Rapamycin in humans

I'm cautious on pharmaceuticals but am considering Rapamycin. Downsides are cost, difficulty to source and potential side effects (some people suffer from stomach issues IIRC). So balancing that I'm looking at potential benefits, aging being the benefit. Let's take this explanation of the benefits as an example, in particular

It has been known since the 1930s that caloric restriction extends lifespan and slows aging. Rapamycin could be characterized as caloric restriction in a pill. In a mouse study discussed in the "Cardiomyopathy" section, rapamycin had similar effect in aged mice as 40% caloric restriction in restoring the dysfunction of old hearts to normal function of young hearts.

Now separately we know that research has determined that caloric restriction does not have the effect for humans/chimps that you see with shorter lived species in life extension. It can increase health span (e.g. making you less prone to heart disease) but it won't add years to your life. AFAIK the Rapamycin studies have been done on mice and dogs which have a much shorter life span than humans. 

Anybody have any data that says otherwise? If the main effect is  to decrease TOR, well there are other ways to do that (periodic fasting which also has other benefits). 

So at the moment I'm remaining skeptical of the benefit of Rapamycin in humans, adding in the other difficulties I'm holding off using it, but am open to research and evidence to the contrary. 

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  • Hi Dan,

    I'm interested in Rapamycin as well, and just took the plunge and ordered a bottle.

    I also take Metformin, and supplement with NMN (NAD precursor), ubquinol, quercetin, ptersostilbene, cruciferous veggie complex, Transfer Factor Multi-immune, astaxanthin, tocotrienol complex, turmeric, low dose Naltrexone, and a low dose of Nature-Throid.  I don't go to doctors (formerly worked as an RN), and practice intermittent fasting most days.  I order all my own stuff, and stopped going to doctors after having to "fix" a rheumatoid type nodule with topical tacrolimus cream (its an immunosuppressant like Rapo), and Minocycline , when all the doctor could offer was surgery~no thanks!  

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      • DanMcL
      • skipping my funeral
      • danmc
      • 2 mths ago
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      angie4life your story sounds familiar, I’m doing similar supplementation and likewise realize the medical profession is too status quo and 10 years behind the news. And to be fair they also are a service industry and most people don’t want to take care of their own health.

       

      Anyhow curious how it works out for you but like most supplements it probably won’t have overtly noticeable effects I think.

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  • I am very suspicious of the lifespan vs. healthspan dichotomy that Dan states above.  I believe it is a cop-out employed by age-treatment researchers to convince the FDA and NIH that they are working to improve a patient's health (which the NIH funds) rather than making the patient live longer (which the NIH refuses to fund).   Why wouldn't a significant improvement in health make a test animal (or human) live longer?  It makes no sense.

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      • DanMcL
      • skipping my funeral
      • danmc
      • 1 mth ago
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      JGC Well actually I first learned about health span vs life span from exactly those life extension researchers, specifically the ones at the Buck Institute for longevity which I visited. Their messaging is that they work on health span, not life, and that's what they use in their funding pitches. Fact is there is nothing to date that we've found that will increase our lifespan past the observed maximum of some 120 or 130 years, but there are many ways we can be healthy throughout older age. So no I don't think there's a conspiracy in that community, but the opposite. 

      There is a subtlety here though that gets missed. Suppose you're prone to heart diseases or diabetes, like Ray Kurzweil. Without intervention you would probably die by 50. But if you take care of yourself you can easily live a normal lifespan. This would be classified as increasing your health span I think, but in fact you increased your personal lifespan. So yes depending on circumstances, life span can be individually increased. So you can bring up the mean of a population but no the median (for you stats nerds), but bringing the mean up does make people individually live longer, to a degree. 

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  • As you say, "Their messaging is that they work on health span, not life, and that's what they use in their funding pitches."  That's exactly my point.  It is not in the narrow interest of age-treatment researchers to admit to their funding agencies that increasing healthspan will tend to increase lifespan.  Further, before one can actually investigate any effects on maximum lifespan, one must have a population of extremely old individuals that are in excellent health, and presently there are none.  The extremely old tend to die of amyloid buildup leading to organ failure.  One cannot make statistical arguments about the mean when there are no statistics.  It seems obvious to me that an increase in healthspan will bring with it an increase in lifespan, cop-outs to funding agencies notwithstanding.

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      • DanMcL
      • skipping my funeral
      • danmc
      • 1 mth ago
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      JGC No actually Aubrey De Grey does this extensively (tell the funders that treating the cause of disease - aging - will fix the symptoms - heart disease and such). But guess who gets the smallest funding of them all? Aubrey. He complains about it bitterly, but he knows he doesn't have the personality and the messaging that brings in money. It's obvious, if saying that you want to work on people living forever would result in millions in funding, they would be shouting it. Fact is the billions that the NIH and Nat Cancer Society spends is all on dealing with the symptoms. 

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  • OK, your point is that we should shut up about work on healthspan probably increasing the maximum lifespan, because it gets in the way of desirable funding. I can agree with that, but such blatant misrepresentation in the interest of funding bothers me.  It makes me wonder where else anti-aging researchers are willing to fudge the truth.

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  • I think this is related to subject of this thread.

    There is an amendment (notified by email today) in the order of intervention with more focus on metformin as both AMPK activator and mTOR inhibitor (vs rapamycin).

    I report the note from Faloon got a coupe of days ago:

    "...Our investigations and partial validations resulted in the dissemination of the following multi-step approach to biological age reversal at RAADfest:

    Step 1:  Inhibit mTOR and induce autophagy with rapamycin (or AMPK nutrients
                 and/or intermittent fasting and/or calorie restriction)
    Step 2:  Repair cellular DNA by boosting NAD+
    Step 3:  Purge senescent cells using two doses of dasatinib + quercetin
    Step 4:  Systemic rejuvenation with young plasma and/or stem cells

    We are amending this sequential order in this email.

    Based on ongoing clinical research, we believe most of you are already sufficiently inhibiting mTOR with metformin and/or nutrients like gynostemia leaf extract and hesperidin (found in the AMPK Activator nutrient formula).

    Low-calorie diets and exercise also indirectly suppress mTOR (via activation of cellular AMPK).

    So as of this date, we are revising the age-reversal protocol as follows:

    Step 1:  Inhibit mTOR/induce autophagy with metformin 
                 (or AMPK nutrients)
    Step 2:  Repair cellular DNA by boosting NAD+
    Step 3:  Purge senescent cells using two doses of dasatinib + quercetin
    Step 4:  Systemic rejuvenation with young plasma and/or stem cells..."

    Beneficial effects on humans and differentiating between metformin and rapamycin need to be assessed, but it seems established the mechanisms are different. I understand rapamycin is directly inhibiting mTORC1 (chronic use might also result in inhibiting mTORC2 though which might not be good). Other molecules such as aspirin and metformin feature an indirect inhibition of mTORC1. Metformin seems to regulate REDD1 which promotes TSC2 which leads to inhibit mTORC1 and this independently from the metformin AMPK activation path (e.g. see Kalender et al 2010).

    Any comment?

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      • JGC
      • JGC
      • 1 mth ago
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      albedo 

      In Step 3, you might want to consider whether fisetin should be suggested as an alternative to D+Q.  It's much reputed to be very effective in senescent cell clearance (at least in mice), is much cheaper and easier to obtain than dasatinib (around $10 for 30 capsules of 100 mg), and unlike the latter has no known negative side effects.

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      • Don
      • Don
      • 9 days ago
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      albedo albedo The change in protocol suggests a turning-away from rapamycin. Dr. Faloon should be offering an explanation for this rather significant shift. Might this result from current testing?

       

      That information was posted a month ago. Any news since then?

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      • DanMcL
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      • danmc
      • 9 days ago
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      albedo I asked you this before I think but where did you sign up to get these emails? You said on this site I think, but which list, do you have a link? I'm not getting any of these. 

      Bill (AFAIK he's not a Dr) has said on multiple occasions that they're seeing sufficient AMPK activation, probably because most participants are taking metformin and/or other AMPK activators. I'm not sure it's a turning away from Rapamycin because of R, but rather because it's probably unnecessary for participants. 

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      • Iðunn
      • Iunn
      • 4 days ago
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      albedo Metformin clearly is no substitute for rapamycin. Metformin inhibits mTORC1 is in vitro, in implanted tumors, and in the mouse liver: no one has shown that it inhibits mTORC1 in actual tissues outside the liver.

      Leaving the mechanism aside, rapamycin has been shown over and over again to extend mean and maximum lifespan in normal mice; while metformin has helped lower the mortality in obese, diabetic, mice given artificial cancers, and short-lived mouse stocks like SHR mice, it has either a very small or no effect on median lifespan (only) in normal mice:

      https://onlinelibrary.wiley.com/doi/full/10.1111/acel.12496

      https://www.nature.com/articles/ncomms3192

      It did, however, improve the effects of rapamycin in male mice (only — not females) when used in combination, which again suggests it is not working through the same pathway.

      Reply Like 1
      • albedo
      • albedo
      • 3 days ago
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      DanMcL 

      Hi Dan. Yes I recollect you asked and sorry I am late replying. I cannot retrieve the original protocol changes email but I am pretty sure I am getting these information after having joined the network (button "join" in the new website https://age-reversal.net/join/) . The email you refer to might have had a different sender prior to the name change. Today the sender is info@age-reversal.net . I got an update two days ago, again signed by Mr. Faloon, see the following picture.

      Wrt rapamycin protocol changes I have no additional news.

      I hope this helps.

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      • albedo
      • albedo
      • 3 days ago
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      Iðunn 

      Thank you for the clarification.

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      • albedo
      • albedo
      • 22 hrs ago
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      DanMcL 

      DanMcL said:
      albedo I asked you this before I think but where did you sign up to get these emails? You said on this site I think, but which list, do you have a link? I'm not getting any of these.

       Hi Dan. Have you solved the problem? Did my answer helped? I just received an update email from "Age Reversal Network info@age-reversal.net" (Dec 9) signed by Faloon which I report here just in case you overlooked it:

      "...A drug called rapamycin has been shown to markedly increase lifespan in every animal model tested.

      Initial reports from a pioneering doctor indicated substantive regenerative benefits in response to 5 mg a week of rapamycin taken along with daily metformin and other AMPK-activating compounds.

      Interim results from a clinical study, and feedback from our supporters, indicate that this dose of rapamycin (5 mg/week) may be too low.

      A clinical study on higher-dose weekly rapamycin is being planned.

      Until we verify safety/efficacy of this higher rapamycin dose, please consider lowering mTOR by using AMPK-activating interventions such as:

      • Metformin and/or
      • Restricted eating (including various forms of intermittent fasting) and/or
      • Nutrients like gynostemma pentaphyllum and hesperidin.

      When AMPK activity is increased in cells, mTOR is indirectly suppressed and autophagy is initiated. Autophagy is the removal of accumulated waste from inside old cells. It is an important step in restoring cellular functionality.

      When excess mTOR is lowered, autophagy can help rid old cells of toxic debris.

      We made a change in my video presentation to reflect our current view that the first step to age reversal is to boost AMPK activity via several validated methods...."

      Reply Like 1
      • DanMcL
      • skipping my funeral
      • danmc
      • 13 hrs ago
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      albedo got that email too, thanks!

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  • As someone (healthy 71 yr old) who has taken multiple supplements "forever," metformin for a few years, rapa weekly for a year or two, I took fisetin 600mg daily for 5 days and felt the same result as the others...nothing! lol  I keep waiting for something to knock my socks off. 

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      • DanMcL
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      • danmc
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      peterc Agree, most supplements have no apparent effects. For me the only ones that do are CoQ10 (in large enough dose it does act as an upper), PtC (skin improves after a week of restarting), NAD+ (sleep), and ALA/ALC (improved energy and well being is noticeable). 

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  • Well, I stopped taking PtC and ALC because of their connection to TMAO production in the gut. http://www.clevelandheartlab.com/blog/choline-tmao-heart-health/ I'm not sure whether this applies to vegans such as myself though.) I don't feel anything from ubiquinol at a dose of 100mg or NR at 250. How much does it take to feel it?

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      • DanMcL
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      • danmc
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      peterc Nope, it's not a problem with vegans! I was at the True North center (helping a friend get better) when a researcher came through and gave a talk, including about that result. I asked specifically if it applied to carnivores or vegans, and he was quite clear that they tested both and it was not a problem for vegans. I too am a vegan and take PtC, I recommend it to friends only if they also don't eat meat. 

      For me around 150mg or 250mg I start to feel more 'alive' or something, more energetic certainly. I also take 100 and don't notice it. In the early days I wasn't sure of the dose and I think I had some 250mg pills. It might also be person dependent, if you're CoQ10 depleted you might need more to feel it (e.g. if you're taking statins)

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      • peterc
      • peterc
      • 1 mth ago
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      Dan Mc I do wonder, assuming that most of our choline and carnitine come from animal sources normally....whether taking them long-term, every day as supplements makes us carnivores from the standpoint of our gut bacteria...? It's one thing for a vegan to take them once and measure TMAO, but I wonder whether the long-term studies have been done.

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      • DanMcL
      • skipping my funeral
      • danmc
      • 1 mth ago
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      peterc No studies AFAIK. Don't forget carnosine (with an S) which is a LE recommended supplement for vegans/vegs as that is a substance you only get from meat. I supplement with ALA, ALC, carnitine and carnosine among others (PtC).

      Personally I wouldn't worry about it. I'm somewhat skeptical/unsure of that study anyhow, even for carnivores, and recall that like most studies it found an effect (production of XYZ) but not necessarily a problem.  For example, a study found that our stomachs contain large quantities of hydrochloric acid, which is a cancer causing substance. Of course in this application we depend on it and it does not cause cancer. 

      angie4life  I've been vegan for, not sure, 15 years at least. Been doing supplements for 10 of those years, in quantities that would be generally considered large but is actually moderate (it's about the same as what Ray Kurzweil does). Otherwise I'm in the best health I've ever been and all my stats are those of a young person (literally. So no supplements, applied carefully and judiciously, should not be a problem and can be a great benefit. 

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      • peterc
      • peterc
      • 1 mth ago
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      Dan Mc Well, according to a recent meta-analysis there have been 11 studies that, taken together, indicate an association (haven't proven causation admittedly)  between TMAO levels and heart disease and premature death. I would consider that the problem. Its precursors for the gut bacteria are carnitine (though not "sine" apparently), choline, and lecithin. My understanding is that those substances are what govern the increase in the population of bacteria that will then metabolize it to TMAO. I don't think that bacteria care whether it is from an animal or a bottle.

      It boils down to interactions between our genes and their expression, our gut bacterial population, and what we feed ourselves and them. Complicated to unravel. I think that we just have to realize that we, as self-experimenters, don't have all the relevant info yet, and then jump in. ;)

      Reply Like 1
  • Thanks for the info, as I’ve been vegan 18 years and always wonder about whether it matters with supplements.  The supplement I feel had helped the most is the NMN sublingual powder ... I take several scoops a day , and a pesky long term tendinitis disappeared after a month or so .  I’ve been doing intermittent fasting and taking Metformin for two months , and my pup and I added low dose Rapaymycin this week after we did high dose Fisetin a few weeks ago ..maybe now add CoQ 10 , or even better , ubinquinol .

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    • angie4life did you spell tindionitus correctly? did you mean tinitus as in ear ringing?

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  • Hey, sorry , was typing fast late at night ... tendinitis, as in bicep tendinitis from too many yoga pushups haha .

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  • I found a dr in my city, houston that gave me script for rapamycin (sirolimus) and started taking it at 1mg starting yesterday, followed by 9 days off, then increasing to 2 milligrams for the second 10 day cycle, etc... I also take 500 mg metformin daily and did another full blood panel before starting rapamycin.

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  • I was lucky, the first doctor I asked wrote script for rapamycin (sirolimus) after reviewing Dr. Green's website protocalls.

    I have already been taking 500 mg,d metformin. My Rapamycin schedule is conservative at a 10 day intermitant dosing starting at 1mg, then 2, then 3.... I have been keeping detailed records.

    Possiblble side effects I may have seen from mapamycin are a reduction in left knee arthritus, a slight ocasional dry cough on the first day or two of the 10 day cycle, a bruse that I got on my arm may have taken longer to go away. I have extensive full med panel data befor testing as a baseline I can refer to later as I have a longer dose history. 

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