#105

Can’t you use drugs or supplements that activate mTORC2?

#106

It’s interesting to read various members’ side effects responses to rapamycin.

There is a difference between “canker” and “cold” sores. From reading several papers, it appears the sores caused by rapamycin are cold sores, not canker sores.
One is caused by the immune system responding to germs and foreign objects while the other is likely a flair-up of the herpes virus caused by the immunosuppression properties of rapamycin. By suppressing the immune system, rapamycin can potentially increase the risk of viral reactivation, including the herpes simplex virus that causes cold sores.

Herpes:
“90% of the world’s population are infected by the age of 40 years, and 40% of these will experience a recurrent infection”

Are the forum members who take rapamycin, but don’t have a herpes simplex flair-up of cold sores in the lucky 10% who don’t have the simplex virus?

"Key Differences Between Cold Sores, Fever Blisters, and Canker Sores
Cold sores (fever blisters) more commonly occur on the lips and face, though they can be in the mouth. Aphthous ulcers are found inside the mouth.

Cold sores are blisters that form in groups and crust after they break. Canker sores are ulcers inside the mouth that heal from the outside as long as they don’t get infected.

Cold sores are caused by the herpes virus, a contagious virus that readily spreads from person to person. Canker sores are not contagious and have several potential causes."

“What causes canker sores?
Experts aren’t certain of the cause, although it’s likely that they are the result of your body’s immune system response against germs and foreign objects. A canker sore can appear after an accidental bite on the inside of the mouth, after a visit to the dentist, or after emotional stress, a viral infection, an allergic reaction to food, or a menstrual period.”

“Oral herpes is a disease caused mainly by herpes simplex virus-1 (HSV-1) and primarily affects the face, mouth and throat. It causes pain, burning, tingling or itching at the infection site which is normally followed by clusters of blisters. After the first infection, the disease can recur as episodes of cold sores on the lips. It’s usually mild and self-limiting, lasting 2–3 weeks, but can cause severe disease in those who are at risk such as the immunocompromised. It’s a very common disease – 90% of the world’s population are infected by the age of 40 years, and 40% of these will experience a recurrent infection. Infection is lifelong.”

4 Likes
#107

What is 5€ or how much is that? Was it in oral form? If you have a link to studies, please provide.

#108

Scientists Discover That Taurine Promotes Anti-Aging - General - Rapamycin Longevity News

2 Likes
#109

That’s what I think Acarbose and 17aplha estradiol (and fasting) do, do you know any other drugs (or things) that increase mTORC2?

#110

So the basis of 3 ng/mL is that is the lowest acceptable trough level I can find, and this would be in the context of taking it for organ rejection, BUT also in combination with cyclosporine/steroids. So this would be the tiniest level that has some objective potency in that setting.
LabCorp Sirolimus see Reference Level
Quest more detailed similar
Used as a solitary agent, for various indications levels typically need to be in the 10-15 ng/mL range, and used for lymphangioleiomyomatosis has various ranges as a solitary agent with some indicating therapeutic efficacy even below 5 ng/mL, but most listing 5-10 ng/mL as goals.

These conditions however all require pretty potent and constant levels, which is why I’ve gone with the minimum level demonstrated to have efficacy as a level to want to be above for some period of time.

This is obviously all theoretic, but we are dealing with a potent medication, and I suspect most people are not getting levels sufficient to do much, and some people may be pushing themselves into risky high levels (probably unlikely in this group as most have been pretty conservative on dosing).

The good news is, so much of the other items like SGLT2’s seem to be panning out well, likewise with GLP’s and other agents. I suspect, however, most individuals might be going with a homeopathic dose? I guess on the good side, the study showing immune enhancement on low dose Rapa with the influenza vaccine is hopeful on at least that improvement being possible without getting a therapeutic (if we want to call therapeutic >3 ng/mL) level.

What do others think?

5 Likes
#111

I am glad you brought up the Mannick study for low dosing impacting immune response in the elderly. In an interview with @Krister_Kauppi , she further makes the case that a strong immune system response impacts a broad number of anti-aging benefits systematically in the body. And she is part of a company (Tornado Therapeutics) that is developing almost unlimited dosage mtor inhibiting drugs without inhibiting mtor2. Seems to me she should be followed closely for clues. Why take the risk with Rapamycin at high dosages at least until the new drug developments point the way forward?

2 Likes
#112

Thanks. I’ll probably be reading up on this a lot more this fall.

#113

Thank you so much!!!

#114

Great read! Thank you

#115

In Mannick study higher doses didn’t result in better endpoint efficacy. It is possible that if a fraction of the dose was used or different frequency - the benefit for lifespan would be even greater. I wished they run more doses, dog studies used 0.05 mg/kg so 1/20 of the dose used in Marmosets.

4 Likes
#116

I agree that the new Tornado Therapeutics mTOR1 inhibitors look extremely interesting. But, any new drug in development right now still has to go through Phase 1, 2 and 3 clinical trials, so likely 5 to 10 years away from any possible commercial availability… and of course any new drug is going to be priced like a new drug.

Everolimus in the USA prior to going generic was something like $15,000 per month - see link here (if not covered by insurance). I suspect that any new mTOR inhibitor will be priced similarly (and for anti-aging purposes won’t be covered by insurance). So then the calculus has to be is the marginal benefit of the new mTOR inhibitor worth the marginal cost (an extra $15,000/month) to you over the older mTOR inhibitors… See the price quote below for brand name everolimus (Afinitor) from GoodRX.com

AfinitorTop
AfinitorTop700×166 28 KB

Afinitor
Afinitor700×339 49.3 KB

And, of course, it will take many years of animal clinical studies to prove that any new mTOR inhibitor works as well in animal lifespan extension as rapamycin. Each mouse study takes at least 3 or 4 years, so it will be 10 or 15 years before we really know if a new drug is as good as rapamycin.

So - for the next 5 to 10 years (even if price is no object for you) rapamycin is really all that we have.

This is why I really think maximal effort should go into optimizing the dosing strategies for rapamcyin in humans. Its a great time to start some serious human clinical trials, ideally funded by a group like Hevolution fund. This would move broad interest and adoption of longevity drugs forward the quickest.

7 Likes
#117

0.05 mg/kg for a dog is 0.03 mg/kg for a human (conversion factor of 1.8). The marmoset study used 1 mg/kg, which is equivalent to 0.16 mg/kg for a human (conversion factor of 6.2). So not a factor of 20 but 5. Still a big difference as for a 60 kg human, the dog dose is 1.7 mg/day or 12 mg/week, which is close-ish to what humans here do.

4 Likes
#118

I listened to the tape of @RapAdmin ‘s interview with the senior author

I was doing chores around the kitchen, so was not taking notes in real time, but thought these point relevant to a lot of the discussions above

  1. Almost undetectable levels in blood left after 24h in marmosets if given less than 1mg/kg - so def much faster half life than humans. (From around when there is about 13min left of the audio). At one point I think he says clearance speed more similar to mice than humans.

  2. While they are doing daily dosing, it’s important to note that it is not given/eaten around the clock as in the ITP rodent studies. Rather it is as once a day “in their yogurt” (and there is a full 24hr before any new dose).

  3. Then when there is around 7 min left of the audio: peak rapa levels seem to go up to 30ng/ml vs through levels of 7-10ng/ml

7 Likes
#119

Is this based on the “antibody titers after flu vaccination” type end points? Or was it also the case for measures of mTORC1 inhibition, autophagy levels, IGF-1 lowering, etc?

#120

just titers, other measures have dubious clinical significance.

#121

Have those conversions been clinically validated and standardized ?

#122

I think he’s taking the numbers from this:

2 Likes
#123

Does that mean that this whole 120+ post thread is just of dubious clinical significance?

Most people here are probably not interested in rapa primarily as a way to improve their response to vaccines or infections.

Seems to me that much of the evidence that can and should be weighted for rapa in health and lifespan (the general focus of this thread it seems) is based on mechanistic relationships that are conserved across vast genetic space, a billion years of evolution and hence results are probabilistically more consistent than many/most other medicines across species.

1 Like
#124

I am not sure you understand the term “clinical significance”.

Antibody titer increase has clinical significance because it is standard of care for immunology practice like mine. That’s how we measured vaccine response for decades.
Similarly LDL levels have clinical significance.
Obviously lifespan increase or improvement in a given medical condition would be clinically significant.

AFAIK autophagy level has not proved its usefulness to detect or track any real life health issues or outcomes.