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.

46 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.

    • 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.

  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.

  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.

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