Senolytics

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

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.

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. 

Mark Thimineur I did get the DMSO and Cream.... so I am ready to go.... once i get the Sirolimus.  

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)

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.

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...

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.

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. 

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. 

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...

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...

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.

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

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.

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?

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.

Mark Thimineur Are you selling it?

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.

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.

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.

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?

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

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.

Michael