Rapamycin Redux

Rapamycin is the best anti-aging treatment yet discovered.  Most treatments that work in flies and worms fail when they get to mammals, but rapamycin has consistently extended lifespan more than 20% in mice [review as or 2014].  It works even when administered late in life, and intermittent dosing works as well or sometimes better than daily dosing.

Too bad that rapamycin is too dangerous for general human use.  It is a powerful immune suppressor, used, in fact, to keep kidney transplant patients from rejecting the foreign tissue.  People who take rapamycin are at elevated risk from infectious disease, and who knows but that the immune suppression might inhibit the body’s ability to detect and eliminate incipient tumors.  So there’s a search on for safer “rapalogs” that work through the same TOR (“target of rapamycin”) pathway, but without the side effects, especially with respect to immune suppression.

But what if rapamycin isn’t dangerous?  What if people who take rapamycin don’t get sick any more often, and their cancer risk is actually significantly decreased?  Might rapamycin be a safe and effective anti-aging drug, available now?

Last month, two encouraging reports came out of the research on rapamycin.  One short-term test in marmoset monkeys seemed to show that “immune suppression” was a bogeyman.  There were no adverse effects, even from continuous, long-term administration.  Daily dosage in this test was 1mg/kg, which is the same as used in mice, and 50 times larger than typical human dosages, if calculated with strict scaling by body mass.  (For organ transplant patients, dosages range from 1 to 5 mg per day.)  Scaling of dosage is a not an exact science, and 1 mg per kg of body weight is certainly too large a dosage for our body size.

Marmosets live about 12 years, and there is not yet any data on whether lifespan is affected by rapamycin.

Marmoset monkeys weigh less than a pound.

Mice and some people on rapamycin tend to have high blood sugar, which in humans and mice is associated with risk of all age-related disease.  But the marmosets didn’t have high blood sugar.

Authors of the marmoset paper note that all studies of rapamycin in humans involve people who are sick enough to need an organ transplant, and are taking many other drugs.  We don’t know anything about the effect of rapamycin alone in healthy humans.  Maybe rapamycin enhances the suppression of tissue rejection from other drugs without in itself suppressing the immune system.   This study claims that everolimus actually enhances immune function in elderly humans. (Everolimus, a.k.a. RAD001, is a chemical cousin of rapamycin, a.k.a. Sirolimus, that is used similarly to prevent tissue rejection by organ transplant patients.  Both rapamycin and everolimus act by suppressing the mTOR signal.

Coming down to earth, this study found that in cancer patients treated with everolimus, risk of infection was about double, and in this study, mice infected with influenza and treated with an anti-viral agent did a little worse when rapamycin was added to the cocktail.  But there are other indications that the relationship between TOR and immune response is complex and not yet understood.  Rapamycin seems to inhibit the age-related reactivation of dormant cyto-megalovirus, though it has no direct action against the virus itself..  Already in 2009, it was seen (in mice) that rapamycin can slow the loss of white blood cells that cripples the immune system with age.  In this study, rapamycin was used successfully to aid in treatment of  a mouse model of malaria.  It is the particular action of inflammation against healthy, native tissues that is arguably the greatest source of metabolic damage in aging, and rapamycin may offer a particular protection against this destruction.

Remarkably, animals were protected against ECM [experimental cerebral malaria] even though rapamycin treatment significantly increased the inflammatory response induced by infection in both the brain and spleen and elevated the levels of peripheral parasitemia.

 

Dogs

Last month, 40 aging dogs in a limited trial of rapamycin seemed to show improved health without troubling side-effects.  Some dog owners reported a resurgence of puppy-like activity in older dogs.

Cautions from the dog study paper:

The doses used clinically to prevent organ transplant rejection are associated with side effects, such as impaired wound healing, edema, elevated circulating triglycerides, impaired glucose homeostasis, gastrointestinal discomfort, and mouth ulcers (Augustine et al. 2007; de Oliveira et al. 2011).

Triglycerides in the blood spike upward when people first take rapamycin.  Triglyceride levels are associated with increased risk of CV disease, and are in fact a better predictor than any of the many measures of cholesterol [ref, ref].  “Impaired glucose homeostasis” means type 2 diabetes, which is tightly correlated with aging, and probably has a causal relationship to many of the losses and risks associated with age.  It’s a big warning sign, and also a paradox.  At minimum, it suggests that anyone self-experimenting with rapamycin should be taking metformin as well.  Or, maybe the insulin challenge is part of what makes rapamycin work–it wouldn’t be the first time that throwing a challenge at the body had the paradoxical effect of extending lifespan.

Blagosklonny

The Russian-American biochemist Mikhail Blagosklonny is our foremost enthusiast for rapamycin in humans.  (Read about him in this Bloomsburg article from last year.)

“Some people ask me, is it dangerous to take rapamycin?” Blagosklonny says. “It’s more dangerous to not take rapamycin than to overeat, smoke, and drive without belt, taken together.”  Many colleagues have regarded his advocacy as a bit over-the-top.

It’s rumored that Blagosklonny takes rapamycin himself, but I couldn’t get him to talk about it.  (Actually, I agree with him that it’s one thing for him to experiment on himself, another for him to publicly encourage others to do so.) Blagosklonny writes

  1. Rapamycin suppresses geroconversion: conversion from cellular quiescence to senescence. Geroconversion is cellular basis of organismal aging.
  2. Genetic manipulations that inhibit the TOR pathway extend life-span in diverse species from yeast to mammals
  3. Rapamycin extends lifespan in all species tested
  4. Calorie restriction, which inhibits MTOR, extends lifespan
  5. MTOR is involved in diseases of aging and rapamycin prevents these diseases in animal models

Caveats and Obstacles

Rapamycin is presently the best candidate we have for a drug to extend life in humans.  It is expected to extend “health span” as well as lifespan, lowering incidence of cancer, heart disease and stroke.  But is it “safe and effective” for use in people?  We may never know, because its patent has run out, and there is no company motivated to invest the cost of a human trial.

Proper dosing for human anti-aging purposes is hard to guess.

A short course of Sirolimus (a name brand for rapamycin) can cost thousands of dollars and requires a prescription.  You can buy rapamycin more cheaply from a number of lab supply houses, but only if you provide a delivery address for a university lab, and certify that the purchase is for research purposes only.  It is less pure and quality control is unregulated.

Addendum

In this recent paper, D. W. Lamming of UWisconsin suggests that the effects of rapamycin can be divided into inhibition of two complexes, mTORC1 and mTORC2.  C1, he says, is good for longevity, while C2 is responsible for the side-effects.  C1 responds quickly, while C2 responds more slowly.  Hence, he suggests that intermittent dosing might be effective at safely increasing life span.  The definition of “intermittent” remains undefined until a variety of schedules can be tested.

98 thoughts on “Rapamycin Redux

  1. Honestly it beats me why people aren’t taking rapamycin, why physicians aren’t prescribing it when is seems at least an anti-aging stop-gap (20% isn’t nothing -if it’s an extra 15 to 20 years of healthy added life it’s certainly worth doing.) If the mechanism is correct in that by inhibiting mTOR it’s allowing macroautophagy as its mechanism, you would think that periodic treatments for as long as it takes to produce that state would work better than constant treatment. I’d be willing to try it, unless it’s prohibitively expensive.

    • Dear Harold,

      I take Rapamycin 6 mg a week for past 6 months. (cost $ 4.00) for 1 mg from Canada. I also include Metformin 500mg daily, exercise and diet. I have had no side effects. The improvement in cardiovascular function has been extraordinarily good. My weight has gone from 170 to 150 and waist line from 38 inches to 33. After ! year if my results continue as good as seems, I intend to prescribe Rapamycin off label for middle age persons who make proper informed consent. I am 73.

      • Dr Green,

        Did you start with the exercise, metformin (and any dietary changes) before you added in the Rapamycin? What I’m really asking is can you attribute the improvements mainly to Rapamycin (if you were already doing the other things mentioned) or if you only saw these effects AFTER adding Rapamycin?

        • Hello Joyce,
          I started with program advocated by Dr Blagoskonny in open access article “Koschei the immortal”. So all parts program was started together consisting of Rapamcin 6mg a week, Metformin, caloric restriction and exercise, although not very much exercise until Spring. I had tried diet alone for years with minimal results. With Rapamycin the results were extraordinary as regards taking inches off waist. My impression is for a man, the size of your waist is best indicator of how aging disease is killing you. All side effects Rapamycin are for rejection therapy with high daily dose. Nobody has reported on side effects with intermittent weekly dose. I will draw conclusions after 1 year. However, 6 month results are excellent. The reality is anti-aging management is a Rapamycin program or check back in 20 years.

      • Hi Charles,

        I buy Rapamycin from Canada on line for @ $3.50 for 1 mg. My guess is if an anti-aging drug is approved and makes it to market in 10-20 years, the cost will probably be @ $50,000-$100,000 for cost of 1 year treatment.

      • Hi Alan. Im relatively young (42 years old) as was turned on to Rapamycin from a colleague in the technology community out of SF. Do you know of any credible places to get both Rapamycin and Metformin here stateside?

        I’m also curious as to how you deduced your dosage? I can assume for legal reason please only give me examples as it relates to you.

        • Hi Jeremy,
          At age 42 I would not recommend Rapamycin. I started Rapamycin when age 73 and suffering from Aging. Aging is a disease that usually doesn’t become clinically significant until around age 65-75. When you have it, you know it.
          How I chose dose is a great question. There have been no Phase II trials to show right anti-aging dose. Therefore, I chose 6 mg a week as a pure guess. I was looking for dose that would have positive anti-aging clinical effects; but not be associated with undesirable side-effects. Now completing 1 year and have had great results with no significant undesirable side-effects.
          At age 42 all I would suggest is physical activity and not over eating.

    • Right Harold,
      That’s why just opened medical office, rapamycintherapy.com is domain name and I call new specialty, “Blagosklonny Medicine”; the application of the Blagosklonny principles of aging first presented in 2006 paper to clinical medicine with rapamycin as cornerstone of therapy.
      Alan Green M.D.

    • Yes – it was linked in the blog above, and it was also mentioned prominently in the Bloomberg article. It is truly the best evidence we have that rapamycin might not put elderly humans at increased risk of infection. But it’s just one study, and it uses the newly-patented version of the molecule that is similar to rapamycin but not exactly the same (Everolimus).

  2. Incidentally – Blagosklonny has an interesting view of where aging comes from. He has acknowledged the overwhelming evidence that aging is programmed into our DNA. But he wants to preserve the standard view of how evolution works, and so he says that programmed aging is a kind of accident. The developmental genes overshoot, and continue to act after their work is done, with consequences that are ultimately disastrous.

    Of course, I agree with him completely that aging is programmed. But I think the “accident” part strains credulity. First, evolution doesn’t make big, costly mistakes like this. Second, the end of development is sometimes the beginning of aging, but sometimes the two can be decades or even centuries apart. The best evidence that Blagosklonny cites for his view is actually the TOR gene itself, which is important both for development and for aging. But what’s missing is that aging schedules in nature are every which shape–gradual aging, sudden aging, no aging, backwards aging! Blagosklonny’s “accident” really can only account for one shape.

    • Evolution makes all sorts of mistakes. Any mistake that doesn’t prevent reproduction will persist, and aging, especially in humans, who may live many years past fertility, is an excellent example of how such mistakes aren’t selected out. If any of those traits confer a reproductive advantage they will persist and increase, even if they make aging worse. Underlying even evolution is entropy, which means things tend to chaotic breakdown, especially when repair or defense mechanisms, like immune systems, are involved.

      • Kerry is certainly correct that this is a “must read” paper and thanks to Josh for link. Ref 1 is “Aging and Immortality, quasi-programmed senescence”, 2006, which is the start of modern anti-aging theory. The paper continues from ref 245, “Koschei the Immortal” 2014, which forms the treatment formula for my rapamycin based anti-aging practice, which could by called, “Blagosklonny Medicine”. Blagosklonny adds two important new treatments, PDE5 inhibitors (Cialis) and Doxycycline.
        It is a great tragedy that Blagosklonny seems to be only person in anti-aging research that seems to believe that anti-aging should be something for humans today, not fifty years from today. Some of most important Blagosklonny papers are discussed at rapamycintherapy.com. Alan Green, M.D.

          • This is very nice summary posted by Kerry.
            Few comments:
            Neff says rapamycin not “anti-aging” as effects some parameters of aging and not others. My view is aging is the sum of all the different age-related disease. Aging is not one discreet thing. Only thing rapamycin does is lower TOR, no other effect. So if a disease of aging is caused by elevated TOR then that disease reduced by rapamycin and if a disease of aging UNRELATED to elevated TOR, then that disease not effected by TOR. Saying rapamycin not anti-aging as doesn’t effect everything to me is like saying Penicillin is not an antibiotic as doesn’t effect malaria, HIV and tuberculosis etc. Penicillin kills only those bacteria susceptible to penicillin; same with rapamycin. Neff and I have very different concepts of what is aging.
            As regards effects and side effects (unintended effects) its all a matter of dose and schedule. The discussion is a blend of effects in animals at various doses and effects in humans at the high daily dose used in transplant medicine. I stipulate, daily rapamycin is bad for your health.
            As regards comments on mouth ulcers and local effect that was pure nonsense. I am sure if gave rapamycin in same dose IV would get mouth ulcers if used in high dose. As stated, I have used weekly rapamycin for 18 months with no episode of mouth ulcers. To me, mouth ulcers are a toxic effect, probably related to decrease production of epithelial cells which constitute mouth mucosa (lining) due to decrease in mitosis caused by rapamycin.
            Cataracts not due directly to rapamycin; but due to non-enzymatic glycosylation of lens protein molecules (lysine) caused by by elevated glucose. So if rapamycin for whatever reason causes elevation of HgA1c which reflects average glucose level, expect increase risk cataracts. On the plus side, rapamycin best preventive agent for age-related macular degeneration which is leading cause new blindness in old people. My plan is keep glucose low by high level of exercise leg muscles to increase insulin sensitivity.
            Generally, an excellent paper, thanks Kerry.
            Alan Green, M.D.

  3. I guess we’ll have to wait then, until we have bioreactors at home to produce our own =/ tho by then better medicine will be available (I hope!)

    I didn’t get this bit: the quote you pasted says rapamycin *drastically increased* inflammation.. a couple lines after you reminded us how inflammation is one of the major drivers of aging and that rapamycin may offer protection against this. ^_^’ I’m confused.

    • Thank you for noticing, and you’re right that this wasn’t at all clear. The point was that the danger of ECM comes from inflammation that overreacts back against healthy, uninfected tissue. With rapamycin, even though the inflammation was increased, it seems to have spared the healthy tissue, so that there was less damage to the body from the same disease.

      • Oh, I see now. Thanks : )
        btw, I hope you and Harold have seen my comment about Francis Prick the other day.. couple blog posts back. (alright, you got me, I missed this joke at the time and I’m making it now.. sry ^_^’)

  4. Josh, this is at minimum your third “best anti-aging” treatment. NAD+, Telomerase, Parrish’s nonsense (smh) – You’ve got waaaaay too much time on your hands and you focus on the wrong subject. After the worst mass domestic terrorist shooting a n our countries history instead of addressing THE issue of the moment you fall back into your pseudoscientific mind mush. However just as hate begets hate, love begets love – please, please please, take 55 seconds of your time and listen to the words of Lin Manuel Miranda’s acceptance speech last night at The Tony’s, you need to hear it and reset your priorities. Please, Do us a favor, get a job. https://m.youtube.com/watch?v=YCbBkb8hMEk

    • I’m so sorry he’s not writing about what you think everyone should be writing about. You can go away now.

    • You are aware that about 100,000 people die EVERY DAY from old age, right? Ballpark 5000 of these are in the US. Since 1995 there have been about 3300 Americans who have died in terrorist attacks (2900 of them on 9/11.) That’s an average of 0.45 Americans dying in terrorist attacks per day.

      5000 Americans die every day of old age.

      0.45 die every day of terrorist attacks.

      Who exactly is focusing on the wrong subject again????

  5. Thank you for the article but I believe deprenyl has shown better effects for longevity. I have been using it for over 20 years and feel 21 at 65. Of course I have been eating right also.

  6. Mr. Roberts, if you don’t care about improving the health and longevity of possibly every person on the planet, then why are you subscribing to this blog? I suggest you rant somewhere else. I hope I speak for the majority of the subscribers in thanking Josh for his insights. It’s clear to me that there are currently many ways already discovered to reduce mTor and thereby improve our health and longevity. Eating vegan, low protein, and low methionine as well as certain supplements all reduce mTor activity as well as providing other health benefits. However, it appears that our government has no interest in increasing our health and lifespan, rather they seem more interested in protecting the dairy and meat economy. The media’s descriptions of “healthy diets” are so contradictory that the average person believes high protein diets are healthy. My point is that we have to study these issues ourselves and figure it out ourselves with the help of scientific studies and support and discussion in the like minded community such as this blog.

  7. Mr Roberts,

    Let’s see, Josh is according to you wasting his time researching and writing about ways to fend off the horrific results of the aging process with the hopes to discover and spread to all of us the best information for keeping ourselves and our loved ones happy and healthy for years and decades to come while you would rather he “get a job” and spend his free time watching award shows. Tell me again who has their life priorities out of whack!? Go Josh go! Let’s defeat aging and age-related disease—feats genuinely deserving of award shows.

  8. Thanks for a very useful discussion and set of references.

    You note that “…in cancer patients treated with everolimus, risk of infection was about double…”

    These patients had presumably been subject to other therapeutic measures, which are typically cytotoxic and quite harsh. For those of us without cancer, it is interesting to ask how susceptible these patients were relative to the general population.

    From “Infections in patients with cancer undergoing chemotherapy: aetiology, prevention, and treatment” (http://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(03)01218-X/abstract):
    “Patients with cancer who are undergoing chemotherapy are highly susceptible, especially if neutropenic, to almost any type of bacterial or fungal infection….Weakened immune components include the complement cascade and immunoglobulin production, T lymphocytes, monocytes/ macrophages, neutrophils, and integrity of the skin and mucous membranes.”

    However, from a primary treatment study, “The study population consisted of adults (aged 18 years and above) with metastatic renal cell carcinoma that showed a clear-cell component, which had progressed on or within 6 months of stopping treatment with sunitinib or sorafenib, or both drugs. Previous therapy with bevacizumab, interleukin 2, or interferon alfa was also permitted.”

    It would be interesting to know the immunological status of the everolimus-trial patients at that point, post-treatment with other agents.

  9. Re. infections in cancer patents treated with rapalogs (apparently after other chemotherapies):

    http://www.lrjournal.com/article/S0145-2126(01)00138-2/fulltext
    “It is the intent of this commentary/review to discuss the effects of chemotherapy on selected immune cell populations and approaches to reconstitute immune function following chemotherapy…..In the cancer patient, there are a variety of factors that favor the suppression of the immune system, including the cancer itself (especially, malignancies of B and T lymphocytes), high dose chemotherapeutic agents, and corticosteroids….it is critical that antigen-specific adaptive immunity, in the form of B and T lymphocytes, become reestablished following chemotherapy.”

    This suggests that cancer patients were seriously immunocompromised going into the rapalog trials, hence weren’t a good model for healthy individuals.

  10. Any thoughts on how rapamycin would compare to intermittent fasting? IF is also a fairly potent mTOR inhibitor if I’m not mistaken. Perhaps one could reap most of the benefits of rapamycin by practicing intermittent fasting? (Let’s assume that this intermittent fasting results in a slight caloric deficit.)

  11. The only benchmark I have is that, in mice, life extension from IF and from rapa are comparable.

    And, of course, IF is safe, known, used for thousands of years, free (negative cost?) and available.

    So the only question about the comparison with rapamycin would be how fasting and rapamycin interact. Do the benefits add, or are they mutually redundant. I’ve seen speculation that the benefits might add, but it seems to me that the pathways overlap too much, and my guess would be that you don’t get much from combining the two that you wouldn’t get from either separately.

    • Excellent — I guess I’ll just keep with my intermittent fasting routine then. (And yes, it can be a bit of a budget-saving measure — my food bill goes down somewhat when I’m fasting.) Thanks for the reply!

      • Hi Joshua,
        Humans have been doing “intermittent fasting” for last 50,000 years; so if real anti-aging treatment,’ secret to manage aging would have been known for thousands of years. However, at this point in time caloric restriction and intermittent fasting is best thing available; so by all means stick with it. The problem is, the mTOR response to food is set so high; that in order to sufficiently turn off mTOR by caloric restriction to get a real anti-aging effect; your weight would go down to less than 80 pounds and then you would die of starvation. (Welcome to Auswitz concentration camp).

        • And it HAS been. Jewish have weekly fasting, Christians have yearly animal protein restriction, ayurveda has lots of fasting…

          btw, where did you get these numbers from? Wouldn’t weight depend on height, for starters?

  12. This is a new study just published showing that sea urchins don’t appear to age, even when they are short-lived. Because these findings are unexpected in light of the prevailing theories about the evolution of aging, we may have to rethink theories on why aging occurs:

    Andrea G. Bodnar, James A. Coffman. Maintenance of somatic tissue regeneration with age in short- and long-lived species of sea urchins. Aging Cell, 2016; DOI: 10.1111/acel.12487
    http://onlinelibrary.wiley.com/doi/10.1111/acel.12487/pdf

  13. Dr. Green,
    Is there a way of contacting you directly? I would be interested in this:
    “After ! year if my results continue as good as seems, I intend to prescribe Rapamycin off label for middle age persons who make proper informed consent. I am 73.”
    Thanks,
    -Kevin

  14. SELF-EXPERIMENTATION, RAPAMYCIN

    Have been reading this blog for the last couple of months because I’m aging and feeling the effects. (loss of energy, fatigue, weight gain, etc.) I’m 70 yo, in good health, but have pre-diabetes because of being overweight. I’m 5‘11“, 195 lbs., work out everyday, but have really slowed down. Aging makes us all vunerable to all the diseases that come with it. After educating myself about the different drugs used to delay aging, have decided to start taking low dose Rapamycin. If one does not intervene, we all know what the outcome is at my age. Upfront, I would like to say that this is a personal decision and would not recommend it to anyone else. I have spent most of my life in the medical and biotech industry, but am not a trained medical professional (MD, RN, PHD). Any drug that has the potential to compromise one’s immune system can be dangerous. The limited human trials have not established the long term safety of Rapa for human aging. One also has to be aware of any possible drug interactions with your medications. I take a statin, and low dose aspirin daily.

    Ordered Rapamycin (Sirolimus) 1mg tablets and have started taking Rapa a few days ago. Intermediate dosing of 7mg. once weekly along with 500 mg Metformin daily. There is a strong likelihood that the 2 drugs work in synergy. Am fully aware of all the side effects, as outlined in the Novartis trial of 2014 for elderly people and will keep close tabs on my health.

    Any questions or comments would be appreciated.

    • Hi Kerry,
      Great, very balanced post! Applaud your courage in starting on Rapamycin. I was thinking of doing the same!
      may I have link for Ordering Rapamycin (Sirolimus) 1mg tablets ? Would appreciate this greatly!
      Best,
      Milind Padki, PhD (pharmaceutical sciences)

      • Was quoted $1.75 mg for 300 mg rapa by dropshipmd.com. They pay shipping, but you have to wire money to their bank account because no rx. I have used them for rapa and metformin. Very satisfied, but it takes 4-5 weeks to receive it from India. Also charged me $100 for 550 Metformin SR.

          • Yes $1.75 mg. That is a very good price. With Rx Canada sells it for $3.00 mg. If you took 6 mg weekly that is 50 week supply. Also I bought 550 ea 1000 mg Metformin SR for $100. Read rapamycintherapy.com for complete ageing formula

      • Rapamycin is a prescription drug for very good reason. Rapamycin as used in transplant medicine causes insulin resistance and diabetes and rapamycin as used in transplant medicine results in decreased survival compared to other transplants medicines.
        Drugs which are classified as supplements are sold legally on internet because they are relatively harmless. Rapamycin not in this category.
        Anybody who does not want to see a physician to be treated with rapamycin to stop diseases of aging is probably better off sticking to caloric restriction and physical activity. Alan Green, M.D. at rapamycintherapy.com.

  15. This article talks about a study that seems to be a big deal…

    https://www.sciencedaily.com/releases/2017/04/170405130952.htm

    Researchers at Oregon State University have found that a compound called rapamycin has unusual properties that may help address neurologic damage such as Alzheimer’s disease.

    A study just published in Aging Cell outlines a new understanding of how this compound works.

    “It’s possible this could provide a new therapeutic approach to neurologic disease,” said Viviana Perez, an assistant professor in the Department of Biochemistry and Biophysics in OSU’s College of Science, expert on the biological processes of aging and principal investigator in the Linus Pauling Institute.

    Scientists have now identified two mechanisms of action of rapamycin. One was already known. The newly-discovered mechanism is what researchers say might help prevent neurologic damage and some related diseases.

    “The value of rapamycin is clearly linked to the issue of cellular senescence, a stage cells reach where they get old, stop proliferating and begin to secrete damaging substances that lead to inflammation,” Perez said. “Rapamycin appears to help stop that process.”

    This secretion of damaging compounds, researchers say, creates a toxic environment called senescence-associated secretory phenotype, or SASP. It’s believed this disrupts the cellular microenvironment and alters the ability of adjacent cells to function properly, compromising their tissue structure and function.

    • This was excellent paper till went off rails and crashed in last 2 paragraphs, when writer could not stop himself from bashing Rapamycin. For real story on Rapamycin side effects or lack there-of see my website, rapamycintherapy.com.

    • I have a rare mutation for which i have inferred that rapamycin may be one of the few things that will help. The mutation will lead to all the diseases of aging, except sped up my some inknown amount of time. I’m trying to write a paper about it and will post if it ever sees light of day.

      Assuming i can get an MD to prescribe (i’m a ph.d.) and assuming those cheap prices from canada can be ordered online from the states, i still have questions and am not sure yet to do

      One question i have is did you previously have herpes simplex or recurrent shingles and dolid the rapamycin cause more recurrences? Not all of these viruses are the nuicances peopke think- they can be serious in some of us. Interesting data on cmv. I will look at the study

      Also need to know more on gut and mouth sores. Already have trouble with both, so could be an issue.

      And gum and dental issues/infrctions as well as sinus infections would be issues for ne if this was supressing both t and b cells.

      Btw, for me i cannot take metformin because i i predict will have adverse effect on my muscles.

      Does anyone know if rapqmycin has an effect at the neuromuscular junction?

      I expect btw also that rapamycin should increase inflammation. I plan to use that as the way to tell its working and to titrate a good dose. Sometimes that inflammation itself can be problematic but most of the time overall the rapamycin effects will be positive

      What i hate most are tge obstacles the system puts in the way. Besides cost and obstacles of convincing someone to order, i want a few simple blood tests first that are cheap and easy to do- but they are not comercially available (except rare exception) tho used often in research. And i am having trouble getting them despite some connections i have- its not my area. Very frustrating i cant just order them.

  16. If mTor is activated by protein consumption especially leucine, why has no one discussed reducing protein intake to block or reduce mTor? One easy way is to eat plants. It is a sacrifice just like fasting and the risk of taking rapamycin. I eat Vegan and fast Mondays and Thursdays, and recently…I purchased Rapacan Sirolimus made by Biocon in India ($4/mg). I just started taking just 1mg once per week on Fridays. I also take Metformin daily. Rapamycin has a 72 hour half life in males and 60 hours in females. That’s a long time in your system. So with only 1mg I have the following minor side effects: I have a more rapid heart rate which is worse between 3-6 hours and gradually goes back to normal by the third day. This causes me to have a bit of difficulty sleeping the first night. I also have slightly strange feeling that I can’t describe especially in my mouth and with taste. None of these seem serious or alarming but I would not raise my dosage because of them. I am surprised that some can take 6 mg without more serious side effects. I would be interested in hearing what others are finding.

    • I am currently in a study that has just begun a month or so ago. They are gradually upping the dose from 1mg to 5 mg over several weeks. This weekend I will go up to 4 mg. Then we will be in the study for 1 year at the 5 mg. dose.
      At the beginning, there was a brief moment of rapid heartbeat. Has not been an ongoing issue. No disruption noticed in sleeping. I also had a tongue sore, but I think that was more due to some dried pineapple I had eaten. Nothing more since that moment in time.
      They have done and will continue to do many blood tests to monitor and address any issues that may arise. They also did telomere tests and BMI tests. I have genetic high cholesterol, so I am working on natural ways to address that to avoid it going any higher on this med. Glucose level is low to begin with.
      I had also done DNA testing and had it analyzed for 1400 genes and mutations that targeted nutritional needs. That information was sent on to the Dr. monitoring the study at his request. This was not a requirement of the study, but just something I had done for my own use that came in handy for the doctor.
      So, so far, so good.

        • This is being done in Thousand Oaks, Ca. through Life Extension and Betterhumans. With all the initial testing of telomere length, BMI, bone density, and blood tests, they will be looking at changes over time and with increases in doses in these and other markers. They will be looking for side effects and to determine if 5 mg once weekly is a safe and effective dose for otherwise healthy seniors.
          Anything else they may be looking for, you would have to ask them about.
          Having my genetics will also help them see what variants may make a person more prone to different side effects or more receptive to the drug. I am interested in seeing how this all plays out over the year ahead.

          • Thanks Linda,
            Unfortunately, I don’t expect results to look good. Number one concern for everybody in regard to rapamycin is glucose intolerance. Main effect rapamycin is lowers output of insulin. That is very good from anti-aging perspective, but blood test look bad.
            Need to counteract low level of insulin output with measures to increase insulin sensitivity. These measures are metformin, losing weight, decrease in caloric intake and increase in physical activity such as walking.
            Problem IRB (institutional review board and others) wanted “clean” results. That means no other factors like metformin, caloric restriction, exercise to interfere with results of just rapamycin.

            According to Blagosklonny, rapamycin should be used as part of anti-aging formula which also includes metformin, exercise, caloric restriction to compensate for low insulin output

            Big problem with clinical studies, the IRB dictates and that is like tail wagging the dog.

            Expected results: increase in fasting glucose, increase in HgA1c and support for general belief that can’t use rapamycin as interferes with proper glucose metabolism and causes glucose intolerance.

            Now if they used rapamycin with complete Blagosklonny anti-aging formula and focused on protective effect on age-related disease; that would have been excellent study.

            This phase I drug study; not a clinical study of use of rapamycin based formula in clinical study of age-related disease prevention

          • Thanks for your post Linda. I am in the same study. To date I have not noticed any changes.
            I do continue to follow and to appreciate Dr Green’s writing on this subject. He is a treasure.

    • In case noone mentioned it in this thread…
      It was found that protein restriction in mice increased life span the same amount as caloric restriction…But there were a few deaths in some of the mice….

  17. Lai ZW et al: Arthritis Rheum. 2012 Sep;64(9):2937-46
    N-Acetylcysteine, at 2400 or 4800 mg/day, given to patients, “profoundly” reduced mTOR activity in T cells from systemic lupus erythematosus patients: clinical trial.
    very minor toxicity at the higher dose.
    https://www.ncbi.nlm.nih.gov/pubmed/22549432
    Free paper.
    So some pretty simple, cheap and easily available, non-toxic molecules can do the trick, too!

    • Good point about NAC. Word of warning though, I had to give it up because it gave me a deudenal ulcer. NAC reduces and thins protective mucous. I reduced it to one tablet per week and replaced it with sublingual glutathione for antioxidant activity; I doubt it blocks MTor.

    • NAC and lots of other drugs all claim to be equivalent to rapamycin as regards blocking mTOR. 2014 study oral feeding rapamycin to heterogeneous mice increased lifespan male and female mice 23% and 26%.
      So very easy; just give drug in question to heterogeneous mice and show increase lifespan @ 25%.
      If have an anti-aging drug it does 3 things: increases lifespan all living things including heterogeneous mice, prevents almost all age-related disease and decreases senescent cells.
      So real easy to know what is real anti-aging drug and what is not.
      Don’t take anybody’s word for it; just look at life extension studies of heterogeneous mice for starters. Life extension of mice should be gold standard for anti-aging drug. Of course, prevention age-related diseases like Alzheimer’s disease is more important than lifespan increase; but lifespan is very easy test for real thing.

    • NAC metabolized to methamphetamine. Meth causes anorexia. So apparent “anti-aging” effect of NAC is the usual suspect, caloric restriction.

      • I wasn’t very impressed with the size of the effect with the 2012 NAC study i read on the treatment of lupus patients.

        ‘N-acetylcysteine reduces disease activity by blocking mammalian target of rapamycin in T cells from systemic lupus erythematosus patients: a randomized, double-blind, placebo-controlled trial.’

        So yes, rapamycin far more effective. But the study did establish a mechanism for MTOR activation being a high mitochondrial membrane potential. Not sure what this means.

        • NAC is one of the most powerful antioxidants. NAC does NOT metabolize to methamphetamine. NAC is used to treat Meth overdoses.
          Lots of literature on this usage, here’s one:
          Research Article
          N-Acetyl Cysteine Protects against Methamphetamine-Induced Dopaminergic Neurodegeneration via Modulation of Redox Status and Autophagy in Dopaminergic Cells – Kanthasamy
          “In conclusion, the present results reveal that loss of cellular levels of GSH is one of the pivotal mechanisms involved in MA-induced neurotoxicity and autophagy in mesencephalic dopaminergic neuronal cells and that treatment with NAC partially reverses MA-induced apoptotic cell death, possibly by replenishing GSH levels. ” GSH is glutathione the most important cellular antioxidant.

          Mtor is activated by high ROS levels. NAC reduces ROS thereby reducing mtor only if it is activated by excessive ROS such as in Lupus. If mTor (your cellular protein sensor) is activated by protein intake, then NAC will not reduce mTor activation. Of course rapamycin will, as will reducing protein intake to around 10% as in a vegan diet.

          Also NAC cuts mucous production and can cause stomach ulcers (first hand experience there). NAC taken after alcohol consumption prevents some of the negative effects. Besides meth overdoses, it is used to treat tylenol overdoses.

          • This is exactly what Dr. Alex Vasquez is pointing out. That excessive ROS leads to mTOR activation, which leads to increased inflammation, which again activates mTOR and suddenly you have a vicious cycle. NAC will break that cycle.

            @Allan, please supply reference regarding NAC being metabolized to MA

          • Josh made statement in prior bit about NAC. Josh said doesn’t want anything messing with his thinking and NAC metabolized to meth.
            Then Josh said hard to understand why speed would increase lifespan.
            Many comments by Josh and can’t find

          • That is very interesting Neil and Ole, thanks for the clarification. All makes sense now. Also MTOR increases mitochondrial biogenesis, tipping the scales away from mitophagy. So you’ll get more but worse quality mitochondria with chronically activated MTOR, and this will lead to higher ROS. So you can see how the viscous circle of aging happens from this direction too.

          • I wonder if there is an autocorrect issue here: NAC does metabolize to Cysteine and then metabolize to Methionine (the amino acid). Methionine may have autocorrected to Methamphetamine?

          • Interesting that NAC can end up as methionine. That is about as potent an actovator of MTOR as you can get. So NAC probably isnt the antioxidant of choice for minimising MTOR, even if the boost in glutathione does help woth ROS induced MTOR.

          • If a human has a dysfunctional MTHFR gene it will effect the conversion of homocysteine to methionine.

            That’s likely why the affect of supplementation directly with methionine or by NAC metabolism to methione, has positive effects in some humans and negative in others.

            Along with being used for Tylenol overdoses, NAC can also reverse acute liver toxicity in Labrador dogs caused by Rimadyl.

            Labradors are apparently more prone to having this type of adverse reaction to Rimadyl than some other breeds.

  18. @Mark, I am quite sure that the benefits of NAC supplementation outweighs the downsides. Besides being crucial for proper liver function, methionine can help raise the body’s level of glutathione. As always, the picture isn’t black and white. 3x700mg of daily NAC supplementation will not lead to chronically elevated mTOR.

    • There is no doubt we need methionine, it is an essential amino acid. But the benefits of NAC just seem to come from leading to higher glutathione levels then protecting mitochondria from toxic insult. And there are many ways to do with other anti oxidants or up regulating our endogenous defences. So I won’t be adding NAC to my supplement list.

      • I’ve tried NAC on and off over the years and it always makes me feel like I have the flu, so it’s off of my list as well

        • https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3726163/
          Rapamycin extends murine lifespan but has limited effects on aging

          In summary, our findings confirmed the extension of mammalian lifespan by rapamycin. However, rapamycin had limited effects on a large number of murine aging phenotypes. Although age-related changes in several traits were opposed by rapamycin, this was often due to aging-independent drug effects (i.e., similar effects of rapamycin were observed in young mice), which indicates that rapamycin influenced these traits in a direct way and not by slowing aging. Our data therefore seem to largely dissociate rapamycin’s longevity effects in mice from effects on aging itself.

          • Blagosklonny response to Neff paper was, “Rapamycin extends life and health span because it slows aging”. 2013.
            Blagosklonny response was essentially Neff has no idea what aging means.
            Blagosklonny said “aging is an exponential increase of the probability of death with age”. Blagosklonny answer was Rapamycin extends life span so rapamycin delays aging.

            My answer is rapamycin ONLY reduces mTOR. To the extend that elevated mTOR cause age-related disease, rapamycin reduces elevated mTOR pathology.
            So question is what age-related diseases are due to elevated mTOR.
            If elevated mTOR not responsible for something; then rapamycin will not change it.
            For me, the term “aging” should be declared; VOID FOR VAGUENESS

          • Charles:

            I think that confirmation is accurate.

            Life extension does not guarantee that all aspects of that longer life will be of good quality.

            People can live a very long time in a debilitated state. …Not being able to walk or think clearly, etc.

            As Alan states, the term “aging” is still somewhat nebulous.

          • Yes, and therefore, to win the political battle for research funding, we need to focus on “the need to avert the diseases of old age” as the main focus, and “life extension” almost as an side-effect. This will have the salutary effect of not freaking people out.

          • Hi Milind,
            Oliver Wendell Holmes wrote a poem. “One-Hoss Shay” in 19th century which anticipated the real anti-aging goal. The shay “was built in such a logical way, it ran a hundred years to a day” and then went puff.

            The current goal of traditional medicine is to keep sick people alive, the goal of anti-aging is to keep people in good health.

  19. If you can take grapefruit juice with any or all or your meds as I can with pravastatin and metropolol, then consider reducing your rapamycin/rapamune/sirolimus dosing by 1/2 to 1/3rd of your ‘normal’ dose. eg. I take 3mg equivalent once every 8 days which is actually 1mg with Grapefruit juice. Review this use of grapefruit juice with sirolimum https://www.scientificamerican.com/article/grapefruit-juice-improves/ and carefully carefully check your other meds. I reduced my cialis intake by 1/2 to 1/3 on days with rapamycin w/ grapefruit juice. Dr. Green, sure would appreciate any updates on your health…. Age 64, BPH, osteoporosis (treated successfully w/ Androgel), former smoker, history of ‘eventual death’ runs in my family 😉

    • Hi Oleg,

      Studied paper provided.

      I think 1mg every 8 days as you suggest OK as too low dose inhibit mTOR2.
      Also grapefruit juice may be good if want to save money or have GI problems and can only tolerate low dose.

  20. Yesterday I drove to Los Algodones, in Baja California, Mexico to buy rapamycin, Sirolimus after being assured that they had it in stock by two different pharmacists. A large number of Americans obtain their medications from this small Mexican town on the borders of California and Arizona. This is a 6-hour drive, round trip from my home in Palm Springs, CA.

    Needless to say no pharmacy in Los Algodones stocks any form of rapamycin. Once there, and talking face to face with individuals at 6 different pharmacies, I was told that it was too esoteric and expensive for them to stock.
    They did inform me they could obtain it from their wholesaler for $500.00 for 60 pills. ($8.33 for a 2mg pill)

    Can someone please provide me with a source for rapamycin? Online would be preferable. Here is my email address if you prefer not to post it online: [email protected]

    I am 68 and an antiaging student, Thanks, Michael Slattery

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