO/30% ALoe cream base and dissolve the rapa powder in a few cc's of pure DMSO before adding to the base and mixing thoroughly. I make it at 25 micromolar strength by using 3mg rapa in the 4 ounces. Tailor made compounding has 10 micromolar available but the price is about $30 for 30 grams which is equal to about $100 for 4 ounces. By making yourself the cose is about $25-30 per 4 ounces.
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Mark Thimineur Thanks that is awesome... Sounds like you maybe able to have quite a following if you decide to start a practice in Anti-aging. I may just buy it at the pharmacy to save time... I have rapa but it is in pill form so I am not sure how that works...... does this formulation work with Creamy skin? That would amazing if it does... do you just use it on the skin that show some aging? Or try to put it all over.....
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Mark Thimineur I just called Tailor made compounding and they claim that they do not have Micromolar .... what a bummer...
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garland They have .001% topical which is about 10 micromolar and it is available only with prescription. THe following link explains how I make the topical cream from tablets: https://forum.age-reversal.net/t/63j272?r=m1hq503
Here is the email response from Tailor compounding regarding my inquiry about rapamycin:
Hello Dr. Thimineur,
Yes, we do compound both topical and capsule versions of Rapamycin. They are available in our system under the name Sirolimus. Here is an idea of the pricing for the oral and transdermal versions.
Sirolimus 0.001% Transdermal Cream: $32
Sirolimus 3mg Capsule: $3.00/cap
Please let us know if you have any questions or if you require any additional information.
It seems they may provide health care providers who have established an account with them more accurate information than the general public. The reason(s) are probably to not promote products and draw attention which can lead to problematic interactions with state pharmacy boards and other agencies which seem to exist only to make licensed professionals lives miserable. Don't take offense to it.
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garland The answer to the other part of your question. Put the topical where it will do the most to enhance appearance. Usually that involves the face, front of the neck, back of your hands. If necessary, the other parts of the body that have suffered exposure to inonizing radiation (sun) - forearms etc. Once per day or once every other day seems to be more than adequate. It takes several months to notice the biological effect.
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Mark Thimineur thanks so much...Makes sense what you are saying. Which explains why they seem to hesitant to talk. Well let me know if you decide to do anti-aging I would be on board.......have you tried it on skin? Curious if it works with crepey skin....I guess that I will try it... I will report back... also how often one does it is another question...
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I’m currently starting my first Dasatinib (compounded generic formula) - 100mg + quecertin (1,000mg) In split doses for 3 days prescribed by Dr. Green. This is in addition to my weekly Rapa (6mg), candasartan (16mg daily), and tadalafil (5mg daily). Dr. Green is following a similar regimen. He only prescribed me one course of treatment and wants to see labs 2 weeks post treatment. He feels this senolytics treatment is complementary to my other meds. This is somewhat consistent with Mikhail Blagoskonny’s research although he has recently posted on twitter that the senolytics research is much weaker. Dr. Green’s formulation of D+Q for 3 days is similar to a recent human study that showed some positive results for a small study. After day 1 I haven’t really had any side effects except for a slight headache towards the end of day 1.
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Sam Biller Slight headache is what I always get too. Please check your pre-post balance ability if you can.
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Sam Biller Is both the dasatinib and quercetin taken in split doses? eg: 50 mg D and 500 mg Q, taken twice a day?
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Dan Nave Yes. Dr. Green asked me to split both the Dasatinib (50mg morning / 50 mg evening) and the quercetin (500mg morning / 500 mg evening).
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Larry Please clarify - post balance ability??
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Sam Biller
Where are you getting the D&Q from and would you mind telling the cost?
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