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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      • Larry
      • Larry.1
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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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      • Van
      • Van
      • 1 yr ago
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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.  

      Like
  • 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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      • garland
      • garland
      • 1 yr ago
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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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      • garland
      • garland
      • 1 yr ago
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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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      • garland
      • garland
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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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      • garland
      • garland
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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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      • Larry
      • Larry.1
      • 1 yr ago
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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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      • Dan Nave
      • Dan_Nave
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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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    • Charles Grashow The dasatanib was compounded by TMC http://ww.tailormadecompounding.com/

      6 50mg capsules were approximately $30. 

      The quercetin 250 mg capsules were purchased on Amazon. The supplier was Pure Encapsulations. $21.70 for 60 capsules. 

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    • Sam Biller These folks require a prescription but will send you a list of clinics in your area that may be able to assist with that.  We'll see 2what happens.

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      • Larry
      • Larry.1
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      Sam Biller I had a remarkably better balance on a yes4all board after taking D&Q. Try it, very unexpected. 

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    • Larry Interesting on the improved balance. 

       

      Here are my blood test results received earlier today. The change in some of these numbers is probably more related to my recent change to a ketogenic diet versus the pharmaceutical additions. 

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      • garland
      • garland
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      Sam Biller I just tried to call them up and they refused to give me a price unless I get a prescription and then they will only give the doctor a price... wierd.... are you sure on the price? It seems rather low....

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    • garland I've communicated with them directly and set up a physicians account for my practice. The price quoted to me was $3.50 for each 50mg capsule of dastinib. They also fill prescriptions for rapamycin at $3.00 for a 3mg capsule. They are a pharmacy and require a prescription which they recieve by fax directly from physicians office. I plan to begin using them for patients and personal.

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      • garland
      • garland
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      Mark Thimineur Thanks so much..... are you a doctor that specializes in Anti Aging stuff? Sounds like it. Where are you out of? Do you do phone apts? You sound like an incredible resource. I was using the pharmacy in Florida where the pharmacist recently passed away. SO alot of us are in the same boat with no source for Dasatinib

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    • garland Interventional pain management specialist who has integrated several anti-aging treatments into the long term treatment plans for a growing number of my older chronic pain patients with notable effects on disease and pain. I also personally treat some non-chronic pain patients - namely myself, my family, and some close associates and friends. I may set up a limited anti-aging practice because I see the need but I am very busy with my current practice. If or when I do this I will make it known. Right now I'm just in a stage of thinking about the mechanisms and structure that will allow a legit doctor patient relationship with proper follow up and monitoring. My location is Connecticut

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    • Mark Thimineur 

      FYI, I emailed Taylor made compound pharmacy and they did respond with a price that comes out to two dollars per milligram available in 3 mg tablets and my dr  is required to set up an account.

      So maybe prices are going up?

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    • Mark Thimineur I have been wondering if rapamycin could be beneficial for my 30-year-old daughter immune system as she  is constantly getting sick with colds? She has been chronically sick for the last 10 years and has had Graves’ disease, is on cortisol 35 mg a day as her adrenals do not work and she was  recently diagnosed  with Lyme disease which we think is the cause of all these problems, (that we think she contracted in high school.) She does a lot of alternative therapies including nutritional IV‘s, hyperbaric oxygen and has had exsomes injections which the doctor hoped would possibly benefit her inflamed biceps, in addition to the lymes.

      I don’t see a downside to experimenting with it other than it possibly impacting her digestion which  is a daily problem part of which is related to fighting colds and having her gallbladder removed.

      In your experience with rapamycin have you observed  a benefit for the immune system and how often does it affect digestion?
      We are desperate to try to improve the quality of her life as she never has a normal day and if she wasn’t constantly fighting colds that would be A big help. 
      Thank you in advance for your observations!
       

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    • John Mcgough The combination of Graves dz, Addisons dz, diffuse pain, gut symptoms, frequent "sickness" may be related (polyglandular autoimmune syndrome(s) or other related disorders). I assume there has been some eval on this and perhaps no clear answer. Seems like a coexistence of variable autoimmune and immunodeficiency. This is complicated and I have no clear answer for you in regards to mtor inhibitory treatments.

      General observations and known effects of mtor complex 1 inhibition is to improve immune function among older individuals. People treated with anti-aging rapa dosing seem to report less illness or shorter recovery.

      Rapa treatment in rodents and flies, and presumably all animals and humans will change gut microbiome from the mouth through to the colon. This has generally been considered benevolent or has improved health (periodontal disease improvement) and resulted in less measurable stool produced in rodent studies. People seem to observe they poop less.

      The youngest person I have treated is 30. This was due to a very stubborn rectal pain syndrome which was evaluated by multiple specialists without a clear etiology and required my prescription of clonezepam to suppress somewhat. At 3mg per week in this 62 kg person (over 6 months) there was reduction in pain and reduction in ADHD and anxiety, both of which were lifetime significant disorders. I have monitored this young person closely - no signs of anything adverse.

      I can't point to any specific personal observation or scientific study which would contraindicate a trial of rapa. I cannot provide specific medical advise other than that. Effects on your daughters condition would be of interest.

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    • Mark Thimineur thank you for your response. Are there any specific  test or special clinics or great Drs.  that you know of you that you recommend to check out  and treat polyglandular autoimmune syndrome? What type of doctor  specialize in this? I have googled APS-1 and it certainly seems to fit my daughter as an addition to the above problems I mention she has been on bio-identical hormones for years. It sounds like the treatment is to manage each problem as it occurs which is what we have done.

       The only other reason I can think of not to try rapamycin is that Lyme is from a bacterium and Dr. Green states you are at risk of bacteria infections with rapamycin. So do you think this could make the Lyme  disease worse because of the higher risk of bacteria infections or is it unrelated and not a risk factor?

      Her weight is about 145 pounds similar to the person you mentioned so you would recommend a 3 mg dose?

      thank you for your help and it seems like you have identified the exact problem.

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    • John Mcgough Antibiotic eliminates the tick borne borrelia burgdorferi spirochete completely. If treated, there is no infection. Chronic lyme symptoms occur in rare patients. However, these occur despite bacterial clearance and represent a baffling array of symptoms of unclear cause(s). What we know is there are no "lyme bacteria" in the body after treatment and none in the chronic symptom sufferers. That said, if she has had treatment, there cannot be worsening of Lyme with rapa. 

      To my knowledge, treatment for APS syndromes is hormone replacements. Probably the specialists with the most knowledge are endocrinologists but the treatment is simply to replace the deficient hormone. No preventatives that I know of.

      3mg dose (0.05mg/kg)  in a 30 year old make sense. consider maxing at 4mg (0.067mg/kg). Ages 45 and older usually means higher dosing between 0.08mg/kg to 0.15mg/kg per week. This has been my approach. Much of that is empiric and I think follows Blogsklonney and Alan Green parameters.

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    • Mark Thimineur 

      Thank you for your enlightening response. 
      At this point I think we should retest since she never underwent antibiotics treatment  because the doctor thought the side effects would be too rough on her fragile system so he used natural medicine products that she could start in small doses and slowly increase in an attempt to kill it. 

      If it is in-fact killed then we will try rapa. Thanks again.

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      • garland
      • garland
      • 1 yr ago
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      John Mcgough 

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      • garland
      • garland
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      John Mcgough Hello, John. I would start on LDN before I did anything else. LDN has accomplished miracles in the field of autoimmune diseases. It is a modulator of the immune system. And even seems to work with Lyme as well as other most other immune system diseases. Wishing you well. In your search

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    • garland 

      thank you for your suggestion and I appreciate input from anyone with  information. She has been on LDN starting  right after she had Graves’ disease about 10 years ago and it helped lower her antibodies from 1200 to below 50over many years.

      it’s only after many years of struggle, having to go on by identical hormones, and her having Addison’s disease two years ago that one doctor tested for Lyme disease last summer which came up positive. At that point we recalled A high school camping trip in which we think she contracted Lyme  disease.

      now she is often sick with a cold and I was thinking of trying rapamycin  as there are Studies that show it helps the immune system. But the problem is we don’t want the Lyme  disease to get worse if it has not been fully killed since she never took antibiotics as the doctor thought she couldn’t handle them and only took Chinese herbslike cat claw, skullcap and garlic which she could start in small doses and gradually increase. Currently she is off them as she is taking Candida medicine and plans to go back on them after the  candida is eliminated.

      and again thank you for your suggestion.

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    • John Mcgough I've now set up a practice account with Tailor and trying to master their EMR. Created and sent first patient script for rapamycin 3mg capsules. Total invoice for a 3 month supply of 6mg per week is $68.40 which comes out to $0.95 per milligram. There may be an additional charge for shipping. It may be that a script billed to practice account is discounted. Not sure.

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      • garland
      • garland
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      Mark Thimineur hello again... I bought 5 bottles of the Sirolimus transdermal Cream with the idea of mixing a capsule of the Sirolimus with the cream but the bottles are not easy to break apart.  Once we get it apart where do you store the material after you have mixed in some of the Sirolimus? I assume that you first mix the new Sirolimus with the DMSO etc and then add it to the one prepared from Tailor Made? I assume that you found that the higher concentration of Transdermal Sirolimus gives better results then the one from Tailor Made? I know you use DMSO as one of the new ingredients to mix with...what are the other ones you mix it with? How much does a one mg amount of Siromilus integrated into one of those bottles create? Are we close to the amounts that you use in your batches? Any ideas would be greatly appreciated....thanks

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    • garland The Tailor Made topical is .001% which is .01mg sirolimus per gram of the cream. I believe the Tailor Made topical is sold in 30 gram containers (of some sort). The total milligrams of Sirolimus in the 30 gram containers at .001% concentration is 0.3mg. I prefer to express in molar concentrations so that is just about 11 micromolar. I have mixed my topical at 25 micromolar and have found it to be extremely effective.

      To make this concentration using the topical you have purchased you would add 0.68mg of sirolimus to each 30 gram container. That is impossible doing this at home. Rather, if you combined all of the sirolimus topical you have purchased together getting 150grams, you would need to add 3.4mg sirolimus to get 25 micromolar. Since there is bound to be some wastage, adding 3mg would also get around this concentration.

      In essence, add 3mg sirolimus to all of your purchased topical.

      It would be much less expensive if you simply make your own. First purchase Dimethyl sulfoxide liquid (3.4 Oz - 100ml), Pharmaceutical grade, High purity, Heiltropfen from Amazon for $13.70. Then purchase DMSO Cream With Aloe Vera - Lavender Scented, Made With 99.9% Pure Pharmaceutical grade DMSO - 70% DMSO/30% Aloe Vera, Made in USA for Live Better Naturals 4 oz from Amazon for $19.87.

      Take 3mg of sirolimus - if from capsule it is already powder, if from tablet you have to use mortar and pestle. Mix that with 3-4 ml of DMSO. I suggest using a small capped test tube or something that can be shaken vigorously and allowed to sit for 10 minutes so all the sirolimus is dissolved. The fillers in the capsule or tablets won't dissolve completely so the solution will be cloudy.

      Scoop the DMSO cream into another bowl and mix in the DMSO/sirolimus thoroughly and place back into the original container and label it as containing 3mg sirolimus. With the expected wastage this will give you about 25 micromolar topical for a cost of about $33.60 plus the cost of rapamycin which is about $1 per milligram from Tailor Made, more or less from other supplies. My total cost is $36.60. The amount of grams in the 4 ounce cream tub is 118. So I am able to easily create the equivalent of four 30 gram containers of more potent (25 micromolar) topical for the cost one less potent (11 micromolar) topical from Tailor Made.

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    • garland Noticed a error in my prior post on the topical formula. Funny how my mind came back to this one day later as if it was bothering me. The total amount of sirolimus reguired in all 5 of your 30gram containers (150grams) is 3.4mg. Since the .001% already contains 1.5mg, you only need to add 1.9mg which is close enough to 2mg to just make it an even 2mg. If you already mixed it as I stated in previous post, it would be 33 micromolar which is about 3X the potency of the original.

      This is also probably OK but I just can't speak to it in terms of personal experience because mine is 25 micromolar. I've now applied to face, neck, and the back of one hand an average of 1.7 times per day for about 4 months. Others for whom I have provided this have been applying 1-2 times daily for about 3 months. Observable effects are becoming more obvious and clear in that there is a reversal of skin aging. Skin thickness and wrinkles are markedly improved, age spots are fading, the people using it, myself included, look younger.

      Word of caution - avoid applying to close to the hairline as this concentration is predicted to slow down hair growth because follicles require adequate mtor activity. I have noticed my facial hair has a decreased growth and I no longer have 5 oclock shadow and it is easier to shave in the am. I do apply a 2 micromolar solution to scalp and this is predicted to mainly effect autophagy which improves growth (induces anagen) and enhances melanocyte activity. Observations seem to indicate increased thickness and more black hair versus gray.

      It is all quite interesting and somewhat fun to observe these effects.

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      • garland
      • garland
      • 1 yr ago
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      Mark Thimineur Thanks a bunch for the increased clarity on what you do. So much of the time you do the solution 2 times a day rather then  one time. I am sure that makes a huge difference. I just put my order in for the DMSO and Aloe etc. Interesting Amazon is now pairing them together so that tells me that plenty of people are now doing this. I guess you are making a difference!!! 

      I also take Hyaluronic acid.... should I put that on before I do the topical solution or afterwords? I am starting to think that I should do that afterwords.... but wondered if you have any experience with adding other things? 

      Pertaining to the applying it to the scalp for the hair. I gather that the topical cream supplied by Taylor Made would be too strong for that purpose? Or would it be close enough we could use it? 

      I am still seeing if my doctor will give me a prescription for Rapamyacin from Taylor Made. She evidently talked with the pharmacist for a good while on Friday so I should know what the verdict is tomorrow. 

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    • garland the 11 micromolar Tailor Made would be to strong for scalp. My 2 micromolar is made by adding 0.2 mg sirolimus to 100ml DMSO and using the pump spray attachment that comes with the bottle to spray on hair then rub into scalp. It stings a little at first

      I can’t comment specifically about co-administration with hylaronic cuz i don’t use that product. I would suggest that you apply sirolimus first and give it an hour before applying anything else.

      I use two products in addition to sirolimus which I have used for years. They are Differin (Adapalene) 0.1% and lifeline skin care - the basic original stem cell product. Both of these have sound science behind them and are proven to work on fine wrinkles. The Differin should be applied at night and will take 3-5 weeks before you desensitize to the drying effect, after that no problem. The lifeline product can be used anytime. Btw, the sirolimus blows these others away but I feel that attacking skin aging via three distinct mechanisms is still advantageous

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      • garland
      • garland
      • 1 yr ago
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      Mark Thimineur Wow... which of the Life Skin products  with stem cells do you suggest? I have tried all kinds of things to work with my skin damage from the sun and nothing really helped very much.  I tried the life extension with stem cells and nothing happened...  HOwever I am Doing some laser now and am getting much more results that way...but still  more is needed....so this is very encouraging that the Sirolimus blows the others away

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    • garland Laser resurfacing and microneedling work because they create microscopic areas of injury in the epidermis which promotes collagen production and this technique is proven to improve the appearance of sun damaged skin and scarring.

      Dermal mtor inhibition and induction of autophagy with topical sirolimus involves inhibition of senescent fibroblasts and (it seems) eliminating senscent cells from the dermis/epidermis. The net effect is greater collagen production which is better organized, rejuvenation of skin stem cells, and repair and organization of the basement membrane. There are probably other mechanisms at play as well.

      In vitro (skin cell cultures) there also appears to be a protective effect in skin fibroblasts from solar radiation damage. "Rapamycin Protects Skin Fibroblasts from Ultraviolet B-Induced Photoaging by Suppressing the Production of Reactive Oxygen Species" Cell Physiol Biochem 2018;46:1849–1860. 

      Last summer my spouse and I became quite lax about applying sunscreen when boating and beaching as we noticed we seemed not to sunburn. I've tested this observation this winter on our many trips to the carribean and noted I needed less suncreen than previous and it really took alot of sun to get any kind of burn. We have been taking oral sirolimus between 0.08-0.18mg/kg weekly for about one year.

      I have performed about 30,000 flouroscopy guided medical procedures in my medical career in which my hands have been in the radiation beam. Between my enjoyment of the sun and the repetitive exposure to xray, my hands show significant radiation induced aging. I now see in my sirolimus treated right hand a progressive improvement in the skin compared to the untreated left side which has become pretty impressive at 4 months. 

      My opinion at this point is that the topical sirolimus appears to be among the most robust (if not the best) treatment for skin aging. It takes time as it does not induce it as quickly as laser but I'm observing a far greater net effect with the twice daily application than other techniques I have observed. I know a few plastic surgeons who would not like this to be known widely.

      The lifeline skin care product is either their "daily defense" or "night recovery" I would say these help, but nothing like the sirolimus. They are also a little expensive. I just use them because they work through a different mechanism as well as the differin which works as a retin-A product which increases cell turnover. Hope all this helps

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      • garland
      • garland
      • 1 yr ago
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      Mark Thimineur Wow...everytime you explain more about what you discovered it gets better and better! I noticed that there is a study published in Geroscience that found that topical Sirolimus was able to reduce skin aging and P16 significantly by using a topical solution of 10 μM which when I looked it up seemed to be 0.01 Sirolimus. I think you said that the amount from Taylor Made was 0.001 so it would seem that the amount used in the study is even greater then the amount you used in your explorations. Is my estimate correct?  I am not sure why it took almost 8 months to get any results from this study since the dose was so much greater than the onr that Taylor Made creates..... Any thoughts or ideas you might have would be helpful....here is the link...thanks......

      /www.sciencedaily.com/releases/2019/11/191125131311.htm

      Like
    • garland The last page of that publication under the heading "Discussion" states the following "A notable aspect of this study is the use of such a low dose of rapamycin (10 μM, or 0.001%)." The Tailor made and the study concentrations are identical. Mine is 25 microgram so it is 2.5x more. Read the rest of that discussion section and note the discussion of higher concentrations used to treat a condition known as tuberous sclerosis which causes, among other things, disfiguring benign skin growths. In higher concentrations it inhibits growth. The low concentration is used to influence the cells of the dermis but not impair growth or proliferation of skin cells. I had reservations about using 25 micrograms but proceeded and have seen the results to be positive. I can tell that mtor is inhibited because of the facial hair growth inhibition. Studies on rodent fur indicate that a 17 micromolar concentration inhibits fur growth but that concentrations of .017-1.7 micromolar make it more exhuberant. Thus the use of 2 micromolar on my scalp.

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      • garland
      • garland
      • 1 yr ago
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      Mark Thimineur Ok here is the latest from Taylor Made from my doctor who is willing to prescribe Sirolimus or rapamycin for me. Taylor made said that they will not do it because they only do compounded drugs. In short they claim that they do not do rapamycin because it is not a compounded drug. I think the nurse practiioner used the name rapamycin since that is what they got for me before from a different pharmacy. But how can they not know that Sirolimus is the generic form? It is going to be hard to get the capsule form of Sirolimus since they are primarily made in tablet form. I know that you feel that the tablet form is  still viable...but with the solid fillers I am sure that it is harder to extract this Sirolimus from  a capsule form. I did see some liquid forms that maybe available (one gram for one ml of fluid) Also I say a pharmacy that does this for animals.... I wonder if it is the same drug?  I suppose I can use that link you sent about how to extract Sirolimus from the pills.....just seems a lot easier to do this with the capsule form... If I can find it... sorry about being  a pest. I assume that others will also have similar problems as me though. 

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      • garland
      • garland
      • 1 yr ago
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      Mark Thimineur I did get the DMSO and Cream.... so I am ready to go.... once i get the Sirolimus.  

      Like 1
    • garland Tailor Made lists it as "sirolimus" and I have recieved the 3mg capsules from a script. It seems they are currently backlogged - not sure if from pandemic or recent FDA inspection. The 1mg pills that I have from Biocon are easy to grind to powder in a mortor and pestle and that is what I used before (for the topical)

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    • Mark Thimineur Will Tailor Made allow orders "for Office Use" for licensed doctors?  I know some compounding pharmacies don't even though it's not DEA schedule drugs.  I'm thinking about setting up an account.

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      • garland
      • garland
      • 1 yr ago
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      Mark Thimineur Yes I finally figured out what happened. The nurse practitioner for my Doctor  asked about Rapamycin... and the two people that she talked with did not know that Sirolimus was the generic form. But you are correct they are out... supposedly get some in Two weeks... I am currently using the topical from TaylorMade... so maybe I will keep on that. I tried to find the Biocon pharmacy in India but all I could find is the main company website... so no luck there. However if Taylor Made really does get some in in just 2 weeks then I can get some more there. I am currently using the topical of ,001 from Taylor Made... should have enough for 2 or 3 weeks... I use it all over my arms and am trying it on creepy skin on my arms.... and my sun damage face. I do notice that during the night i seem to have some night sweats on my upper torso near where I applied the topical.... any correlation?  I am starting to apply it two times a day now...see if it works faster. My forehead does look smoother though already after about 2 weeks...

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    • garland Topical takes time - by 4 months there will definitely be effects. Cant speak to sweats you experience - it does not go systemic but just sits on top of the cornified epithelium. Maybe since you are applying it on so much body - don't know. I don't see any harm.

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      • garland
      • garland
      • 1 yr ago
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      Mark Thimineur Sounds good. From what you were saying the topical you make seems to work in half the time. But right now I am stuck. Walgreens does not have any Sirolimus for at least 2 weeks....so I am going to try Taylor Made this week again. They said 2 weeks about 10 days ago or so. I want to try your version which is significantly more potent then the one from Taylor Made and much cheaper. Waiting 4 months is very time consuming. LOL.... I am still using Taylor Made topical which is ok but not sure if i see anything concrete or not.  Almost done with my second bottle. Maybe 2.5 weeks into this. I still would prefer the capsules although I have seen that some pharmacy's have Sirolimus in liquid form. Although it says that one is not mix in anything but water or orange juice. So I wonder whether it would not be absorbed very well in DMSO and Aloe.... but I assume it would be the same with extracting it from the pills since there is a lot of additives in the pills. I am sure they interfere some with the absorption of the pill form of Rapamycin. Likewise there is probably some additives in the capsule form as well. 

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      • garland
      • garland
      • 1 yr ago
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      Mark Thimineur Ok Taylor Made has Sirolimus in 2 mg tablets for 30 dollars a piece.  These are commercial tablets. SO they do not make them. And they do not know when they will be getting the Sirolimus that they compound into the cheaper capsules. So I am not sure whether they absorb as well as the ones you got from India. So I think it would be about 1.5 Tablets crushed which would be 3 Mgs and then mixed and Shaken in the DMSO which will then be combined to the 4 Oz DMSO Cream with Aloe Vera. I think I am reading you correctly. If you know of anyone with a capsule form of Sirolimus let me know. 

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      • garland
      • garland
      • 1 yr ago
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      Mark Thimineur Hello Mark... I have not seen you around here since the corona Virus hit so maybe you are tied up saving lives. If so Awesome!! I just did my first batch. I used 2 mg tablets which are harder to find. It tood a while to mix it maybe almost 3/4 of an hour. I wanted to make sure everything got mixed up thoroughly. I notice that I had to use at least 15 ml of DMSO to mix the pills with and maybe it was a bit more. But I wanted the extra liquid to make sure that it got evenly distributed in Aloe DMSO mixture. When I put it on my body I noticed it was very heavy and thick and it had a white coat to it until it sank in my skin. I was wondering if you had a similar experience? My skin feels as ifI have sun block on it... .. Also I was wondering how you get the topical for the head? No big deal on this one. When you get a chance. You might be saving the world.... so we have time... Talk to you when it is convenient.... keep up the good work...

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      • garland
      • garland
      • 1 yr ago
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      Mark Thimineur Another question for when you finally do make it back on this site. I am doing the topical solution that your told me about once a day and want to try 2 times a day. I noticed that you did not mention whether you did this after washing the area first or did you just apply it on top without first washing. Again no rush on this.... I hope you are ok...

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    • Mark Thimineur to refresh your memory I asked you about starting my daughter on rapamycin three months ago and you also have diagnosed her as possibly having APS syndrome.

      she  is constantly getting sick with colds? She has been chronically sick for the last 10 years and has had Graves’ disease, is on cortisol 35 mg a day as her adrenals do not work and she was  recently diagnosed  with Lyme disease which we think is the cause of all these problems, (that we think she contracted in high school.) She does a lot of alternative therapies including nutritional IV‘s, hyperbaric oxygen and has had exsomes injections.

      she has had her gallbladder removed and takes nystatin and probiotics including flora maces for persistent candida.

      so two weeks ago she started on weekly, 1 mg of Sirolimus. We decided to start on a very small dose since her body is very sensitive and always reacts to any type of medication and usually affects her sleep.  And she has noticed that it affects her sleep the first night, and she has intestinal gas pain starting The day she takes it which diminishes some each day and diarrhea since she started. She has also noticed that she feels hungrier the first three days after taking it but overall more hungry.

      so I was wondering if you have any observations and have seen similar side effects in any of your patients? I’m wondering if it is a detox reaction and hopefully will go away as her body adjust to it. The reason we decided to start sirolimus I found  research that supports the theory that Mtor contributes to lyme disease and that’s slowing it down would be beneficial.

      We would increase her dose to 2 mg if we thought it would not make her side effects more severe. So for now we’re continuing on 1 mg hoping her body will adjust before we increase the dosage.

      Thanks for any observations you may have.

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    • John Mcgough Appears to be idiosyncratic reaction which I have observed in very few patients treating with rapamycin. My observations are that these type of reactions do not get better with time and always occur when such a patient takes the drug. One of the key's here is that they are occuring at a dose of 1mg. I have seen this phenomenon in about 4-5% of patients and it always occurs even if the dose is 1mg. Sorry

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    • Mark Thimineur so even if we increase the dose or decrease to 1/2 mg the  reaction will probably be the same? Has anyone tried spreading the dose out to once every 10 days or two weeks? The main symptom seems to be the gas and diarrhea (which my dog also had for the first six weeks but then it did go away and she really improved) . 

      so none of the 4-5% who had this reaction were able to continue? Did they get any benefits in spite of these side effects? And how long did they try it?

      as always I appreciate your time and response.

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    • Mark Thimineur Thanks for your formulation help. Could you use higher concentrations but then use it less often say weekly?

      what would be the upper limit of safe?

      I found a guy on longecity formulating with 35mg per half ounce of topical solution. That would be about almost 300mg per 4 ounce, 100 times the amount!

      I wonder what could happen with such high amounts?

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    • Fred Cloud Treatment of tuberous sclerosis skin lesions utilizes higher concentrations by 10-100 fold. Inhibition of mtor with higher concentrations is effective against angiofibromas because it inhibits growth. No reports of problems but rodent studies indicate concentrations higher than 16 micromolar result in hair loss and open wounds. (see below)

      B.H. Walpoth, M. Pavlicek, B. Celik, B. Nicolaus, T. Schaffner, U. Althaus, O.M. Hess, T. Carrel, R.E. MorrisPrevention of neointimal proliferation by immunosuppression in synthetic vascular grafts Eur. J. Cardiothorac. Surg., 19 (2001), pp. 487-492

      Stimulation of Hair Growth by Small Molecules that Activate Autophagy. MinChai1MeishengJiang2LaurentVergnes3XudongFu2Stéphanie C.de Barros4Ngan B.Doan4WilsonHuang2JessieChu2JingJiao2HarveyHerschman256Gay M.Crooks46KarenReue35JingHuang2567

      https://doi.org/10.1016/j.celrep.2019.05.070

      The Drexel study on human skin aging showing positive result used 10 micromolar.https://link.springer.com/article/10.1007%2Fs11357-019-00113-y.  I made 25 micromolar because I did not want to inhibit cell division and growth but rather enhance autophagy and eliminate senescence as suggested in the Drexel study. I did not think 25 versus 10 would be detrimental and perhaps would be a little more effective for anti-aging. Why would anyone wanting to decrease aging concentrate rapamycin so much that it inhibits growth in an organ (skin) which relies on cell turnover? My opinion, for whatever it's worth, is to avoid harming myself while trying to extend years of health and to look better. I can tell you that the 25 micromolar mix that I have described has been highly effective for wrinkles and age spots in about 50 people that I have shared with (patients and personal). Takes several months to be sure of the effect.

      Like 3
      • Michael
      • Michael.1
      • 1 yr ago
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      Mark Thimineur Are you selling it?

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      • Michael
      • Michael.1
      • 1 yr ago
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      I spoke with Dr. Green on the phone a few times over the last 3 weeks and went from certain I was going to fly in -including  booking a flight and ordering blood work - to not wanting to see him based off what seems to be a really large cognitive issue. I don't know if it's simply age or whatever comorbidity others have mentioned elsewhere in this forum but, during call number two he forgot who I was, confused me with another pending initial visit. Separately, he accidentally dialed my number and left a three and a half long minute voice mail containing nothing but him moving around his house... I just don't feel comfortable based off of these three calls of mishaps to use him as a guide through this process. The money spent is under 1K.

      Big deal.

      Like 2
    • Mark Thimineur Thank you for your thorough response. I have followed your directions and made up a 25 micromolar concentration and have been using it for a couple of weeks already I just figured if it was a much stronger concentration I would only need to apply it once a week or so rather than everyday.

      Like 1
    • Michael Yeah, he is getting old. So what is your plan B for rapamycin? There are other docs that will prescribe it if that is what you want. I didnt use a doc and just sourced it myself and started it last month.

      Like 2
    • Mark Thimineur How about whole body application? I decided in addition to applying it daily to face that I would also apply it once a week to my whole body. I figure skin health is important beyond just asthetics of your face. I heard 70% of senescent cells are in your skin so keeping your skin healthy important to protect your whole body health. What do you think about this?

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      • Michael
      • Michael.1
      • 1 yr ago
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      Fred Cloud Two days ago I actually went to have the blood work done I paid for in preparation to visit Dr. Green. I'm not sure what I'm going to do. I might go after all. If you have any sourcing leads that would be greatly appreciated.  I DO want to try it for a year, just like I did with beberine, TRU NIAGEN and resveratrol throughout 2019. Those three seemed to not have any photogenic effect for myself at least and, as a previous decade long adderall user, energy was definitely not something they helped with. I was hoping to potentially get a source and try it for a year, along with potentially using MarkThimineur's idea on the hands and face. Smoking for decades has taken it's toll.  

       

      Since February 2020, I've started exercising again for the first time in decades. Lost 25 pounds, 4 1/2 inches off my waist, mainly doing loads of treadmill and walking with changing my diet. I'm ready to commit to the next program and I'd really like rapamycin to play a role in it. Ideally: rapamycin, metformin and hgh for one year. WITH PHOTOS lol

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      • Michael
      • Michael.1
      • 1 yr ago
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      Fred Cloud BTW. I am willing to pay you for a supply for face and hand photo aging purposes. I privately mentioned this to Mark Thimineur but haven't received a response and completely understand this is likely due to his professional standing. Anyway -There's that. Please post photos as you traverse the path! Thank you, Fred.

      Like 2
    • Michael 

      Like 1
      • Michael
      • Michael.1
      • 1 yr ago
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      John Mcgough Yes, Sir

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    • Michael you asked me about HGH but before I answer let me mention that I saw your problem with Dr. Green and I can tell you I love my doctor in Las Vegas Dr. Garcia. (702) 870-0058. 
      he is knowledgeable,  very good with regenerative medicine including stem cells and peptides and bio denticle hormones.

      in regard to HGH I have been taking it and bio identical hormones for 14 years. Because I’ve started rapamycin  and I don’t want HGH to interfere with that I now do not take it daily but a weekly dose, five days after my 7 mg rapamycin dose.

       

      I can’t tell you that I’ve ever noticed any improvement from taking all of the above as I didn’t have any severe problems when I started and I am extremely health-conscious having had terminal cancer when I was 30 years old so I’ve always followed a strict healthy lifestyle After doing an extensive natural(Gerson) program to heal myself.

      But no one I meet thinks  I am 71 years old given my athletic muscular body without  sagging skin which passes for 50 something. My endurance is great as I workout an hour to an hour and a half every day, doing weights, interval training on the bicycle daily, and tai chi. In addition to walking 3 miles.

      so I can’t tell you this is a result of HGH as I  have no definitive proof.
       

      But I’m not going to change my regiment and I personally believe everyone should be taking bio-I denticle hormones to maintain a middle of the range testing level. I’m surprised it’s  not discuss more on this website.

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      • Michael
      • Michael.1
      • 1 yr ago
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      John Mcgough Thank you, John. Here's my thing. I've smoked for 35 years and my eye bags and face make me look like I'm a sith lord apprentice. I used to do competitive power lifting (over 350-375 pound benches x 12 - 15 at a body weight of 130 in my 20's) and run 8 miles a day 7 days a week WHILE SMOKING a pack and a half of cigs a day. I'm now 52. I don't want a blepharoplasty before exhausting all non surgical means.

       

      A doc client/now friend of mine, uses hgh via scripts from another doc in CA and SWEARS by it for skin/face issues and cognition. Makes him "feel like he's in his 20's". That's what I want.  Not the body building component-The positive cognition and wrinkle effects.

      After trying the David Sinclair method for a full year and getting nothing, I was about to try the Blagosklonny (Rapa) method but, time's a running out.

       

      Thank you brother

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      • Michael
      • Michael.1
      • 1 yr ago
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      John Mcgough The other issue specific to someone beginning the journey is doc mind set.  Some are onboard with anti aging and will do rapa and metformin (The doctor Greens of the world - god bless them) and the other camp (Adderall- hgh - hormone therapy).

      To date, if I want to combine both worlds, I need: A. two different docs, B. two different sets of blood tests, C. two different monthly script refill fees going to the docs, D: Two different sets of scripts to pay for E: Quarterly / Annual Fees. 

      What am I missing here? 

      Like 1
    • Michael I think my doctor in Vegas Dr. Garcia would do all of those except I’m not sure about HGH. Most doctors are afraid of the FDA and getting in trouble for prescribing HGH without blood test showing efficiency levels. I  get my hgh without a prescription from another source.

      good luck.

      Like 2
    • Michael I would just source it from one of the several places everyone is getting it here and you can also make the face cream yourself very easily. I crushed up 3 tabs and put in a bottle of lotion, very easy. PM me if you want a source.

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      • yz
      • neon_ocean
      • 1 yr ago
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      Mark Thimineur could you show us some before/after photos? Thanks!

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      • JOHN
      • JOHN.1
      • 1 yr ago
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      Michael Hello Michael. I am a patient of Dr. Greens. My wife and I saw him July 3rd. He was fine. He's a brilliant guy. He has over 500 patients so it has to be confusing at times. Since seeing him I have emailed him asking for a couple other prescriptions and had a phone conversation with him. He sent the prescription in the mail like he said he would and he called me after emailing him with my test results on APOE4. Let me know if you notice any more concerns. I certainly hope he is ok.

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      • Michael
      • Michael.1
      • 1 yr ago
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      JOHN Thank you, Bro. I'll probably fly in.

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      • JOHN
      • JOHN.1
      • 1 yr ago
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      Michael Let me know how your visit goes when you get back. We flew in as well and I was very impressed with him. He spent about 5 hours with us. His office is his home and it's modest which to me is impressive.  It shows you where his intentions lie. He's an interesting man. 

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      • Michael
      • Michael.1
      • 1 yr ago
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      JOHN Thank you!

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      • garland
      • garland
      • 1 yr ago
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      Mark Thimineur Hello Mark...I have some questions but wanted to tell you that I have learned alot about your wonderful recommendations for topical treatment of Sirolimus after experimenting with them myself. I feel they work far better then anything out there however unlike you  I was not totally blown away with my success. Then after rereading your post I realized that you did this 2 times a day most of the time. So after trying that it seemed to make things happen a bit quicker. With this treatment you need to have lots patience as it takes time ... I have been doing this since April.. but my under eyes, neck and forehead is 70 to 75% better and most of the time I only did once a day. Now I am trying to 2 times a day for at least 3 or 4 a week. I did add a retinal product which seemed to help as well. I put it on every night after waiting for bit. I did not try your product Adapolene as I called the company and they did not think that it worked at all for getting rid or wrinkles. However it is supposed to be much stronger then regular retinal products so maybe it would work the same way only better? .SO I HAVE A QUESTION ABOUT THE RETINAL PRODUCT AND IF COULD CLARIFY THIS THAT WOULD BE AWESOME! Also my creepy skin is maybe 25% better on my arms which is huge as I never thought it would work there. Hopefully it continues to improve. ALSO I HAVE A QUESTION ABOUT APPLYING THE SIRULIMUS? I notice that that if I apply it on my skin while it is still wet if seems to go on smoother and lighter then if I put it on dry skin? MIGHT THAT ACCOUNT FOR MY RESULTS NOT BEING AS EARTH SHATTERING AS YOURS? I am wondering if I apply it in greater amounts than maybe it would be significantly above the threshold for optimal results. If you add too much Sirolimus then the results would be nulified.... What do you think about that. Wishing you well and thanks a bunch for sharing your experience with topical Sirolimus ...it is a huge gift you have shared with us!!!! 

      Like 1
    • garland Application frequency of topical sirolimus for skin aging is not established. Twice daily seems like it may allow a faster response than once daily, but who knows for sure. Applying more topical (versus less) may also lead to faster results. So to, maybe concentrating it more than my chosen 25 micromolar may be better, or worse - we don't know. The Drexel study used 10 micromolar applied once every other day and the results seemed impressive as seen on the biopsy histology. Most impressive was the elimination of all senescent cells after 8 months. As far as retinoids - they are well established to improve photo-aging (wrinkles, discoloration etc). Adapalene .3% is as effective as tretinoin .05% and a heck of a lot less irritating. The 0.1% has been studied as well and shown about as good an effect as 0.3% - and it is OTC (buy it on Amazon). Topical sirolimus and topical adapalene (or other retinoids) work by different mechanisms and thus should complement each other. I've noticed that patients who use both topical sirolimus and adapalene seem to have a better overall affect than just using one type.

      Like 2
      • garland
      • garland
      • 1 yr ago
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      Mark Thimineur Yes I think that 2 times daily seems better ... and mixing it with Retinal seems to make it better as well. I did 3 months with doing it once a day and  no retinal and I still got good results.  I will get the Adapalene... I have a doctor who could probably get me the .3 % if you feel is even better? Thanks so much for clarifying everything. I look at your interaction with me as way for others to follow along and they can be helped as well. And if you ever open up to seeing anti-aging clients please let me know as I would love to work with you. You are a good man and I appreciate your heart because you have helped alot of us in different ways! 

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      • garland
      • garland
      • 1 yr ago
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      Mark Thimineur Hello again... I found some research that shows that .3 Adapalene is more effective than .1. However it was looking at Acne so not sure if that relates to Wrinkles but I think it applies to repair of skin so most likely it is more effective. Anyway I will try the .3 if I can get it or else use the .1.... Take care

      Like 1
  • just finished second dosage of dasatinab and quercetin. First time had a slight headache and hours of diarrhea. Had taken on an empty stomach which I've learned is not good for anything I take.  This time no issues at all

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      • Michael
      • Michael.1
      • 1 yr ago
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      Paul Beauchemin The ONE TIME I tried quercetin I felt like I had to pee for hours but couldn't. I have a full bottle if you'd like me to mail it to you! lol

      Like 1
  • Question for group: can any of these products help boost immune system for protection against coronavirus? 
    Rapamycin? 
    Dosing for this ?

    My wife and I will be traveling to Hawaii and worry a bit about all the exposure. 

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      • Karl
      • Karl.1
      • 1 yr ago
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      BobM you’re considering taking an immune suppressing drug when you’re worried about exposure to an infection?

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    • BobM low doses (.05-.08mg/kg) once weekly will enhance immune response but offers no protection against corona virus infection

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      • BobM
      • BobM
      • 1 yr ago
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      Mark Thimineur 

      Hi Mark, thank you for the thoughtful reply. 

      I guess we will just take masks along in case we get around suspicious people or situations. 

      cheers

      bob

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    • Mark Thimineur  Blagosklonny wrote in a paper that Rapamycin also inhibits viral replication [18,19]. As a noteworthy example, rapamycin inhibits replication of the 1918 flu virus (the deadliest flu virus in history) by 100-fold [19], and also protects against lethal infection with influenza virus when administered during vaccination [13].

      Since coronavirus is a virus, at least hypothetically, it would seem Rapamycin might give some protection or slow down viral replication.  Might be off base and connecting dots that aren't there 

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      • BobM
      • BobM
      • 1 yr ago
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      Edward Meininger 

      Good post.

      I’m interested in all the opinions here. Is our dosing possibly helpful? 
      Thanks!

      Like 1
  • Here is another Doctor Who prescribes rapamycin in Las Vegas.

    I thought I would provide the name of my Doctor who does prescribes rapamycin but his practice  is different from Dr. Green in New York. 

    I have found him to be veryknowledgeable and extremely helpful as he is versed and prescribes bio-identical  hormones, PRP, peptides and other healing modalities. See below. 

    Julio L Garcia, M.D. 

    Regenerative Medicine Institute of Nevada
    dedicated to helping patients with mesenchymal stem cell/ cytokine/ growth factor therapies and peptides for the treatment of acute and chronic medical issues
    www.rminlasvegas.com
    (855) 786-2356 toll-free  

    (702)838-0571 local 

    Like 1
  • A new wide spectrum senolytic SSK1 in development.  They imply that it works on all senescent cell types and works better than Dasatinib, Fisetin, and Quercetin.

     

    https://www.nature.c...1422-020-0314-9

     

    In this study, we designed a new prodrug based on the major senescence marker — the elevated β-gal — to selectively target senescent cells. This prodrug, SSK1, specifically killed both human and mouse senescent cells independent of senescent cell types and inducers. In a mouse lung injury model, SSK1 cleared stress-induced senescent cells in vivo and alleviated associated symptoms. Importantly, SSK1 also effectively reduced naturally occurring senescent cells in aged mice, decreased the senescence- and age-associated gene signatures, down-regulated SASP both locally and systemically, and restored physical functions. These results demonstrated the robustness and specificity of our prodrug in reducing senescent cells.

    We successfully developed a new prodrug strategy that directed gemcitabine to kill senescent cells in a highly selective manner. The foundation of our prodrug strategy was to select a highly specific senescence marker and identify an appropriate potent drug to efficiently kill senescent cells. First, the elevated enzymatic activity of β-gal, a universal senescence biomarker both in vitro and in vivo,18,52 was utilized to direct the prodrug to specifically target senescent cells. Second, through the screening of hundreds of FDA-approved drugs, we found gemcitabine to be one of the most potent agents in killing non-dividing senescent cells (Fig. 1a; Supplementary information, Fig. S1b, c, and Table S1). In addition, gemcitabine is a widely used FDA-approved drug with proven safety and short plasma circulation time.25,26 Our designed prodrug SSK1 is activated to release gemcitabine selectively in senescent cells (Fig. 1c), following which senescent cells were effectively eliminated (Fig. 1d). Our further study showed that gemcitabine activates p38 to induce apoptosis in non-dividing senescent cell (Supplementary information, Fig. S2a, b). As a nucleoside analog, gemcitabine could kill senescent cells through inducing mitochondrial DNA damage (Supplementary information, Fig. S2d), similar to a reported nucleoside analog, Ganciclovir.33 These results demonstrated that prodrug SSK1 is superior to current reported senolytics in terms of design strategy and specificity.

    Cellular senescence is a highly heterogeneous process due to the different cell origins and stimuli,6,53 whereas the key feature of SSK1 is the ability to efficiently clear senescent cells with a broad spectrum of cell types and senescence inducers, including replication, irradiation, oncogene and genotoxic stress (Fig. 2a, c). In this study, we compared SSK1 with other reported senolytics on HEFs, human preadipocytes and HUVECs, which were used to test senolytics. ABT263 (a classical anti-apoptosis BCL-2 inhibitor) eliminated senescent HEFs and HUVECs, but showed little effect on human preadipocytes (Supplementary information, Fig. S3b, f, j), which was also reported by other previous studies.12,13 The combination of dasatinib (a pan-tyrosine kinase inhibitor) and quercetin (a plant flavonoid) killed all three types of senescent cells in a dose-dependent manner (Supplementary information, Fig. S3c, g, k), but had a high toxic effect on non-senescent cells in consistence with others’ results.11,16,36 Another natural flavonoid fisetin, reported as a potential senotherapeutic agent,15 showed modest effect on eliminating senescent HEFs and preadipocytes even at higher concentrations (Supplementary information, Fig. S3d, h) which was comparable to other’s results.54 Most importantly, SSK1 could overcome these limitations, including cell-type dependency, high toxicity on non-senescent cells, and low efficiency on senescent cells (Supplementary information, Fig. S3a, e, i). Therefore, SSK1 possessed a better senolytic activity regarding of specificity and efficiency on a wider range of cell types, demonstrating the superiority of β-gal-based prodrug strategy to target senescence.

    Moreover, we found SSK1 exerted its elimination effect on senescent cells in vivo. SSK1 eliminated stress-induced senescent cells effectively and decreased different senescence markers in bleomycin-induced lung injury model, highlighting its effectiveness in vivo (Fig. 3). SSK1 treatment also relieved lung fibrosis (Fig. 3d; Supplementary information, Fig. S4c, d) and attenuated the impaired physical function as tested by treadmill assay (Supplementary information, Fig. S4f). In this study, we also treated naturally aged mice with SSK1 and tested its effects on senescent cells, chronic inflammation and physical function. First, SSK1 could remove senescent cells in multiple tissues and decrease the senescence-associated signatures as shown by the GSEA analysis (Fig. 4b–g). Second, SSK1 could decrease the expression of SASP-associated genes in aged livers and kidneys and reduce chronic low-grade inflammation in the blood (Fig. 5a, b, e–h). Third, SSK1 ameliorated the impaired motor function, balance, exhausted exercise, muscle strength, and spontaneous exploration in aged mice (Fig. 6a–e). Most importantly, the performance of rotarod and beam balance in the SSK1-treated group was improved compared with that in the initial pretreatment condition (Supplementary information, Fig. S8e, f). Collectively, our prodrug SSK1 targeting β-gal-positive cells exerted very significant biological effects in naturally aged mice.

    While SA-β-gal is widely used as a marker of cellular senescence,20,21,22 its elevated activity can be found in some other cells such as activated macrophages.48,55 These SA-β-gal-positive macrophages can be harmful and have been found to accumulate in injured and aged tissues contributing to chronic inflammation.44,45 Importantly, we have shown that SSK1 decreases the number of SA-β-gal-positive macrophages in injured lungs and aged livers (Supplementary information, Fig. S6g–j), which is consistent with our observation of reduced secretion of chronic inflammation-related cytokines. Therefore, eliminating macrophage accumulation by SSK1 might reduce chronic inflammation and benefit aged organisms. In addition, activated macrophages play crucial roles in acute inflammation and cytokine storm,56 especially those induced by virus infection. During virus-induced acute inflammation, macrophages produce pro-inflammatory factors and trigger initiation of cytokine storms.57 For instance, the depletion of macrophages could protect mice from coronavirus-induced lethal infection.58 Accordingly, activated macrophages could be potential targets for treating acute inflammation and cytokine storms via SSK1. The future potential for SSK1 in treatment of acute inflammation, injury, and age-induced chronic inflammation is promising.

    An understanding of the toxicological effects of SSK1 in vivo is critical to clinical applications. Importantly, our data showed that high concentration (100 mg/kg) and high frequency SSK1 treatment had no apparent systemic toxicities (Supplementary information, Fig. S9). This provides strong evidence for the in vivo safety of SSK1. This safety profile is further supported by comparison to gemcitabine, an SSK1 effector and approved clinical drug. First, our effective in vivo dosage of SSK1 was approximately 60-fold lower than the clinical dosage of gemcitabine (30 mg/kg) and implies a greatly reduced risk of in vivo toxicity of SSK1.24 Second, gemcitabine is a nucleoside analog that potently affects rapidly dividing cells and the off-target effects of gemcitabine could be shown in different proliferating cell types.59,60 SSK1, however, targets only β-gal-positive cells. Notably, in addition to macrophages, we found that the majority of non-senescent β-gal-positive cells are rapidly dividing epithelial cells (Supplementary information, Fig. S10a, b). As a result, the potential types of proliferating cells with SSK1 sensitivity are greatly narrowed relative to gemcitabine. Even though small numbers of β-gal-positive epithelial cells are targeted by SSK1 treatment, these cells have robust self-renewal ability.61 Consistent with this self-renewal property, we found that epithelial tubular cells in the kidney with elevated β-gal activity had a high percentage of Ki67-positive cells (Supplementary information, Fig. S10c). Following SSK1 treatment, we observed only a few cells of this tubular cell population undergoing apoptosis (Supplementary information, Fig. S10d), and such low-level impairment could be easily repaired by the rapid self-renewal of tubular cells during SSK1 treatment. Moreover, the short duration of SSK1 treatment might avoid significant impairment in related tissues and further minimize its side effects. In summary, our study demonstrates the superiority and safety of this prodrug strategy by targeting β-gal to selectively remove senescent cells of multiple cell types. These findings open a new avenue for the treatment of age-associated diseases and provide a clinical opportunity for intervention into the aging process.

    Like 2
    • Dan Nave That is fascinating news. I wonder how effective regular gemcitabine would be if we compare it to Dasatinib? great info thank you.

      Like 1
    • Staffan Olsson i don't understand, gemcitabine and ssk1 is the same? Or does it act with the same benefits without affecting other cells that are not senescent?

      Like 1
    • Pablo Reinaldos López As  I understand, they have created something that is better to deliver gemcitabin into senescent cells. "..designed prodrug SSK1 is activated to release gemcitabine selectively in senescent cells"

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      • Karl
      • Karl.1
      • 1 yr ago
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      Dan Nave great find. Unfortunately sounds like this would become a patented drug and fetch a high price?

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      • Dan Nave
      • Dan_Nave
      • 1 yr ago
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      Karl We can only hope for a reasonable price.  Who wouldn't want to use it. 

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      • JGC
      • JGC
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      Dan Nave 

          I don't think SSK1 could be made available here in the USA without having first a trial on humans. It would be very hard to get the FDA to approve such a trial on a drug that treats aging (because in the view of the FDA, aging is not a disease and therefore doesn't require treatment.)  Oisin Bio, with their plasmid/liposome treatment to clear senescent cells by inducing aptosis, has just that problem in getting a trial, and it took many years to get approval for the ongoing Mayo trial of metformin.

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      • JGC
      • JGC
      • 1 yr ago
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      Dan Nave 

          On the other hand, the Chinese paper gives explicit instructions for how to synthesize SSK1, and it's simple enough that most organic chemists in well-equipped labs could do the job.  I calculate that SSK1 should have a net molecular mass of about 925.9 Da.  That's not a very large molecule.  Vitamin B12, which is taken orally, has a mass of 1,355.4 Da.  I wonder what the water solubility of SSK1 is.

      Like 2
  • attacking senescent cells is evolving as the #1 treatment for aging

    Like 2
    • Paul Beauchemin 

      I just took my first senolytic cocktail yesterday and had a unusual reaction and wondering if anyone else had similar

      I am 70 yr old male (n=1) who has taken rapamycin for two years weekly.  Also metformin for years (nondiabetic).  Took the following after lunch yesterday :

      90mg dasatinib , 1200 mg quercetin, 250mg AZM, 300mg fisetin

      No reaction for 5 hours. Then had a bout of diarrhea for 30 minutes.Then OK.  Eat dinner. 2 hours later started having some body aches but not bad.  Went to bed 2 hours later had more aches and then the chills and shivering in bed and had pain in all my joints.  Lasted 2 hours and then went away.  Woke up fine.

      I was going to take 2 more days of this protocol but now I'm having second thoughts.

      Anyone have similar complaints.  Was it a reaction to dasatinib?  I think senolytic's is the future but maybe a different protocol.  Any ideas appreciated

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      • Van
      • Van
      • 1 yr ago
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      Edward Meininger Wow, it is not necessary to take all of them at one time.  There are 4 different types of senolytics, and each supplement works best on one.  Please read Dr. Green's new website.  At the bottom he recommends the one's your taking and the doses and schedules.  I have also taken Rapa for 3 years, and do the senolytics quarterly.   https://senolyticstreatment.com/

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      • Joe smith
      • Joe_smith
      • 1 yr ago
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      Edward Meininger please stop what you doing and see doctor ASAP!

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      • Dan Nave
      • Dan_Nave
      • 1 yr ago
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      Edward Meininger Do you normally have joint problems, arthritis, rheumatism, etc?

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    • Dan Nave I don't have any joint problems or pre existing conditions.  Read Dr Green's page re senolytics.  Seems some of studies used D + Q and others just D. I combined all 4 senolytics which may heve been a mistake.  Do most people use Singular senolytic?

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      • Karl
      • Karl.1
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      Edward Meininger I have only taken D&Q once, but it kicked my ass.  Nausea started at 2 hrs and last for about 10 hrs with vomiting at the end. Body aches and fatigue for several hrs, and about 10 hrs post dose I had fever and rigors. I will definitely change dosing next time.

      Like 3
    • Karl Your reaction was certainly worse than mine.  I was able to do 3 days of AZM 250 mg with no real problem.  I will try fiesetin alone 1500 mg next quarter.  I think senolytics with weekly Rapamycin is a game changer

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      • Joe smith
      • Joe_smith
      • 1 yr ago
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      Edward Meininger My concern with the senolitics is that big-time researchers like Judith Campisi and Dimitry Bulavin clearly state and demonstrate through their research that senolitics don’t extend the lifespan. Further, Dimity Bulavin research indicates that senolitics may actually very negatively affect quality of life. For instance liver is not very good at regenerating after senolitic treatment in older age resulting in fibrosis. The fibrosis is not just in liver. He actually has to kill poor mice under treatment as their bodies are clearly damaged and they are suffering due to experiments. He doesn’t care that they may live longer. He does the humane thing and terminates them. Based on this controversy, I question the value of senolitic treatment at this time.

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      • Van
      • Van
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      Edward Meininger I really feel that this is important.  In Dr. Green's new website he talks about the 4 different kinds of senolytics and the different treatments for each one.  He recommends quarterly treatments for anti aging benefits, and monthly for people treating specific diseases.  Fistein 1500 mg X 3 days.   Azithromycin 500 mg x 3 in 1 week. (appx. every other day)  This is the same dose that has been used by MS patients for years to prolong there lives.   Dasatinib 100 mg x 3 days.  On his website he talks about the science behind using these drugs and dosages.  Either way, I would not take them together.  Rapamycin reduces the amount of senolytics, but cannot clear out the zombie cells like specific senolytics can.

      https://senolyticstreatment.com/

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      • JGC
      • JGC
      • 1 yr ago
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      Joe smith 

          You said "big-time researchers like Judith Campisi and Dimitry Bulavin clearly state and demonstrate through their research that senolitics don’t extend the lifespan."

          I am very suspicious of the lifespan vs. healthspan dichotomy.  I believe it is a cop-out employed by age-treatment researchers to convince the FDA and NIH that they are working to improve a patient's health (which the NIH funds) rather than making the patient live longer (which the NIH refuses to fund).   Why wouldn't a significant improvement in health make the subject live longer?  It makes no sense.

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      • JOHN
      • JOHN.1
      • 1 yr ago
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      Edward Meininger The first time I took Dastinib I took 100mg plus 1500mg quercetin. I too had chills and shivering in bed. I also had a temperature and threw up constantly for a few hours. Next day I was fine. I waited a few more months to try this again. Just finished a 3 day protocol and was relatively fine. Bad headaches and loss of appetite at times but nothing serious. I too am a Dr Green patient and take rapa as well.

      Like 2
  • this is what Dr Green lists:

    Dasatinib 100 mg dose for 3 days.

    Quercetin 1000 mg for 3 days

    Fisetin 1500 mg for 3 days.

     

    I get diarrhea every time I take more than 500 mg of quercetin and I imagine the antibiotic would affect me the same

    I never had aches and pains but I read others report flu like symptoms the first time they take Dasatinib

    Like 2
  • Just received my order for Fisetin 50 grams and Dasatinib 5 grams from China.  No problems with Customs was shipped via Fedex.  Fisetin was $2.50 gram including $25 Fedex.  Dasatinib was $20 gram + $25 shipping.  I received exactly 50 grams of Fisetin, and 5.6 grams of Dasatinib.  Over paid for Fisetin, better to order online.  Dasatinib and Rapamycin also are such small amounts that they can ship in an envelope and less likely to have a problem with customs.  Dr. Green is now recommending to take Fisetin and Dasatinib together and you can skip or not quercetin because Fisetin works better.  Green recommends 1500 mg Fisetin x 3 day x quarterly for anti ageing.  I prefer to use Mayo clinic's formula of 20mg/kg.  On July 01, 2020, I will take Fisetin 1700 mg x 3(with olive oil) + Dasatinib 100 mg x 3.(quarterly)  The next week will  take 250 mg Zithromycin x 6 days (quarterly)  Will try taking Vitamin C, 500 mg with all of the above.  These 3 drugs target 3 of the 4 senescent putrid cells, (aka, zombie)  WIll be waiting for a treatment for the 4th. cell type.

    Like 2
  • Paul Beauchemin said:
    attacking senescent cells is evolving as the #1 treatment for aging

         In my view, clearing senescent cells is the first step (but by no means the last) in treating aging.  The cell's internal programming has declared senescent cells to be too damaged to replicate, and that decision should be taken seriously.  One should clear them before any other intervention.  After that, if quasi-embryonic pluripotent stem cells are available, they should be provided to replace the cleared cells.  (Apparently, given the recent Unity Bio trial failure, this is important.)  Then, if an intervention is available to reset the epigenetic programming of the remaining cells (e.g., by AAV delivery of DNA or liposome delivery of mRNA to cause OSK Yamanaka factor expression), this should be done.  In principle, we know how to do all of these steps right now.  However, FDA roadblocks and the expense of human testing put access to these therapies far down the road, at least in the USA.

    Like 4
      • JOHN
      • JOHN.1
      • 1 yr ago
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      JGC In your opinion do you think Unity Bio has a shot with their next trial on vision?

      Like 1
  • JOHN said:
    In your opinion do you think Unity Bio has a shot with their next trial on vision?

         I wouldn't put any money on it.  Essentially, the flawed approach of Unity Bio involves repurposing a highly toxic anti-cancer drug that they call UBX-0101 and have patented for senolytic applications.  UBX-0101 cannot be used as a general senolytic because of its toxicity.  To avoid whole-body toxic effects, they inject UBX-0101 into relatively isolated body systems like the knee capsule or the eye capsule.  The problem with this approach, in my opinion, is that the cleared senescent cells need to be replaced with healthy one, they are not clearing nearby senescence outside the capsule, and the SASP effects of these neighboring senescent cells are preventing replacement by stem cells.

        In my view, one needs to use a general non-toxic senolytic that clears all senescent cells.  Oisin Bio's DNA plasmid/liposome technique does this.  The recent Chinese paper describing a new synthetic small-molecule senolytic called SSK1 that targets the senescence-marker beta-galactosidase seems to promise to do the same.  However, the toxicity of SSK1 under all conditions has not been well established, it has not been tested on humans, and all senescent cells do not express beta-galactosidase.  Both such treatments should be followed up by providing a supply of pluripotent stem cells to replace the cleared senescent ones.

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      • JOHN
      • JOHN.1
      • 1 yr ago
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      JGC That's interesting. I didn't realize they were repurposing an anti cancer drug.  I've seen you make a few posts on taking senolytics yourself. Do you think it's necessary to replace these senescent cells with stem cells?

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      • JGC
      • JGC
      • 1 yr ago
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      JOHN '

      I think that it is highly desirable to do something to replace the cleared cells  if you want to get the maximum effect of senolytics.  However, as yet I have not done anything in that direction.  Even of you cleared them all, you would only to replace a few % of your total cells, so in most organs it wouldn't make much difference.  However, if you are trying to fix eyes or joints like Unity is, it is important.

      Like 3
  • JGC said:
    I wonder what the water solubility of SSK1 is.

     I found HERE that the solubility in warm water of Gemcitabine, the principal molecular component of SSK1, is 25 mg/ml.  That isn't bad.  Maybe it could be taken orally, if it is stable enough to survive digestive acids.

    Like 1
  • I wil start with senolitic 

    Wats  is the best brand 

    To use every day .

    Please  answer 

    wil.zengers@hotmail.com

    75  years  man 

    Gr. Wil zengers 

    Livr  in Holland . eu.

    Like
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