955 replies to this topic

[DareDevil]

I had been taking 1 mg rapamycin EOD along with naringin for a few weeks. No discernable effects, positive or negative. More recently changed to 3 mg rapamycin every 5 days, also with naringin.  Same results so far.

 

Hi Tintinet,

 

Naringin is the flavone that gives Grapefruit its bitter taste. Are you taking it is a purified chemical form at a specific dosage, or are you using this term to refer to the active ingredient ingested with Grapefruit Juice?

 

Thanks for clarifying

 

DareDevil

[Valijon]

Read the new Yorker article just before bed and thought this was a real coincidence. I believe they mention Metformin, and a few other things we know about already. I was very surprised Rapamycin wasn't discussed.

[Jaris]

Two things I've noticed about the rich:

1. They don't value something unless they have to pay a lot for it. To them, Rapamycin is essentially free. They don't want something just anyone can afford.

2. They rely on experts (because they can), but experts will milk them for all they are worth. Even if R does work, they'll wrap it up with expensive therapies. But until then, they'll lead their clients on a merry and expensive chase.

[Jaris]

Read the new Yorker article just before bed and thought this was a real coincidence. I believe they mention Metformin, and a few other things we know about already. I was very surprised Rapamycin wasn't discussed.

 

Maybe they added it, but they do mention Rapamycin, if only to "prove" that having sex causes us to die sooner! This article is a joke; interesting only because it shows just how shallow and deficient reporting can be. Here's the quote:

 

"The immune suppressant rapamycin makes mice live longer, yet shrivels their testicles. "(yikes!)

 

I'm happy to report that this hasn't happened to me yet, nor do I expect it to. If I was taking 90mg a week for years, then yeah, maybe. But then, the reporter also writes:

 

"Likewise, the most proven way for a man to live fourteen years longer than average is to become a eunuch."

 

(double yikes!) I haven't checked lately, but I doubt that this a popular topic here on Longecity?

Edited by Jaris, 27 March 2017 - 09:05 PM.

[tintinet]

 

I had been taking 1 mg rapamycin EOD along with naringin for a few weeks. No discernable effects, positive or negative. More recently changed to 3 mg rapamycin every 5 days, also with naringin.  Same results so far.

 

Hi Tintinet,

 

Naringin is the flavone that gives Grapefruit its bitter taste. Are you taking it is a purified chemical form at a specific dosage, or are you using this term to refer to the active ingredient ingested with Grapefruit Juice?

 

Thanks for clarifying

 

DareDevil

 

 

 

"Naringin is a flavanone glycoside, which exerts a variety of pharmacological effects such as antioxidant activity, blood lipid lowering, anticancer activity, and inhibition of cytochrome P450 enzymes."  Yeah, that one, from Swanson, 300 mg TID.  Don't have time for grapefruit and I generally avoid juices. 

[Brett Black]

I found this...
 
"Getting the dose correct is another problem. A normal human dose of rapamycin is between 2 and 5 milligrams per day, much lower than the dose given to the mice, which was 2.24 milligrams per kilogram of body weight per day.[/size]
 
http://www.nature.co...s.2009.648.html
 
A 200 pound person = 90 kilograms. So to equal the life extending rat test...a 200 pound man would need 90 X 2.24...= 201.6 mg per day.. That's 1411 mg per week...and you would be taking...1 mg per week vs the 1411 mg. 
 
So if this info and math is correct I can see where it would be a safe play. But I question if it would be an effective amount to attain your life extensin goal.

 
 
 
WARNING! WARNING! WARNING!

Drug doses used in animals do not necessarily linearly scale to doses in humans based on simple relative body weights! Simple linear scaling of dose based upon weight could lead to MASSIVE OVERDOSE!

Please see the following guidance/recommendation from the FDA about estimating equivalent doses between different species (particularly pages 6 & 7):
https://www.fda.gov/...s/UCM078932.pdf

Quoting from those FDA guidelines: "Note that mg/kg scaling will give a twelve-, six-, and twofold higher HED(human equivalent dose) than the default mg/m2 approach for mice, rats, and dogs, respectively."

In other words, giving the same mg/kg dose used in mice to a human could result in the metabolic/pharmacological equivalent of a twelve times higher dose to the human - potentially extremely dangerous.

[VP.]

Very interesting article from today's MIT Tech Review. Big Pharma is working on selling you Rapamycin analogs for $$$.

https://www.technolo...en-waiting-for/

 

 

 

  http://www.fiercebio...ams-to-puretech

 

 

Edited by VP., 28 March 2017 - 09:17 AM.

[Razor444]

I've been taking 1 mg rapamycin every other day, and there doesn't seem to be a build-up in my system, despite the long half-life (something like 63 hours). Doing a quick search, it seems the half-life is shorter than 63 h once a steady state is reached (from a study):

 

The true elimination half-life of sirolimus is approximately 63 h, although the effective half-life is shorter with patients reaching steady state in 5–7 days.

 

 

It seems--subjectively--the rapamycin has cleared by the 48-hour mark.

[PAMPAGUY]

Razor 444,

 

Thanks for the post.  You might want to read this post I made a few days back about dosing schedules.  This is from a practicing physician who has taken rapa + metformin for over a year, experimenting on himself.  You are taking the rapa just like a someone who had a kidney transplanted.  You want to take it for longevity purposes/aging.

 

osted 24 March 2017 - 03:57 PM

As per excellent post by VP

 

 

Alan,

I assumed (not sure why) you took 1mg of Rapamycin six days a week.In reality you take 6mg at one time, once a week? Why do you prefer this over taking 1mg six days a week? Thanks.

 

Dr. Alan Green went on to comment.

 

Hi Jason,
mTOR physiologically is supposed to go up and down. If you take rapamycin daily you keep mTOR at constant low level. This is needed if you want to have somebody stick a foreign kidney in you; but associated with many side-effects. If take once a week, this is like intermittent extreme fasting as regards effect on mTOR and prevents side-effects. To slow down disease-of-aging want mTOR mostly at low physiologic levels consistent with not eating a lot of meals; like maybe you make a big kill once a week and gorge yourself (no refrigerators) and then went hungry to next big kill a week later. To keep mTOR happy need to let it go up to high physiologic levels once a week; otherwise will bite you. Transplant patients can’t do this as soon as mTOR up to high level; acute rejection, no more kidney.

 

 

[tintinet]

Razor 444,

Thanks for the post. You might want to read this post I made a few days back about dosing schedules. This is from a practicing physician who has taken rapa + metformin for over a year, experimenting on himself. You are taking the rapa just like a someone who had a kidney transplanted. You want to take it for longevity purposes/aging.

osted 24 March 2017 - 03:57 PM

As per excellent post by VP


Alan,
I assumed (not sure why) you took 1mg of Rapamycin six days a week.In reality you take 6mg at one time, once a week? Why do you prefer this over taking 1mg six days a week? Thanks.

Dr. Alan Green went on to comment.

Hi Jason,
mTOR physiologically is supposed to go up and down. If you take rapamycin daily you keep mTOR at constant low level. This is needed if you want to have somebody stick a foreign kidney in you; but associated with many side-effects. If take once a week, this is like intermittent extreme fasting as regards effect on mTOR and prevents side-effects. To slow down disease-of-aging want mTOR mostly at low physiologic levels consistent with not eating a lot of meals; like maybe you make a big kill once a week and gorge yourself (no refrigerators) and then went hungry to next big kill a week later. To keep mTOR happy need to let it go up to high physiologic levels once a week; otherwise will bite you. Transplant patients can’t do this as soon as mTOR up to high level; acute rejection, no more kidney.

To wit: http://jim.bmj.com/content/64/4/932.2

[Jaris]

Dosing has been discussed quite a bit here. For example...

 

This is perhaps the most useful study that shed light on rapalog dosing in elderly humans: https://www.research..._in_the_elderly

 

From the PDF you can download:

 

"...receive(d) placebo or one of three doses of oral RAD001(Everolimus): 0.5 mg daily, 5 mg weekly, or 20 mg weekly"

No major side effects: "'adverse events were similar to those given a placebo." 

Just one (more serious?) side effect stood out: "mouth ulcers in a subject treated with 20 mg weekly"

 

The main goal was to see if subjects had improved immune response to several flu strain vaccines. Those who received any rapalog as treatment were seen to have an improved response.

You can read and interpret it for yourself, but the way I see it, the 20 mg / week dose had over double the number of (minor) side effects (and one more serious?) as the other doses and performed only slightly better.

Based only on this study, the 5 mg / week did about as well, with about the same side effects as the 0.5 mg / day dose.

 

Another study - with mice* - compared alternative dosing (5 days* vs daily dosing) and Everolimus vs Rapamycin: https://www.ncbi.nlm...pubmed/26463117

 

* thanks, tintinet

 

It should be noted that everolimus has a shorter half-life (30 hrs) and is designed to have less affect on mTOR2, so fewer serious side effects. If you can afford and get Everolimus, that is.

Edited by Jaris, 29 March 2017 - 12:43 AM.

[tintinet]

Mice, to be precise, and ya gotta love the 5 day week!

[Jaris]

Very interesting article from today's MIT Tech Review. Big Pharma is working on selling you Rapamycin analogs for $$$.

https://www.technolo...en-waiting-for/

 

 

 

  http://www.fiercebio...ams-to-puretech

 

It's interesting that they don't talk much about autophagy; that it can break down damaged and unusable proteins and even broken mitochondria. I guess they're still too squeamish to say anything might actually recycle and repair damage.. It's much safer to just say that it "extends lifespans". 

[PAMPAGUY]

Jaris,

Just keep in mind that the mice studies showed greater lifespan from the higher dosage.  We want to inhibit mTOR as much as possible, but not too much.  

 

The elderly volunteers were all 65+ years of age, and they tolerated it very well.  Here are the results posted in that study on the amount of inhibition at the doses given for the study.

 

In the intent-to-treat population, the low-dose RAD001 (0.5 mg daily 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-mediated S6K phosphorylation almost completely, the 5 mg weekly

dosing regimen inhibited S6K phosphorylation by more than 50%, and the

0.5 mg daily dosing regimen inhibited S6K phosphorylation 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. 

 

Keeping in mind that a larger dose does mean a longer lifespan, as far as we know at this point.  My personal sweet spot is 6-9 mg once a week to achieve 75-85% S6K phosphorylation inhibition.  If you get side effects back off, keeping in mind everyone's metabolism is different.  The intermediate dosing schedule of once weekly should keep most side effects at bay.

[Jaris]

Sounds about right, PAMPAGUY.  Keep in mind that the study used Everolimus, which has a half-life of about 30 hrs vs about 60 for R. And the molecule has been modified somehow to have less impact on mTOR2, so theoretically fewer mTOR2 related side effects.

Still I think your estimate of the best dose is in the ballpark, until we know more.

[VP.]

Are mouth sores a serious side effect? What is the cause of the mouth sores? Immune system dampening? I get a sore with 2mg and GF juice once a week. Like a minor cold sore.

[Razor444]

 

 

Thanks for the post.  You might want to read this post I made a few days back about dosing schedules.  This is from a practicing physician who has taken rapa + metformin for over a year, experimenting on himself.  You are taking the rapa just like a someone who had a kidney transplanted.  You want to take it for longevity purposes/aging.

 

 

 

I've got an autoimmune disease (ulcerative colitis) which affects how I take rapa. Raising the dose--for example, to 2 mg every other day--gives me diarrhoea.

 

I've also tested taking rapa every day. That didn't work well for my gut.

 

With the dose I'm on, I can still build muscle. I also have minimal side effects. It may not be the best regime; agreed. I think it could be the best in my situation, though.

 

At some point, I want to experiment with spiking mTOR. Like, consuming leucine during workouts and/or looking into CYP3A4 inducers to decrease concentrations of rapa for a larger window. 

[Jaris]

Are mouth sores a serious side effect? What is the cause of the mouth sores? Immune system dampening? I get a sore with 2mg and GF juice once a week. Like a minor cold sore.

 

The following are my opinions, based on what I've read/heard - and could be wrong:

 

VP, small mouth sores aren't usually considered a serious side effect. They are common with R, and at high doses they're almost expected. When that report said that they had only one "severe adverse event" of "mouth ulceration" I'm pretty sure that they meant that they saw one case which was more severe than the other cases of minor mouth ulcers. If you look at Table 1 of side effects they saw in the study, they had several cases of it and only mentioned one as being "severe" (at 20 mg / week).

 

Normally, as we get older, our cells get stuck in the growth/reproduce state; damage continues and mistakes in DNA get reproduced in the new cells. Cells in aged people get "sloppy and leaky" and cause inflammation. R switches cells from "growth/reproduce" state to "autophagy" state.

 

Mouth cells are constantly being damaged externally (as opposed to internal damage) and replaced, so they work a little differently from other types of cells; the whole cell gets replaced rather than repaired. So when our cells are told to stop reproducing, our mouth cells aren't being replaced as quickly as before. The externally damaged cells, rather than being replaced very quickly as they normally would be, can leave gaps between cells that can get infected, causing the mouth sores.

 

So it's not that the immune response is dampened (the elderly/flu study shows the opposite). Everyone I've heard of who's studied the differences between low "pulse" dosing vs very high "chronic" (daily) dosing has said that the immune response is actually healthier (more youthful) for low/pulse dose, but greatly suppressed by high/chronic doses. For those on high/chronic doses (for cancer or organ transplant), the danger with suppressing the immune system is that they can't fight off brain infections, such as meningitis. But, again, the study showed that low/pulse dosing actually improved immune response (in at least this one limited study).

 

The first 2 weeks that i took R, I had a small mouth sore. It went away, and I haven't had any until a few weeks ago, and that one went away quickly too. Obviously, I keep an eye on them and will stop for awhile if one gets too bad.

[Jaris]

So... I was reading about mouth ulcers some more, and I don't know if what I wrote is completely true. I still don't think they are usually a serious side effect, but I found this quote;

• There tends to be an increase occurrence of canker sores when the immune system is compromised. Such as with bacterial or viral infections or with autoimmune diseases.

[tintinet]

Etiology of mTOR (mammalian target of rapamycin) inhibitor-induced stomatitis (mIAS) is apparently not well understood.

 

http://www.futuremed...2217/fon.13.141

[Jaris]

Etiology of mTOR (mammalian target of rapamycin) inhibitor-induced stomatitis (mIAS) is apparently not well understood.

 

http://www.futuremed...2217/fon.13.141

 

Returning the favor:

 

The mechanistic target of rapamycin (mTOR), (formerly mammalian target of rapamycin before it was recognized to be highly conserved among eukaryotes.)

 

In other words, mTOR is in any organism that has mitochondria. And that's interesting because Rapamycin was first "invented" by a kind of bacteria to fight other bacteria and fungi, possibly hundreds of millions of years ago, before there were any mammals. The practical benefit of that: mTOR (and Rapamycin) behave similarly in everything from yeast to humans. You just have to love this stuff, if only for the cool stories you get to tell about it.

Edited by Jaris, 30 March 2017 - 12:02 AM.

[MikeDC]

Rapamycin is not native to our body.

[Jaris]

Rapamycin is not native to our body.

 

No, it's not. mTOR is. Rapamycin was "invented" by a kind of bacteria to fight other bacteria and fungi. It works by dialing down mTOR. It works similarly in everything from yeast to MikeDC, because mTOR is similar. (But you have to put it into yeast or MikeDC first.) Sorry if that wasn't clear.

Here's something else that's interesting about that: Mitochondria are evolutionary endosymbionts derived from bacteria and contain DNA similar to bacterial DNA2,3,4

Check out those references.

Edited by Jaris, 30 March 2017 - 01:00 AM.

[to age or not to age]

We have been taking rapamycin in a single low weekly dose (3-4mg) for at least 8 weeks.  Both my wife and I have

experienced minor mouth sores that go away in 3 or 4 days.  I have twice gotten a bit of a sty on the lower eye lid,

something I rarely if ever experience.  This happened to one eye, than a week later to the other. It seems to recede

by using motrin after several days. We feel like something is happening physically but it's hard, at this point, to put a

fine point on it. And again, we also take other stuff, like curcumin, restveratrol and BASIS.

[to age or not to age]

MikeDC's behavior leads me to believe he has an interest, financial or otherwise, in promoting NR.  All his posts are on NR. We've seen this trollish behavior before, years ago, when some parties were promoting resveratrol, and resveratrol from certain vendors.  Coincidentally or not, the ResveraTroll also used a Virginia based ISP.  Mike, please refrain from posting on NR in this or other non-NR related topics.

 

Personally I found NR had no discernible effect.  I suspect there is more than a little individual variability in response.  NR may raise NAD levels, but there is a three-way dance between PPAR, SIRT1 and NAD.  Stimulating one when the other is lacking may be useless.  As is NR for some. Nicotinamide mononucleotide (NMN) is more promising. I look forward to its availability.

 

In the meantime, while waiting for better senolytics than dirty chemo drugs like dasatanib, rapamycin also has senolytic properties if use intermittently. 

Don't want to be off topic here, but it seems that the NAD dance may be the NAD ratio, which NQ01 influences. Beta lapachone 

affects NQ0-1 - I recently had it synthesized and take it - in addition to BASIS

[Valijon]

I forgot all about BL. Wasn't that expensive to get synthed? How are you feeling on it? Any noticanle external effects?

[to age or not to age]

The major component is very expensive.  I am having the chemists get a quote on a bulk buy. I have been combining it with rapamycin, but at a very low dose.

Someone I gave a gram to tripled his dosage and dissolved the crystals under his tongue.  He reported startlingly positive effects. So- between taking rapamycin,

beta lapachone, resveratrol, curcumin and BASIS, something is definitely happening, but what is doing what is the question. 

[Valijon]

The question is, do you look ten years younger yet? I'm very interested in the results.

[MikeDC]

Targeting NAD+ with Niagen has much broader benefits than just sirt1 genes. Hundreds of reactions depends on NAD+. Targeting mTORC1 does not mimic calorie restriction as the following papers shows. We also know Rapamycin is not even a perfect mTORC1 inhibitor which means it has many side effects.
Micotinamide Riboside is natural to our body and will not have any side effects with reasonable doses. From what I know Rapamycin will not have life extension effects in humans.

http://www.tandfonli...01.2016.1221210

[Jaris]

I don't think mentioning other meds we take along with R is off-topic. I'm interested in BL too, maybe combining it with NR and R.