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Rapamycin dosing: 5mg/week vs 25mg once a month vs ?

rapamycin mtor

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#1 smithx

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Posted 03 August 2019 - 08:18 PM


Blagosklonny and some others seem to be recommending 25mg or so of rapamycin once a month, rather than 4-6mg once a week (or every 5-8 days).

 

Questions:

  • Is there any study data which supports one or the other regimen?
  • Anyone out there trying the 25mg once a month, and what have you noticed if anything?

 

 



#2 VP.

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Posted 04 August 2019 - 01:21 AM

Pampaguy did. https://www.longecit...-25#entry877211


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#3 Andey

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Posted 04 August 2019 - 05:24 AM

Where could I learn about Blagosklonniy and his rationale for this?  google search doesnt show much.



#4 smithx

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Posted 04 August 2019 - 06:20 AM

Where could I learn about Blagosklonniy and his rationale for this?  google search doesnt show much.

 

You have to search pubmed:

 

https://www.ncbi.nlm...les/PMC6286826/

 

In these studies, rapamycin was most effective at high doses [88,89,9396,100103]. Its effect and that of everolimus lingers after their discontinuation [104], even after a single dose [105]. What appears to be important is to reach high peak levels using a single high dose [93,94].

 


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#5 Andey

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Posted 04 August 2019 - 07:00 AM

You have to search pubmed:

 

https://www.ncbi.nlm...les/PMC6286826/

 

Thanks.

I have one case study to support it)

  I recall hearing listening David Sabbitini(one ot the `inventors` of mTor pathway) on Tim Ferriss podcast long ago (one that took place at the Easter island) and how stupidly young his voice is like compared to other participants.

He noted that he personally doesnt take Rapamycin, but have taken heroic doses of it at the beginning of his career. He is also looking 10 years younger than his 50.

 

P.S. will try it today, coincidentally its my scheduled day for everolimus anyway. I usually take 5mg sublingually, will up it to 20 same way.


Edited by Andey, 04 August 2019 - 07:34 AM.

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#6 nickthird

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Posted 06 August 2019 - 07:28 AM

Sorry to sidetrack...

 

So what is the evidence this drug helps with longevity in humans (not rats or worms)? is there a main thread for this...?


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#7 smithx

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Posted 07 August 2019 - 04:43 AM

Sorry to sidetrack...

 

So what is the evidence this drug helps with longevity in humans (not rats or worms)? is there a main thread for this...?

 

Read this paper and look at the linked papers in the references https://www.ncbi.nlm...les/PMC6343718/

 

 



#8 smithx

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Posted 07 August 2019 - 05:35 AM

In this article

Disease or not, aging is easily treatable
https://www.ncbi.nlm...les/PMC6286826/


Rapamycin in a single dose of 15 mg was administrated to healthy volunteers without adverse effects [108]. Similarly, a dose of 8 mg/m2 (around 16 mg) was also well tolerated in healthy male volunteers [109]. What is amazing is that the placebo group reported more “side effects” such as astenia than did the rapamycin group [109].

 
There is also this article:
Acute Sirolimus Overdose: A Multicenter Case Series
https://journals.plo...al.pone.0128033
 

Five cases of acute sirolimus overdose were reported – three in young children and two in adults. Four were accidental and one was with suicidal intent. Two patients developed symptoms probably related to sirolimus overdose: mild elevation of alkaline phosphatase, fever and gastroenteritis in a 2.5-year-old male who ingested 3 mg, and mild changes in total cholesterol in an 18-year-old female after ingestion of 103 mg. None of these events were life-threatening. Serial blood concentration measurements were performed starting 24 h after ingestion of 103 mg in a single case, and these followed a similar pharmacokinetic time-course to measurements taken after dosing in the therapeutic range.

Conclusions
Acute sirolimus overdose occurred accidentally in the majority of cases. Even large overdoses appeared to be well-tolerated, however children might be at greater risk of developing complications. Further study of sirolimus overdose is needed.


So it appears that taking 25mg or so should probably not cause a problem, however I came across this anecdotal report in comments on this site which I found by searching. This person said they took 20mg and didn't notice anything much, then waited 2 weeks and took 25mg.

 

https://roguehealtha...es-weight-loss/

Just got my lipid panel back. Ok, except for the Hypertriglyceridemia . Went from 110 to 490. Seems this is normal with Rapa. Will monitor in 1 month. Increasing my Statin from 5 mg. to 10mg. Crestor for a couple of weeks. Best treatment for lower triglycerides??

 

 

This seems a bit worrisome.

 

 


Edited by smithx, 07 August 2019 - 05:37 AM.

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#9 Andey

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Posted 07 August 2019 - 06:34 AM

BTW my Everolimus experiment was uneventful.

I took 20mg dissolved sublingually during a period of few hours (to not oversaturate sublingual absorption route). I expect that it should double the effective absorbed dosage.



#10 smithx

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Posted 12 August 2019 - 11:44 PM

I decided to take 15mg this month, and if nothing untoward is noticed try 20 or 25mg next month.

Took 15mg on Friday and so far I haven't noticed anything.



#11 PAMPAGUY

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Posted 13 August 2019 - 05:55 AM

The higher dose is mainly for weight loss. (reset defended body weight set point)       https://www.ncbi.nlm...les/PMC4008417/

 

Also, that was me in Rogue Health on increase of Triglycerides.  After 1 week they were back to normal.  It was just a temporary spike. 


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#12 Andey

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Posted 14 August 2019 - 06:42 AM

The higher dose is mainly for weight loss. (reset defended body weight set point)       https://www.ncbi.nlm...les/PMC4008417/

 

 

I probably can attest this. Usually when I dont eat for 12+ hours during a day my hands became cold to the evening. My body shutdowns T3 action in a periphery while central thyroid regulation remains unperturbed.

Its probably too fast for an average person for this mechanism to kick in but I have a low BMI to begin with and additionally my HPA axis is messed up a bit.

After the everolimus megadose my hands dont get cold for more than a week, only recently I ve noticed it started to creep up a little. I havent loose much weight, only about 1 kg, but again my BMI is low already.


Edited by Andey, 14 August 2019 - 06:44 AM.


#13 treonsverdery

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Posted 31 August 2019 - 02:15 AM

Alibaba.com has rapamycin, $45/gram to $90/gram.  I ordered some and it arrived.  If you look online there is a a paper on making nanoparticles each of which simultaneously contain piperine, a GI tract absorption enhancer with rapamycin.  The dose effect multiplier was between 1.7 and 5.1 times the administered dose.  I put my rapamycin in an enteric coated (stomach passing) capsule and will combine it with piperine at my next dose.  My dose calculations are very different than the ones described here:

 

The mice that live 60% longer when given 126 ppm enteric coated rapamycin took it for 6 months, that is about the same as a human taking rapamycin for 7 years.  I do not have the calculations immediately in front of me, but with the mouse compensation factor, and the way mice eat 5 grams of food a day for just a 25-30g body mass, worked out to 89 mg/24 hours.  That is orders of magnitude higher than the 5 mg dose (.71 mg/24 hours) mentioned here.  I take 45 mg/24 hours with lipid rich food, and may take 45mg with piperine very 24 hours until/unless I notice unintended effects.

 

The big 5 mg to 89 mg dose difference could be ascribable to rapmycin also having a published longevity effect at 14 ppm, nine times less rapamycin/24 hours than the 60% longevity dose.

 

A 26 mg/24 hours dose with piperine at the 1.7 times dose multiplier could be similar, but of course an enteric capsule differs from a nanoparticle or an enteric coated version.

 

I do not have references, but I perceive I read (pubmed) humans on rapamycin experienced 20% less illness (I seem to remember colds and flu) even though rapamycin affects the immune system.  I perceive I may have read that the 126 ppm at mouse food study may have also measured 20% more frequent head lifting and look around motions, and heightened performance on a water maze test.  I may or may not have noticed a nootropic effect from 45 mg dose at an enteric capsule.  If I notice there is a nootropic effect from the piperine with 45 mg/24 hours dose I might describe that here as a suggestion that the absorption increase from piperine is effective at enteric capsules.

 

To find the $45/gram rapamycin at alibaba.com I used their get a quote (RFQ) function that shows up when you search an item (rapamycin), click on an item, and then see a RFQ making textarea; after a few days a person sent me the $45/g option.

 

At the $45/gram at perhaps a 5 gram alibaba quantity amount, 45 mg is 40 cents every 24 hours, at the 26 mg dose with piperine it is 23 cents/24 hours.  I actually got the $90/g rapamycin on my first order, so now I know what it tastes like so I can perceive if the $45/g material is actually also rapamycin.

 

I will see if I can duplicate the 126 ppm at food being 89 mg/24 hour human dose:

 

126 ppm is 126 mg/Kg of food, there is a mouse surface area (possibly metabolism) adjustment where you divide mouse doses with 12.6 to find a human dose.  That makes a human dose at 500 grams of food/24 hours at: 10 mg/24 hours, notably though mice eat 5/30ths their mass in food every 24 hours so the dose the mice actually ingested from eating 23.8 times more food was was the equivalent of 238 mg of rapamycin/24 hours at a human being.  That number is much higher than the 89/mg/24 hours amount, and I do not know why the numbers are different.  Perhaps someone here would like to make a new, more accurate human dose calculation.

 

Also it is my perception that mice eat frequently many times during a 24 hour interval, and that a human would benefit from taking two or more divided doses a day, so two 119 mg rapamycin with piperine capsules a day.  I perceive I read that mice given an IP injection once every 24 hours experienced something I perceive as about half the longevity increase as continuous nibbling at food, so that is perhaps a thought. 

 

Also, I read two different values for the plasma half life of rapamycin at humans.  I perceive I read one at pubmed that said .9 hours, and another at the wikipedia page for rapamycin that said 56 hours.  If the plasma half life is actually 56 hours then the two pills a day rapamycin with piperine dose could have stronger equivalence of function to the mouse ad libitum food plasma levels.

 

An optimist though might like to think that the 5.1 times piperine multiplier works on the 45 mg/24 hours rapamycin dose, if so, then that is the equivalent of 229 mg rapamycin/24 hours.  Upping that to a 1.7 piperine multiplier at 140 mg/24 hours of rapamycin, makes the rapamycin $1.24 each 24 hours at a human dose.

 

It looks like a 140 mg/24 hours with a few hundred milligrams of piperine at an enteric (stomach passing) capsule could be a human equivalent dose to the 126 ppm dose at mouse food 60% longevity increase dose.

 

Rather than just go with these numbers I urge you to make a new dose calculation and describe it here, notably at the 126 ppm food, 60% longevity dose.

 

There are some other ideas about a rapamycin dose:  an upper limit on a dose benefit has not been published, so it is possible that more than 126 ppm at food could actually cause greater than 60% longevity, that supports a piperine multiplier causing a higher equivalent dose so long as the human is absent any unintended effects.

 

 


Edited by treonsverdery, 31 August 2019 - 02:38 AM.

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#14 PAMPAGUY

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Posted 31 August 2019 - 05:35 AM

I looked at Joan Mannick's 2014 trial for guidance on dosing Rapa. (8 wk trial)  In that trial she gave elderly subjects .5 mg daily, 5 mg weekly, and 20 mg weekly.  My focus was on the 20 mg dose.  They estimated that they completely shut down the Tor signal at that dose, but with many side effects. (side effects listed in trial)  Tor 2 was being effected which is what you don't want to do.  The .5 daily and the 5 mg weekly accomplished the objectives of the trial which was to get a response to the flu vaccine.  The 20 mg dose also worked, but why use it with all the side effects.  Elderly have compromised immune systems due to ageing.  The .5 mg daily dose inhibition of Tor was around 36%, 5 mg weekly over 50%.  Using these guidelines, I started with 6 mg weekly which I estimated to be around 65-70% inhibition of Tor.  Took this for 2 years with zero side effects.  Have since gone to 7 mg weekly with an estimated Tor inhibition of 75-80% inhibition.  Used 25 mg Rapa, monthly, twice for weight loss and it helped me lose 5 kg.  This trial is the best there is at the moment on human dosing.  Mice models are too complicated and have heard very unreliable when translated to human dosing of Rapa.     https://stm.sciencem...8/268ra179.full    Sci-hub to unlock trial

http://sci-hub.tw/10...anslmed.3009892

 

Noticed that some people are using everolimus instead of rapa.  In his latest paper Dr. Blagosklonny's states that Rapamycin and Everolimus have the same effect and that the more expensive Everolimus is not better than Rapamycin in fact the Rapa is probably better because it has a longer 1/2 life which is what you want in ageing, but not immune suppression as in organ transplants.  Everolimus and other rapa logs are used in trials by drug companies to advertise there products.    https://www.nature.c...1419-019-1822-8



#15 Andey

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Posted 31 August 2019 - 06:21 AM

I looked at Joan Mannick's 2014 trial for guidance on dosing Rapa. (8 wk trial)  In that trial she gave elderly subjects .5 mg daily, 5 mg weekly, and 20 mg weekly.  My focus was on the 20 mg dose.  They estimated that they completely shut down the Tor signal at that dose, but with many side effects. (side effects listed in trial)  Tor 2 was being effected which is what you don't want to do.  The .5 daily and the 5 mg weekly accomplished the objectives of the trial which was to get a response to the flu vaccine.  The 20 mg dose also worked, but why use it with all the side effects.  Elderly have compromised immune systems due to ageing.  The .5 mg daily dose inhibition of Tor was around 36%, 5 mg weekly over 50%.  Using these guidelines, I started with 6 mg weekly which I estimated to be around 65-70% inhibition of Tor.  Took this for 2 years with zero side effects.  Have since gone to 7 mg weekly with an estimated Tor inhibition of 75-80% inhibition.  Used 25 mg Rapa, monthly, twice for weight loss and it helped me lose 5 kg.  This trial is the best there is at the moment on human dosing.  Mice models are too complicated and have heard very unreliable when translated to human dosing of Rapa.     https://stm.sciencem...8/268ra179.full    Sci-hub to unlock trial

http://sci-hub.tw/10...anslmed.3009892

 

Noticed that some people are using everolimus instead of rapa.  In his latest paper Dr. Blagosklonny's states that Rapamycin and Everolimus have the same effect and that the more expensive Everolimus is not better than Rapamycin in fact the Rapa is probably better because it has a longer 1/2 life which is what you want in ageing, but not immune suppression as in organ transplants.  Everolimus and other rapa logs are used in trials by drug companies to advertise there products.    https://www.nature.c...1419-019-1822-8

 

Mannick used everolimus not rapamacyn. Where did you found the degree of mTOR inhibition depending on rapalog dosages in Mannick`s 2014 paper? I believe it doesnt have such thing. 

 

 



#16 PAMPAGUY

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Posted 31 August 2019 - 06:35 AM

In the intent-to-treatpopulation,the low-doseRAD001 (0.5 mgdaily or
5 mg weekly) cohorts, but not the higher-dose (20 mg weekly) cohort, met
the primary endpoint of the study (Fig. 1A). Modeling and simulation
based on mTOR-mediated phosphorylation of its downstream target S6
kinase (S6K) predicted that the 20 mg weekly dosing regimen inhibited
mTOR-mediatedS6Kphosphorylationalmostcompletely,the5mgweekly
dosing regimen inhibited S6K phosphorylation by more than 50%, and the
0.5mgdailydosingregimeninhibited S6Kphosphorylation by about 38%
over the dosing interval (12). Thus, partial inhibition of mTOR-mediated
S6K phosphorylation achieved with a relatively low dose of RAD001 may
be as effective as nearly complete inhibition associated with high-dose
RAD001 at enhancing the immune response of the elderly volunteers.

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#17 treonsverdery

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Posted 01 September 2019 - 07:54 AM

I am aware of two rapamycin like things published as causing 60% greater longevity increase, one is rapamycin at the 126 ppm mouse food for 6 months study, the other is that there is a new rapalog that only effects mTOR type 1 receptors, and unlike rapamycin does not do unintended effect things at mTOR type 2 receptors, it is published at causing 60% greater longevity, I think the rapalog 60% longevity mTOR type 1 chemical and study was a product of the Buck Institute on aging;  I do not know if the mg/kg dose of the mTOR1 active longevity drug is a different amount than rapamycin

 

Also, the paper where they combine rapamycin to get 1.7 times higher dose multiplier effectiveness to 5.1 times higher dose multiplier effectiveness from combining rapamycin with piperine is at https://www.research...ancer_treatment

 

 



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#18 PAMPAGUY

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Posted 08 September 2019 - 02:13 PM

First human study proving that Rapamycin reverses ageing via epigenetic clocks. Major break-though. https://www.ncbi.nlm...les/PMC6555449/



Rapamycin retards epigenetic ageing of keratinocytes independently of its effects on replicative senescence, proliferation and differentiation


In summary, the observations above represent the first

biological connection between epigenetic ageing and
rapamycin. These results for human cells add to the
evidence that extension of life, at least by rapamycin, is
indeed accompanied by retardation of ageing. These
observations also suggest that the life-extending
property of rapamycin may be a resultant of its multiple
actions which include, but not necessarily limited to
suppression of cellular senescence [36-38, 48] and
epigenetic aging, with the possibility of augmentation of
cellular proliferative potential.





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