Using RAPA for AD prevention

Newcomer introductions, personal anecdotes, caregiver issues, lab results, and n=1 experimentation.
Newtothis3/4
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Re: Using RAPA for AD prevention

Postby Newtothis3/4 » Tue Jul 14, 2020 8:25 pm

karelena wrote:
Newtothis3/4 wrote:I am confident that anyone who takes Rapamycin intermittently before AD symptoms appear will never get AD (or cancer, diabetes, etc).


I am not so confident that it will 100% prevent AD, but I started taking it too a couple of weeks ago. It just seems that the mechanism of action would be helpful in particular for APOE 4/4. My prescription also came from Dr. Green. Thankfully sirolimus is now available as a generic in the US, a 3 month supply was $330 at Costco with a GoodRx coupon. It is very off label so insurance is likely to deny coverage.

Dr. Green also recommends senolytics, in particular dasatinib and fisetin once every 2-6 months. Are you doing this also?


I think you can be optimistic that by decreasing your Mtor, AD will be prevented. By using Rapa, you are literally ameliorating the negative effects of your 4/4 status. Rapa crosses the BBB and increases cerebral blood flow as proven by recent studies. Bonus, you won’t get AD and you’ll increase your life span and slow down all age related diseases. I am taking Fisetin every 4-5 weeks for 2 days in a row, 1500 mg. This is the protocol for the human trial Mayo used. Dr. Green did his own calculations and came out with the same conclusion.

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Re: Using RAPA for AD prevention

Postby karelena » Wed Jul 15, 2020 1:15 am

Newtothis3/4 wrote:I am taking Fisetin every 4-5 weeks for 2 days in a row, 1500 mg. This is the protocol for the human trial Mayo used. Dr. Green did his own calculations and came out with the same conclusion.


Are there any results from the Mayo Clinic human trial? All I can find is results of one of their dasatinib and quercetin trials:
https://newsnetwork.mayoclinic.org/disc ... tic-drugs/

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Re: Using RAPA for AD prevention

Postby NF52 » Wed Jul 15, 2020 12:06 pm

karelena wrote:
Newtothis3/4 wrote:I am taking Fisetin every 4-5 weeks for 2 days in a row, 1500 mg. This is the protocol for the human trial Mayo used. Dr. Green did his own calculations and came out with the same conclusion.


Are there any results from the Mayo Clinic human trial? All I can find is results of one of their dasatinib and quercetin trials:
https://newsnetwork.mayoclinic.org/disc ... tic-drugs/

Here's a link to the ClinicalTrials.Gov description of the study I think you are referencing. I did an Advanced Search using the terms "Chronic Kidney Disease" and "Diabetes" for the disease, and "Mayo Clinic" for the Lead Sponsor" with "active" as the study type.

The official title is: Frailty, Inflammation, and Stem Cell Functionality in Chronic Kidney Disease
Detailed Description:
The proposed studies will examine the effect of fisetin on adipose tissue-derived mesenchymal stem/stromal cell function, kidney function, markers of inflammation, and physical function in individuals with advanced chronic kidney disease, particularly diabetic kidney disease. This study will involve a single 2-day oral treatment regimen with fisetin or placebo. Study subjects will be randomized 2:1 to study drug or placebo. Study visits will consist of blood, urine, and abdominal wall skin and subcutaneous fat samplings in addition to testing of physical strength at given time points. Subjects will be followed for a total of 12 months.

You can see the extensive inclusion and exclusion criteria for participants on the link. The study notes an estimated "Primary Completion Date" of January 2023, with a Final Completion Date of April 2025. Since the listed cohort is only 30 participants, and the length of study for each is 12 months, it's not clear if they are having trouble recruiting patients with severe chronic kidney disease (most studies have suspended recruitment during COVID=19 to so far), but the results posted may be with a small number of people. Since this is a Phase II study, small numbers are expected, because the primary goals are to demonstrate safety as various dosage levels and efficacy. Promising results in Phase II would likely lead to seeking funding for a much larger Phase III study of several hundred or more people to meet statistical "power" requirements.

Given the timelines of studies, this is promising for CKD and diabetes, and may hold promise for AD, but seems to be several years away from definitive proof.
4/4 and still an optimist!

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Re: Using RAPA for AD prevention

Postby MichaelR » Sat Aug 01, 2020 4:13 pm

karelena wrote:I have read some newer articles with "low dose rapamycin," as low as 0.5 mg/kg in mice

I'd like to see that 0.5 mg/kg study; please link or cite. In PMID 24341993, 0.75 mg/kd per day of rapa had no effect on lifespan in male mice, and only a modest effect in females (who get higher blood levels at the same dose, though the difference was small at this lower end of the dosing scale, and who aren't as affected by the diabetic side-effects as males).
karelena wrote:I have read some newer articles with ... intermittent dosing (3 times a week, then a week off or once a week)

Intermittent dosing has only been used in small (underpowered) pilot studies, or in obese and/or cancer-prone mutant mice: there's far more evidence in favor of daily dosing — and this already assumes that it works in humans as it does in mice.
karelena wrote: Also, a typical human dose for transplant patients is 1-2 mg/day, much lower than the human equivalent of 8mg/kg (human dose equivalent would be 0.66 mg/kg or 47 mg/day for a 70 kg human!) I'm going to look and see if anyone has measured the mouse blood levels as we do in humans (target level for transplant patients is 6-20 ng/ml);

Happily, we actually do know something about blood levels, as Brian has already noted; unfortunately, they don't support the utility or safety of low-dose, intermittent dosing. On this, see his previouspost, and:
https://www.longecity.org/forum/topic/8 ... t&p=823679
https://www.longecity.org/forum/topic/8 ... t&p=823716
https://www.longecity.org/forum/topic/8 ... t&p=823757

(Longecity post URLs sometimes process screwily: if you don't get 3 posts about rapa dosing by me, drop me a note).

In the Mannick et al vaccine trial (PMID 29997249), they got twice as many total side-effects at 20 mg once/week than at 5 mg once/week, including four times as many cases of mouth ulcers, but no better immune priming. There was no benefit at all at 0.5 mg daily.

Note that this study used everolimus/RAD001, not rapa proper. We don't know exactly how to translate from everolimus to rapa, but the usual clinical dose in transplant patients is 5 to 10 mg everolimus/day and 2-8 mg of rapamycin.

And that's just one outcome (vaccine response) — and not a lifespan benefit, and not prevention of AD. And despite all the knowledge they gained through three clinical trials, their own short-acting mTOR inhibitor (BEZ235/RTB101) failed in Phase III, which says a lot about how hard it is to game this all out.

Now: the main reason I came here to post ;) . No one seems to have posted PMID 32173556 (though it was listed in a ToC posted by user Fiver in April), and it has strong bearing on ApoEε4 carriers — and might raise some concern for those with only one allele. In mouse models, they find that ε3s get few if any of the benefits of rapa that ε4/ε4s do, and actually impairs their brain glucose metabolism, though they did get some cognitive benefit and lower anxiety:

We found that in the [mice that express human APOE4 gene and overexpress Aβ (the E4FAD mice)], rapamycin normalized bodyweight, restored [cerebral blood flow] (especially in female), BBB activity for Aβ transport [that is, efflux of Aβ out of the brain], neurotransmitter levels, neuronal integrity and free fatty acid level, and reduced Aβ retention, which were not observe in the E3FAD-Rapa mice. In contrast, E3FAD-Rapa mice had lower [cerebrovascular reactivity] responses, lower anxiety and reduced glycolysis in the brain, which were not seen in the E4FAD-Rapa mice. Further, rapamycin appeared to normalize lipid-associated metabolism in the E4FAD mice, while slowed overall glucose-associated metabolism in the E3FAD mice. Finally, rapamycin enhanced overall water content, water diffusion in white matter, and spatial memory in both E3FAD and E4FAD mice, but did not impact the somatosensory responses under hindpaw stimulation.


It's unfortunate they didn't include an ε3/ε4 group, but this certainly makes rapa a bigger gamble for one-allele carriers (and arguably contraindicated for ε3/ε3).

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Re: Using RAPA for AD prevention

Postby SusanJ » Sun Aug 02, 2020 5:04 am

MichaelR wrote:In mouse models, they find that ε3s get few if any of the benefits of rapa that ε4/ε4s do, and actually impairs their brain glucose metabolism, though they did get some cognitive benefit and lower anxiety


Thanks for this. Definitely something to watch. As a 3/4 I do see some things that help 4/4s that are at odds with 3/3 and do wonder what the best course of action is in those circumstances. Wish more studies would separate 3/4 and 4/4 responses.

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Re: Using RAPA for AD prevention

Postby circular » Sun Aug 02, 2020 2:38 pm

Brian4 wrote:I decided not to take rapamycin ... mainly because I'd rather wait until an mTOR inhibitor is developed with a very short half-life, so that one could take it late in the evening and it would reinforce the natural mTOR rhythms of the body (lower – though not in all tissues – at night; higher during the day).

Also, evolution gave us a program of longevity and health based on restricted eating, a program that includes a simple way to alter mTOR levels (eat less). Until we have more research, I feel more comfortable lowering mTOR signaling through diet.

My thoughts exactly, although I wonder if we even need an MTOR inhibitor with a very short half-life. Perhaps our ancestral allele is simply ideally suited to reincorporating lifestyles consistent with evolutionary patterns. That said, I think coffee may be an MTOR inhibitor (have seen the claim but not the details), and I'm all for black coffee between waking and breakfast :-D

Also, eating compatibly with circadian rhythms while acutely ramping up MTOR at mealtime(s) for muscle preservation -- through exercise and or high quality protein stimulus -- is going to be critical for preventing AD. If Rapa suppress MTOR to the point of interfering with muscle maintenance, let alone growth, and sarcopenia sets in or worsens, I think it will backfire, but I'm not expert in any way such that I can adequately support that comment.

Are the pro-Rapa folks advocating 24/7 MTOR suppression, or is the intermittent dosing intended to cycle MTOR?
ApoE 3/4 > Thanks in advance for any responses made to my posts.

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Re: Using RAPA for AD prevention

Postby MichaelR » Mon Aug 03, 2020 10:32 am

circular wrote:
Brian4 wrote:I decided not to take rapamycin ... mainly because I'd rather wait until an mTOR inhibitor is developed with a very short half-life, so that one could take it late in the evening and it would reinforce the natural mTOR rhythms of the body (lower – though not in all tissues – at night; higher during the day).

Also, evolution gave us a program of longevity and health based on restricted eating, a program that includes a simple way to alter mTOR levels (eat less). Until we have more research, I feel more comfortable lowering mTOR signaling through diet.

My thoughts exactly, although I wonder if we even need an MTOR inhibitor with a very short half-life. Perhaps our ancestral allele is simply ideally suited to reincorporating lifestyles consistent with evolutionary patterns.

You're getting trapped in the adaptationist fallacy (and Brian is possibly flirting with it). The fact that inhibiting mTOR with drugs or mutations slows animals' aging and increases their lifespans beyond what occurs in the lab and far beyond what happens in the wild demonstrates that lifestyles consistent with evolutionary patterns still allow for a level of mTOR signaling that is bad for one's long-term health and longevity.
circular wrote:That said, I think coffee may be an MTOR inhibitor (have seen the claim but not the details), and I'm all for black coffee between waking and breakfast :-D

Coffee induces autophagy in vivo ... in mice.
circular wrote:Also, eating compatibly with circadian rhythms while acutely ramping up MTOR at mealtime(s) for muscle preservation -- through exercise and or high quality protein stimulus -- is going to be critical for preventing AD. If Rapa suppress MTOR to the point of interfering with muscle maintenance, let alone growth, and sarcopenia sets in or worsens, I think it will backfire, but I'm not expert in any way such that I can adequately support that comment.

That's an intuitive idea, but mistaken: chronic inhibition of mTOR signaling with drugs or mutations better preserves muscle function and (even more counterintuitively) muscle fiber size and weight with age: PMIDs 26738589, 31454792, 31308131, 30927336, 21386136.

You can't just crank up anabolism all the time in muscle and expect that muscle to be preserved: the incessant stimulus to produce more protein and grow leads to increasing accumulation of dysfunctional organelles and damaged proteins, gradually impairing muscle function and even growth in the face of anabolic signaling (hence most studies find anabolic resistance in aging muscle). Couple that with increasing resistance to mTORC1 inhibition with age in muscle and other tissues, and the muscle clearly needs an 'unnatural' clamp-down of mTORC1 signaling if it is to maintain function with age, absent rejuvenation biotechnology to directly repair aging damage.

circular wrote:Are the pro-Rapa folks advocating 24/7 MTOR suppression, or is the intermittent dosing intended to cycle MTOR?

There's more evidence supporting chronic inhibition; intermittent dosing is intended both to cycle mTORC1, which may itself limit some side-effects, and also (in the case of rapa and everolimus) to prevent the inhibition of mTORC2, which latter only happens secondarily after prolonged use of the drugs for reasons that AFAIK are not well-understood. Inhibition of mTORC2 appears to be responsible for the rapa-induced diabetes that is particularly deleterious in males and appears to be responsible for much of the gap in lifespan between male and female mice dosed with the stuff chronically. However, the evidence on all of this is still limited.

(I should make clear that I am excited by rapa as a proof-of-concept, I am not "pro-rapa" in the sense of taking or advocating that anyone take the stuff, tho' I wouldn't go so far as to dissuade anyone from experimenting with the stuff if they're over the age of 65, sufficiently informed on the science, and prepared to be vigiliant in collecting and analyzing their data (which is, however, a very small number of people) ).

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Re: Using RAPA for AD prevention

Postby circular » Mon Aug 03, 2020 11:17 am

MichaelR wrote:(I should make clear that I am excited by rapa as a proof-of-concept, I am not "pro-rapa" in the sense of taking or advocating that anyone take the stuff, tho' I wouldn't go so far as to dissuade anyone from experimenting with the stuff if they're over the age of 65, sufficiently informed on the science, and prepared to be vigiliant in collecting and analyzing their data (which is, however, a very small number of people) ).

Thanks for explaining all that Michael! I haven't had any time to dive into this, or at least have chosen to surface dive into other areas when time allows, or I make it allow. A sad state of affairs, this.

You make some interesting points I'll have to ponder.

To this point:
You can't just crank up anabolism all the time in muscle and expect that muscle to be preserved: the incessant stimulus to produce more protein and grow leads to increasing accumulation of dysfunctional organelles and damaged proteins

Just to be clear I didn't say I plan to crank up anabolism 'all the time' or provide 'incessant stimulus to produce more protein and grow'. My plans are far from that. Do we actually know the point at which intermittent anabolism begins leading to dysfunctional organelles and damaged proteins that can't be cleared during regular, significant fasting cycles?

How much lifespan extension are people seeking to get with Rapa? I personally just want to live a healthy life, and maybe Rapa would help with that (I don't know what I think of it yet) and would be content if I reached the average lifespan for women today. A much bigger fear than dying or even cognitive decline is running out of money before I'm gone.
ApoE 3/4 > Thanks in advance for any responses made to my posts.

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Re: Using RAPA for AD prevention

Postby circular » Mon Aug 03, 2020 1:12 pm

MichaelR wrote:You can't just crank up anabolism all the time in muscle and expect that muscle to be preserved: the incessant stimulus to produce more protein and grow leads to increasing accumulation of dysfunctional organelles and damaged proteins, gradually impairing muscle function and even growth in the face of anabolic signaling (hence most studies find anabolic resistance in aging muscle). Couple that with increasing resistance to mTORC1 inhibition with age in muscle and other tissues, and the muscle clearly needs an 'unnatural' clamp-down of mTORC1 signaling if it is to maintain function with age, absent rejuvenation biotechnology to directly repair aging damage.

More ponderfications:

I think I see that when you say 'crank up anabolism all the time' and 'incessant stimulus to produce more protein' you just mean relative to chronic MTOR inhibition. So what to me isn't incessant would be from that angle.

And are you likening the anabolic resistance to MTOR1 to the anabolic resistance to insulin, whereby increasing one's protein- and/or exercise-induced MTOR1 would be akin to someone with diabetes taking ever increasing amounts of insulin to misguidedly 'address' diabetes, only leading to greater insulin resistance?

If 'parallel mechanisms' (for lack of words) between MTOR1 and insulin resistance have already been seen at play, then I have to wonder how it's good that we are always told that exercise is one of the number one things we should do to preserve health and slow aging (assuming not constant, intense exercise). Wouldn't that amount to chronic, near daily MTOR1 signaling and then contribute to greater MTOR1 anabolic resistance over time. What are the effects of chronic MTOR1 inhibition on exercise benefits?
ApoE 3/4 > Thanks in advance for any responses made to my posts.

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Re: Using RAPA for AD prevention

Postby Newtothis3/4 » Mon Aug 31, 2020 8:21 pm

circular wrote:
Brian4 wrote:I decided not to take rapamycin ... mainly because I'd rather wait until an mTOR inhibitor is developed with a very short half-life, so that one could take it late in the evening and it would reinforce the natural mTOR rhythms of the body (lower – though not in all tissues – at night; higher during the day).

Also, evolution gave us a program of longevity and health based on restricted eating, a program that includes a simple way to alter mTOR levels (eat less). Until we have more research, I feel more comfortable lowering mTOR signaling through diet.

My thoughts exactly, although I wonder if we even need an MTOR inhibitor with a very short half-life. Perhaps our ancestral allele is simply ideally suited to reincorporating lifestyles consistent with evolutionary patterns. That said, I think coffee may be an MTOR inhibitor (have seen the claim but not the details), and I'm all for black coffee between waking and breakfast :-D

Also, eating compatibly with circadian rhythms while acutely ramping up MTOR at mealtime(s) for muscle preservation -- through exercise and or high quality protein stimulus -- is going to be critical for preventing AD. If Rapa suppress MTOR to the point of interfering with muscle maintenance, let alone growth, and sarcopenia sets in or worsens, I think it will backfire, but I'm not expert in any way such that I can adequately support that comment.

Are the pro-Rapa folks advocating 24/7 MTOR suppression, or is the intermittent dosing intended to cycle MTOR?


Rapa’s half life on an intermittent one weekly dose is back to baseline between day 3 and 4. Not MTOR chronic suppression


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