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New Rapamycin Study- up to 60% increase in mouse lifespan- Anyone Experimenting With This?

rapamycin

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#811 geo12the

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Posted 22 May 2020 - 03:12 PM

Dasatinib sounds interesting but very expensive and where on earth do you get it from?

 

Relevant articles:

 

https://web.stanford...Brunet 2019.pdf

https://www.ncbi.nlm.../?report=reader

 


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#812 judge

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Posted 22 May 2020 - 04:02 PM

WOW!  Great info!  Thanks!



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#813 Valijon

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Posted 22 May 2020 - 04:57 PM

There was a group by some time ago on Dasatinib. I cant recall when it was. The thread should still be up. I'm sure that with enough interest, we could get another going again. So long as the guy who was in charge of it all is still around here somewhere.

#814 judge

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Posted 29 May 2020 - 06:25 AM

First 2 weeks I did 5 mg , now on my second week doing the grapefruit protocol with 3 mg . Read the medical information sheet that came with the rapamycin.  Says: because  grapefruit inhibits CYP3A4 it should not be used with or used for dilution of rapamycin.

 

Is this a concern?

 

Thanks!



#815 PAMPAGUY

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Posted 29 May 2020 - 08:39 AM

First 2 weeks I did 5 mg , now on my second week doing the grapefruit protocol with 3 mg . Read the medical information sheet that came with the rapamycin.  Says: because  grapefruit inhibits CYP3A4 it should not be used with or used for dilution of rapamycin.

 

Is this a concern?

 

Thanks!

judge, read my post #803.  Lots of info on grapefruit juice and rapa.



#816 judge

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Posted 29 May 2020 - 08:27 PM

judge, read my post #803.  Lots of info on grapefruit juice and rapa.

Thanks!  I re read the post and it is just a shame they way they lie on these supposed medical information sheets.  So when it says "grapefruit juice inhibits the CYP3A4-mediated metabolism of rapamycin."  That is a good thing, right?  :)

 

Also read fat is a big factor in absorption factor: it says: "absorbtion is affected by high fat meals"  But of course it does not say what the affect is!!!!

 

I am guessing from our knowledge that our digestive system readily absorbs fat that taking rapamycin with a high fat meal will increase absorption.  So that is a good thing?

 

Am I wrong????????

 

Would it affect the amount absorbed or the speed it is absorbed or both?  :)  I am guessing both  lol

 

Thanks for the feedback!



#817 judge

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Posted 30 May 2020 - 05:53 PM

 2019 study shows DL001 analog of rapamycin to be many times more effective and not have side effects of regular rapamycin!

 

Here, we report the identification of DL001, a FKBP12-dependent rapamycin analog 40x more selective for mTORC1 than rapamycin. 

 

https://www.nature.c...467-019-11174-0

 

Hope this stuff comes out soon!



#818 Valijon

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Posted 30 May 2020 - 06:22 PM

Impressive, most Impressive. We must all get our hands on this and soon!

#819 aribadabar

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Posted 30 May 2020 - 08:37 PM

 2019 study shows DL001 analog of rapamycin to be many times more effective and not have side effects of regular rapamycin!

 

Here, we report the identification of DL001, a FKBP12-dependent rapamycin analog 40x more selective for mTORC1 than rapamycin. 

 

https://www.nature.c...467-019-11174-0

 

Hope this stuff comes out soon!

 

The link is bad.

 

Here is a good one to the paper: https://www.ncbi.nlm...les/PMC6642166/



#820 QuestforLife

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Posted 31 May 2020 - 09:11 AM

All that work and no lifespan study. I'll wait for that before I decide all the benefits definitely come from mTOR1 inhibition.

#821 PAMPAGUY

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Posted 31 May 2020 - 01:24 PM

One thing for sure, when they come out with rapalog it will cost as much as the brand names now.  Maybe insurance will cover it, but I wouldn't count on it.  There are now 2 anti-aging treatments, Tor inhibition and senolytics.   https://senolyticstreatment.com/



#822 judge

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Posted 31 May 2020 - 04:47 PM

The link is bad.

 

Here is a good one to the paper: https://www.ncbi.nlm...les/PMC6642166/

Thank you, I don't know why that link failed, hard to confirm since its abbreviated, thanks again!



#823 judge

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Posted 31 May 2020 - 04:52 PM

All that work and no lifespan study. I'll wait for that before I decide all the benefits definitely come from mTOR1 inhibition.

You might wan to go to the beggining of this thread and read all the hyperlinks,  hopefully you will be onvinced after that. 

It mostly started here:

 

In 2006, Mikhail Blagosklonny described how the mTOR pathway causedhyperfunction. In 2009 it was shown that rapamycin increased lifespan in mice by lowering the activity of the mTOR pathway.



#824 PAMPAGUY

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Posted 31 May 2020 - 05:05 PM

Here is Blagosklonny's latest paper.  The more rapa you take without side effects the longer and healthier life you will have.

 

 

 

https://www.ncbi.nlm...les/PMC6814615/

 

 


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#825 judge

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Posted 31 May 2020 - 05:41 PM

Here is Blagosklonny's latest paper.  The more rapa you take without side effects the longer and healthier life you will have.

 

 

 

https://www.ncbi.nlm...les/PMC6814615/

That is the article that got me very interested in rapamycin, I saved it to my library, good info! Thanks!



#826 QuestforLife

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Posted 31 May 2020 - 05:58 PM

You might wan to go to the beggining of this thread and read all the hyperlinks, hopefully you will be onvinced after that.
It mostly started here:

In 2006, Mikhail Blagosklonny described how the mTOR pathway causedhyperfunction. In 2009 it was shown that rapamycin increased lifespan in mice by lowering the activity of the mTOR pathway.


Lol Judge

I started rapamycin in 2016. I've read tonnes of papers on it. A few people know more about rapamycin than me. You're not one of them.
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#827 judge

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Posted 31 May 2020 - 08:14 PM

Yeah, I am a newbie, your post implied lack of knowledge, sorry.  Since you have been taking rapamycin, what benefits have you gotten from your protocol? Which protocol and what amounts are you doing now?

 

Thanks!



#828 QuestforLife

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Posted 01 June 2020 - 07:38 AM

Yeah, I am a newbie, your post implied lack of knowledge, sorry.  

 

Why because I questioned whether the life-extending benefits of rapamycin are definitely only due to mtor1 inhibition? That is the prevailing opinion and may well be correct, but it has not yet be definitively settled hence my wish to see a life-span study in any new rapalogs. There might also be a optimum mtor inhibition level and going below that might reduce lifespan (we don't know). 

 

Personally I think everolimus is a good bet once it comes down in price. It inhibits both mtor1&2 but its shorter half life (than rapamycin) means the effect on mtor2 would be reduced, permitting a larger dose and more profound mtor1 inhibition (again assuming that is what we want).

 

For the same reason I wouldn't use grapefruit juice, unlike many on this site - you'll get more rapamycin in your system for longer, but you'll end up with more side-effects (again possibly because mtor2 inhibition kicks in after sustained rapamycin serum concentration). Dr Alan Green agrees with me on this point. 

 

But the benefits and side effects of rapamycin seem to be heavily dependent on age. The older you are the greater the benefits:side effects ratio. Might be something to do with a greater senescent cell burden (which grows exponentially with age) and/or because the innate immune system gets so much stronger with age. There also seems to be quite a lot of individual variability in serum concentration of rapamycin when taking the same dose (woman have higher serum concentration, but i think this varies between members of the same sex too). So for this reason every individual needs to calibrate their own dose carefully. 


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#829 Engadin

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Posted 01 June 2020 - 02:49 PM

...

 

But the benefits and side effects of rapamycin seem to be heavily dependent on age. The older you are the greater the benefits:side effects ratio. Might be something to do with a greater senescent cell burden (which grows exponentially with age) and/or because the innate immune system gets so much stronger with age. There also seems to be quite a lot of individual variability in serum concentration of rapamycin when taking the same dose (woman have higher serum concentration, but i think this varies between members of the same sex too). So for this reason every individual needs to calibrate their own dose carefully. 

 

 

It is a known fact that as we age, telomeres get shorter and shorter. And back in march, CNIO published a study that may shed some light on why as mice get older, rapamycin is increasingly less and less a friendly aging retardant, because they state that "the mTOR pathway is necessary for survival of mice with short telomeres". Should it work the same in elder humans, perhaps mTOR1 or 2 state should then be kept as intact as possible in our organism to slow down aging. Just my two cents.


Edited by Engadin, 01 June 2020 - 02:51 PM.


#830 Michael

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Posted 01 June 2020 - 04:26 PM

 the benefits and side effects of rapamycin seem to be heavily dependent on age. The older you are the greater the benefits:side effects ratio. Might be something to do with a greater senescent cell burden (which grows exponentially with age) and/or because the innate immune system gets so much stronger with age. There also seems to be quite a lot of individual variability in serum concentration of rapamycin when taking the same dose (woman have higher serum concentration, but i think this varies between members of the same sex too). So for this reason every individual needs to calibrate their own dose carefully. 

 

It is a known fact that as we age, telomeres get shorter and shorter. And back in march, CNIO published a study that may shed some light on why as mice get older, rapamycin is increasingly less and less a friendly aging retardant, because they state that "the mTOR pathway is necessary for survival of mice with short telomeres". Should it work the same in elder humans, perhaps mTOR1 or 2 state should then be kept as intact as possible in our organism to slow down aging. Just my two cents.

You have this backward: as QFL correctly notes, the benefit:risk ratio for rapa clearly improves as mice get older, not vice-versa. This is true for lifespan, for immunity, for muscles, and for multiple other parameters.

 

The so-called "mice with short telomeres"  in the Blasco (CNIO) study you reference are not normal, aging mice with short telomeres (telomeres don't actually shorten much in most aging tissues in humans or mice), but mice with genetic defects in their telomerase RNA template and then bred for multiple generations to further shorten their telomeres from before birth: they are in no way "old," and should not be taken as a model of aging.


Edited by Michael, 01 June 2020 - 04:29 PM.

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#831 judge

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Posted 01 June 2020 - 06:55 PM

Why because I questioned whether the life-extending benefits of rapamycin are definitely only due to mtor1 inhibition? That is the prevailing opinion and may well be correct, but it has not yet be definitively settled hence my wish to see a life-span study in any new rapalogs. There might also be a optimum mtor inhibition level and going below that might reduce lifespan (we don't know). 

 

Personally I think everolimus is a good bet once it comes down in price. It inhibits both mtor1&2 but its shorter half life (than rapamycin) means the effect on mtor2 would be reduced, permitting a larger dose and more profound mtor1 inhibition (again assuming that is what we want).

 

For the same reason I wouldn't use grapefruit juice, unlike many on this site - you'll get more rapamycin in your system for longer, but you'll end up with more side-effects (again possibly because mtor2 inhibition kicks in after sustained rapamycin serum concentration). Dr Alan Green agrees with me on this point. 

 

But the benefits and side effects of rapamycin seem to be heavily dependent on age. The older you are the greater the benefits:side effects ratio. Might be something to do with a greater senescent cell burden (which grows exponentially with age) and/or because the innate immune system gets so much stronger with age. There also seems to be quite a lot of individual variability in serum concentration of rapamycin when taking the same dose (woman have higher serum concentration, but i think this varies between members of the same sex too). So for this reason every individual needs to calibrate their own dose carefully. 

Great info, thanks.  Got my curiosity up on rapalogs and found a decent article.  I had no idea so much study was put into cancer therapy. Sounds promising even though the studies were not conclusive, there were some good results.  I thought the grape juice just increased bio availability, did not read it would extend the half life?

https://cdrjournal.c...ticle/view/3277



#832 Engadin

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Posted 01 June 2020 - 08:25 PM

You have this backward: as QFL correctly notes, the benefit:risk ratio for rapa clearly improves as mice get older, not vice-versa. This is true for lifespan, for immunity, for muscles, and for multiple other parameters.

 

The so-called "mice with short telomeres"  in the Blasco (CNIO) study you reference are not normal, aging mice with short telomeres (telomeres don't actually shorten much in most aging tissues in humans or mice), but mice with genetic defects in their telomerase RNA template and then bred for multiple generations to further shorten their telomeres from before birth: they are in no way "old," and should not be taken as a model of aging.

 

Thanks Michael, I certainly missed QFL's point. For a total outsider like me lacking an ocean of knowledge, Mariana trench deep, terms and concepts, even though many times read about them, turn out blurred when attempting to reason one or two steps using them.

 

Thanks for the your patience and the clarity of your explanation, which I hope I won't missunderstand this time. LOL.



#833 Andey

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Posted 02 June 2020 - 07:18 AM

Why because I questioned whether the life-extending benefits of rapamycin are definitely only due to mtor1 inhibition? That is the prevailing opinion and may well be correct, but it has not yet be definitively settled hence my wish to see a life-span study in any new rapalogs. There might also be a optimum mtor inhibition level and going below that might reduce lifespan (we don't know). 

 

Personally I think everolimus is a good bet once it comes down in price. It inhibits both mtor1&2 but its shorter half life (than rapamycin) means the effect on mtor2 would be reduced, permitting a larger dose and more profound mtor1 inhibition (again assuming that is what we want).

 

For the same reason I wouldn't use grapefruit juice, unlike many on this site - you'll get more rapamycin in your system for longer, but you'll end up with more side-effects (again possibly because mtor2 inhibition kicks in after sustained rapamycin serum concentration). Dr Alan Green agrees with me on this point. 

 

But the benefits and side effects of rapamycin seem to be heavily dependent on age. The older you are the greater the benefits:side effects ratio. Might be something to do with a greater senescent cell burden (which grows exponentially with age) and/or because the innate immune system gets so much stronger with age. There also seems to be quite a lot of individual variability in serum concentration of rapamycin when taking the same dose (woman have higher serum concentration, but i think this varies between members of the same sex too). So for this reason every individual needs to calibrate their own dose carefully. 

 

  Do you have an opinion on cycling it on/off? 

I was forced to discontinue it due to a "limited supply due to recent events" and I would say I started to look a bit younger, gained some muscle even with decreased volume of exercise. Its possible that my stem cell pool was full for some time(thanks to Rapamycin) but wasnt used to a full extent because of rapamycin too. TBH I want to play with some periods on|off, esp as I  think @Turnbuckle protocol would benefit from such adjustment.


Edited by Andey, 02 June 2020 - 07:22 AM.


#834 PAMPAGUY

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Posted 02 June 2020 - 08:54 AM

  Do you have an opinion on cycling it on/off? 

I was forced to discontinue it due to a "limited supply due to recent events" and I would say I started to look a bit younger, gained some muscle even with decreased volume of exercise. Its possible that my stem cell pool was full for some time(thanks to Rapamycin) but wasnt used to a full extent because of rapamycin too. TBH I want to play with some periods on|off, esp as I  think @Turnbuckle protocol would benefit from such adjustment.

Andey, read my post #803.  Lots of info on grapefruit juice and rapa.  The Doctor mentioned there has himself, family members, and 50 patients on cycling rapa.  3 week cycles.  .18 mg/kg high to .07 mg/kg low.  Has years of experience, no substitute for that.  You can search for his name on the site and if I were you I would read everything he has to say.  Seems that chronic Tor inhibition (the chronic spike)  is where you get the most benefit in health and life span without side effects of course.  Large doses spaced further apart to prevent side effects.


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#835 Andey

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Posted 03 June 2020 - 01:41 AM

Andey, read my post #803.  Lots of info on grapefruit juice and rapa.  The Doctor mentioned there has himself, family members, and 50 patients on cycling rapa.  3 week cycles.  .18 mg/kg high to .07 mg/kg low.  Has years of experience, no substitute for that.  You can search for his name on the site and if I were you I would read everything he has to say.  Seems that chronic Tor inhibition (the chronic spike)  is where you get the most benefit in health and life span without side effects of course.  Large doses spaced further apart to prevent side effects.

 

Thank you )

Can you elaborate a bit on 3 week cycles? as #803 doesnt mention it.  https://www.longecit...ndpost&p=892374

So far I ve taken everolimus for a about 2 years, as sublingual, I would probably add grapefruit a top of it to maybe drive it higher. I havent had any mouth sores anyway, so I dont expect it would be too much.



#836 PAMPAGUY

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Posted 03 June 2020 - 01:53 PM

Thank you )

Can you elaborate a bit on 3 week cycles? as #803 doesnt mention it.  https://www.longecit...ndpost&p=892374

So far I ve taken everolimus for a about 2 years, as sublingual, I would probably add grapefruit a top of it to maybe drive it higher. I havent had any mouth sores anyway, so I dont expect it would be too much.

I would suggest you search for Mark at the site and read all of his posts which are not that many, but very imformative.   https://forum.age-re.../rapamycin-cost


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#837 InquilineKea

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Posted 04 June 2020 - 10:10 AM

https://www.slidesha...te-presentation - 5mg/week actually does show effects in some people

 

also can't one just use grapefruits rather than grapefruit juice to potentiate rapa?


Edited by InquilineKea, 04 June 2020 - 10:12 AM.


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#838 judge

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Posted 04 June 2020 - 03:28 PM

https://www.slidesha...te-presentation - 5mg/week actually does show effects in some people

 

also can't one just use grapefruits rather than grapefruit juice to potentiate rapa?

My guess is it would work just as well, but you do absorb it faster in the form of juice.  Not sure if that affects absorption?  I squeeze 2 grapefruits night before and then squeeze 2 more grapefruit 30 minutes before dosing







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