An MD with ME/CFS does a deep dive into the research – and lights upon an unusual drug that works for him.
The first blog in a series highlighting the different ways people have recovered or are recovering featured James’s remarkable improvement from a very severe case of ME/CFS while being treated for CIRS (chronic immune response syndrome) under the care of Dr. Heyman.
The second in the series features another doctor felled by ME/CFS who’d fruitlessly tried many treatments over the course of his ten-year illness. His own research led him to try a drug that’s usually associated with longevity but which ended up working wonders with his ME/CFS. Here is Jeremy Waletzky’s ME/CFS recovery/recovering story.
Jeremy’s Rapamycin Resurgence
I am a 79-year-old physician whose chronic fatigue syndrome (ME/CFS) was initially diagnosed 10 years ago by Dr. Anthony Komaroff, an internist and internationally recognized ME/CFS expert at Harvard. Immediately prior to my CFS, I was in very good health. My favorite activity was mountain hiking and a year earlier I had climbed to the top of an 18,000-foot extinct volcano in Chile. I frequently went on 1-to-2-hour aerobic hikes. “I was living life to the fullest.”
An upper respiratory infection triggered by ME/CFS. My main symptom was severe fatigue which produced brain fog. I suffered from a post-exertional malaise which usually peaked 24 to 48 hours after any demanding (including mental) activity. After working all my life in an intellectually challenging career, I found could only concentrate for two hours at a time. I was mainly housebound but could not do any household chores. At times I couldn’t walk a block. My social life was nonexistent. I recently found a note to myself that I was leading only 30% of my life.
Following Dr. Komaroff’s retirement, I was under the care of an excellent psychiatrist/neurologist at Johns Hopkins, who left practice in 2020. During my time with them, I tried antidepressants, antivirals, erythromycin, doxycycline, N acetylcysteine, trental, Nexavir, alpha-lipoic acid, three omega fatty acids, minocycline, S adenyl methionine, probiotics, courses of intensive Theta TMS (over 400 sessions), direct current brain stimulation, and infrared treatment – all without success. I made sure that all were administered at the correct dose for the correct time interval. I was also taking lithium 300 mg, lisinopril 10 mg, amlodipine 10 mg, Lamotrigine 75 mg, and amitriptyline 75 mg.
Rapamycin
I noticed an improvement in three weeks and by six weeks I was in remission.
I was unresponsive to everything until beginning rapamycin treatment, 6 mg once weekly in December 2021. I noticed an improvement in three weeks and by six weeks I was in remission.
Rapamycin’s tale of discovery is unique and fantastic and can be readily found on the web. Rapamycin was initially approved by the FDA in 1999 to prevent organ rejection in liver transplant patients, is commonly used to prevent kidney transplant rejection, and is also used with similar drugs, called rapalogs for cancer treatment, and to prevent restenosis following coronary angioplasty.
Rapamycin has been used as a cancer treatment, in part because it’s able to reduce cell growth by inhibiting an enzymatic master regulator of growth called mTORC1 (mammalian target of rapamycin complex).
Why was I interested in this drug? In 2009, Rapamycin was found to significantly extend the lifespan of a mammal, a mouse. Only severe calorie restriction (30 to 40%) had previously been shown to increase lifespan and health span. (Severe calorie restriction and rapamycin probably both work to extend life by inhibiting mTORC.)
.jpg)
Rapamycin (in red) interacting with mTOR (Work done with the molecular visualization VMD program developed at the University of Illinois: From Wikimedia Commons)
This was the first time a drug had that effect and the journal Science listed it as one of the major breakthroughs of that year. Of special importance to me was the fact that the significant life extension of life occurred when the treatment was started in the mouse’s late middle age (19 months).
These findings have led to an explosion of research in the longevity field which has become incredibly complex. Over $20 billion in venture capital has been raised, including $3 billion from Jeff Bezos for the company Altos. (This doesn’t include the May announcement that Saudis will put between one to 20 billion dollars into this field).
It’s been said, “when you’re young you want to be rich, and when you are rich you want to be young”. Because Rapamycin is off-patent it will likely receive only a minute amount of research dollars from drug companies. Many other possible mechanisms to extend health span and lifespan are being investigated.
In the end, I turned to rapamycin because it’s an FDA-approved drug that studies suggest can help to make you younger, improve your immune functioning, and can work in the “elderly”.
Besides its possible longevity aspects, I knew that rapamycin has been used by millions of very sick patients following kidney transplants. I also knew that when used daily for immune suppression or cancer treatment, rapamycin was a dirty drug that produced many bad side effects.
Anecdotal reports suggested that when used intermittently – once weekly – at lower doses, these terrible side effects did not show up. While there is no comprehensive data about rapamycin use in smaller intermittent doses, some data also suggest that using the smaller dose use of rapalogs can enhance immunity. It is not FDA-approved for use in this way.
I had been unable to find any literature about the use of rapamycin in CFS or in long COVID, but after reviewing the literature and assessing for myself the risk/benefit ratio (having spent 10 years markedly limited by my CFS), I was very aware of the possibly profound physiological effects rapamycin might have. (In the comments Jeremy noted that he was also taking lithium which conceivably could have interacted with Rapamycin in a positive way.)
Several findings suggest, though, that rapamycin might be able to help with CFS. Its target – mTORC 1 – integrates multiple signals from growth factors, oxygen, energy levels, and nutrients to promote cell growth and proliferation by activation of anabolic processes, stimulation of energy metabolism, and inhibition of catabolic processes such as autophagy.
Rapamycin may help with autophagy – a process by which autophagosomes (pictured) clean up the cells. Autophagy may be inhibited in ME/CFS. (Illustration by Daniel Klionsky at the University of Michigan from Wikimedia Commons).
Some studies suggest that rapamycin’s inhibition of mTORC 1 may be able to reduce lactate production, increase ATP levels, improve cognition, and induce autophagy – a process the cell uses to clean itself up – and which a recent study suggests may be impaired in ME/CFS.
After learning of Rapamycin’s potential for extending health and lifespan on a podcast, over the next two months I reviewed podcasts, read books, and did a very thorough review of the medical literature. After assessing for myself the risk/benefit ratio (having spent 10 years markedly limited by my CFS), I was very aware of the profound physiological effects rapamycin can produce and hoped it might “reset” me. I decided to use a low dose of rapamycin once weekly.
I consulted with Dr. Alan Green, a retired forensic pathologist who initially treated himself with Rapamycin successfully in 2017 for congenital cardiomyopathy and noticed tremendous benefits to his overall well-being. Following that he unretired and has since successfully treated over 900 patients – focusing mostly on those with the aPOE4 gene that confers an increased risk for Alzheimer’s.
Using my Oura ring to monitor my resting heart rate and keep it within a safe activity level, I found I was able to slowly ramp my activity levels. At 79 years old with 10 years of inactivity behind me, progress has been slower than I wished, but I have made remarkable progress. As noted above, by six weeks I was in remission. Seven months after first trying rapamycin, I am no longer housebound, can do my share of household chores, can engage in a full day’s activity, and am regularly increasing my exercise.
My hiking distance is 2 1/2 miles, and I routinely exercise at 85% of my maximum heart rate (age-adjusted) for at least 20 minutes per day. I have now been free of symptoms of CFS for five months despite having re-engaged in full activity. My wife said she doesn’t recognize the new me. She is very, very happy.
At the age of 79, Jeremy is back – after ten years with ME/CFS – to exercising regularly.
The only side effect I experienced was a two-day canker sore on my tongue three weeks after starting rapamycin – a common side effect. Note that there has been a warning about increased bacterial infections because of immune suppression, but this has not been my experience. (One review concluded that Rapamycin is probably more of an immunomodulator than an immune suppressor, and noted that animal studies suggest it may enhance vaccine effectiveness.)
Please note this is not medical advice – it is only my personal experience. This is also not an FDA-approved use of this drug. You will need to consult your physician.
Resources
- “Effect of Rapamycin on aging and age-related diseases past and future”
Ramassamy Selvarani, et al. Geroscience (2021) 43:1135-1158 - For learning more about Rapamycin, I strongly recommend Dr. Green’s 100+ page Rapamycin website which was revised in March 2022 and includes many references.
- For a general introduction, I recommend David Sinclair‘s “Lifespan” published in 2019. It has sold more than 2,000,000 copies
- For a more recent (2021), comprehensive, and scientific review I recommend “Ageless” by Andrew Steele.
Update!
The Simmaron Research Foundation has launched a clinical trial of rapamycin in ME/CFS.
These drive me crazy. How the heck are we supposed to find something that helps when these stories seem like completely unrelated miracles – and every one is different?
I have neither the training nor the money nor the time to follow the thousand new trails every week, and yet it appears SOME people manage remission – it is not a way I can follow!
I think it still brings hope. Although I understand your thoughts.
For me it’’s an issue of bureaucracy not being allowed drugs we know may work. We’d literally have to find a maverick doctor to get them prescribed. But it may be enough to get research into the drug for a subset of ME/CFS patients
The other issue is someone like me would have to initially micro dose, because every new drug I’ve had lately causes severe intolerance issues
No you don’t
You could import the medicine from India for $10 per week.
I am a physician who has worked in the area of Lyme borreliosis and associated diseases. Unfortunately, the Infectious Diseases Society of America bullies and intimidated physicians to stop them from working in this area likely due to financial conflicts of interest on the part of certain powerful members inside IDSA. Still, you can find renegade doctors with serious credential who will treat. Try not to give up so quickly.
Agree. The only way out of the quagmire of possible quack cures and miracles is proper scientific trials.
Scientific trials work best when things are simple and linear. Complicated conditions, like Alzheimer’s and MECFS, are multi factorial, likely with multiple causes and consequences all dropped into the same bucket. We are not a homogeneous population. A great majority of us actually have something else and are misdiagnosed. Trials tell us what a treatment does in general for a population. What good does a treatment do that works for most…but not me as an individual? At the personal level, it’s ALWAYS trial and error.
At age 79, how much time does one have for “scientific trials”?
We will all be dead by then. I live in Atlanta where we have the CDC. Everything is overturned while in testing for us. I have had thee maladies over 20 years. Immune Globulin was the only thing that helped me. Then it became Generic and did not work.I don’t care if it is labeled QUACK- if it gives me help.
What a great story! I’m curious why Rapamycin was chosen over Metformin? Did Jeremy try Metformin prior?
Metformin did not seem to do anything for my severe ME son. We’re about to start trialing Rapamycin. I’m always hopeful.
I am also preparing to start the treatment of rapamycin. I have found a way to purchase medication and have been reading more medical papers recently. Has your plan been implemented now? How is the situation?
If it is not expensive or dangerous, you could try his exact protocol and see if it works. CRT would be great, but that is expensive and nobody is going to invest on an an anecdote especially unless there isn’t gobs of money to be made.
This is great if you can find a Dr to Prescribe it–also a mfg that has it.
Couldn’t agree more.
Why do doctors keep focusing on their own miracle pill without looking for why all this is happening?
I was thinking the same.
I have had very similar frustrations. ME/CFS seems to be caused and cured by something new each week. I wish there would be more writing about what it is that connects all of these causes and cures together. To be fair there have been some great thematic articles like ‘mitochondria’ or ‘vagal nerve’ or ‘microglia’…
I understand your frustration but this is just one of several drugs that are no longer patent bound and thus Drug companies cannot make money. Take Low Dose Naltrexone. It as well as Rapa seems like a miracle for many people. I include myself in this group. I have Seropositive Rheumatoid Arthritis, the worst kind. Low dose naltrexone (LDN) allows me to lead a normal pain free life. I will be trying Rapamycin as well. I read every paper I can find, join FB groups of like minded people. I will not wait for there to be a consensus. Im glad I took a chance with LDN. I shutter to think where I’d be without it. This is how these things work. If you are not leading the life you deserve and one of these drugs possibly can change that, I say don’t wait.
⬆️ This ⬆️
(There’s also ULTRA low dose naltrexone)
Join all the sane (some of them are not so much) groups you can (hive mind) and research research research.
Try to assemble the best team of Drs you can (I’m aware that that’s out of reach for many)
Then you do you.
It’s your right to attempt to save yourself.
Best under a Drs care OBVIOUSLY but if I’m up against dying from this anyway (and no “life” and very ill for the rest of my life, IS a death….. and some ppl actually die. Sometimes from suicide) then I’m going to fight for my life.
Hi there.
I know you posted 2 years ago but I’d love to know what happened!
Can you say more about your LDN experience? Do you take the full 4.5 mg? I’d love to hear more. Last year I was on LDN for about 4 months. It did cause hair loss and my tendons started aching. When I went off it — all of this abated. Wondering how you are?
How did your experience with Rapamycin go?
There’s virtual doctors online that will prescribe this to you. I got mine through one and am slowly healing. I noticed an improvement after 3 weeks too but I can’t even take the full 5-6 mg without getting stomach pain and diarrhea. I take 3mg just fine once every 5days.
Hello, could you send me a link?
What is the ratio of drug to body weight that you found successful? My wife has moderate to severe ME/CFS and this sounds promising enough to pass on to her physician.
I don’t think Rapa is dosed by body weight. It is my understanding most people take 2-6 gm once a week.
Where will you get Rapamycin? It is either an expensive way, From Dr Green if he is taking on more patients, or taking a chance….if you can get it from India or Turkey. Dr Green doesn’t use the internet, so it has to be a physical consultation. Rather difficult if you live in Britain. My daughter is too ill to travel. A doctor’s supervision is needed too, I feel. Hopefully more disgraceful take up and use Rapamycin closer to home.
I meant…l hope more doctoral take up prescribing Rapamycin
Thanks for the writeup Cort! Really interesting. I wonder if rapamycin is one of the 39 drugs Ron Davis said they found had potential for reversing the metabolic trap they have been studying in yeast. It feels related. Maybe this will be the year they find something real for ME/CFS. Remission is a strong word. One I would like to experience. Do you think Dr. Green will try it on more ME patients, perhaps remotely? I don’t see any possibility of getting to try it otherwise. Shifting the immune system seems more likely to help to me than the variety of nutrient supplements people are trying. I think I’ve tried them all, and some help a little, but non made a dent in my post-exertional malaise reaction.
Dr Green’s website invites appointments, perhaps a telemedicine with him can answer all the questions. His website is full of research on Rapamycin, lots to digest.
Please please let us know how you get on…l know we all differ, but Rapa gives me hope for my daughter…ill for 30 years. We have tried many things, and the last 10 years have been hell for her, being housebound and bedbound mostly. We are in S Wales UK, where there is nothing. I have emailed Dr Green and hope for a reply. Dee
I am in NY visiting family, but must leave for home tomorrow Friday. I used Dr.Green’s email on his website last night and he is seeing me today! I emailed him at 10:30 and before 11:00pm he set me up with an appointment. That’s dedicated! I did send a brief medical history ( very brief) as 40 years is overwhelming to anyone.
Court Johnson, Thank you for your commitment to our patient population, you keep us on the cutting edge of medicine and possible treatments. I have been aware of Rapamycin for some time as a possibility due to a super dedicated researcher working on mTOR. Will this work for me??? I don’t know, but if Dr Green thinks it may, then I’m willing to try!
Please keep us updated on your appointment experience.
Best Wishes.
That is wonderful news! I hope it all works out for you and that Rapamycin helps you.
Any update?
Did it?
I have emailed Dr Alan Green twice, without success., I even invited him to talk over Zoom to our Support Group. So you were lucky Robert to be in the right place at the right time. Please let us know your progress. I don’t really want to trust drugs from the East and without prescription, and yet we are desperate for something to help my daughter. Such a waste of the life of an ‘A’ Grade student, who was Musically and Artistically tallented…her life curtailed after gaining a Scholarship to a Public school at age eleven. But more importantly her quality of life destroyed.
Can you share what happened Robert?
Hi Robert, how was your appointment and treatment going?
Any update Robert? I’m hoping this has helped you! I’m currently trialing daily Metformin. It’s only day 3, so no positive effects. Keeping my fingers crossed. I’m having nausea and diarrhea, which is typical of metformin.
Any luck with metformin Rachel?
Hi Kate,
So Dr. David Systrom in Boston is my doctor. He had me trial Metformin for 2-weeks with dose escalation. I was one of his first patients to do so. He’s intrigued by it, which is great! I hope more doctors are willing to trial these things.
Unfortunately, it did not help me. I have stopped taking it. I did not feel any better on it and I had side effects. I had GI distress (common) and also just didn’t feel right. Can’t really pinpoint what.
However, I’m still hopeful that this could help a subset of ME/CFS patients…we just don’t know which ones! And I’m hopeful it could help decrease the chance of Long Covid in some people too.
We are thinking my problems are spinal cord related. I have hEDS. So I’m waiting for a CSF leak workup and also a consult with an EDS savvy neurosurgeon.
Alicia, you are right. However it is part of the ME/CFS journey to understand that… you can not give up! That is how i see these stories.
Cautious attempts to change the health status quo (which is different for everyone) may just spark changes in the body..hopefully beneficial even in small degrees….and then perhaps move forward to try something else.
Good luck in your journey. It’s not easy.
I will add something a bit ‘spooky’. Whilst i was out for a walk this morning the word Rapamycin came into my head for no specific reason and i made a mental note to remind myself what it was.
I get home, open the iPad and bingo…. this story.
Not sure what that means in the greater scheme of things tho as it is my daughter with the illness and she is only 26 so i dont think we would be dashing to try this particular remedy. Sadly!!
What about LOW DOSE NALTREXONE. My daughter is severe. I would consider LDN if I could get the support of a dr. Even Rapamycin….she is 41….maybe too young, as long as they are not harmful..or have side effects. But of course, she would have to decide. Even the talking therapies can be successfful for some.
LDN is very safe. Look up Facebook group on it.
LDN is unbelievably safe. Please research it. Some ppl also do ULDN
(Ultra low dose)
With all due respect, talk therapy doesn’t cure physiological illnesses. It sure can help with dealing with it though 💕
Low dose naltrexone is very safe, very inexpensive. Has helped my son 33 after 14 months of long covid, now ME/CFS they say. Not sure where you live but I’m sure there is a doctor or naturopath somewhere that will prescribe. It is making life much more workable for my son until they find the cure.
How much did he take weekly? I’m giving my dog rapa as per the Kaeberlein studies and it has made a marked difference in her arthritis and overall vigor. I have also heard of some doctors using it off label to treat Lyme disease. Maybe I should give it another try! I didn’t stick with it at the time, but it’s covered by my insurance now.
Hi Remy, Do you mind me asking how it was prescribed/ what was it prescribed for? Was it prescribed for ME/CFS or something different?
Off label, for autophagy and the beneficial effects on inflammation in general by removing senescent cells.
My doctor will not try off label drugs. It’s hard to read about all the things that this doctor got to try. I realize this may open pathways for future research. Just venting, I guess!
Are you concerned by that? Many medications are used off label with success.
Chris is correct, tons of Drs prescribe off label. Perhaps reach out to another Dr, this seems unnecessarily rigid of him.
It says in the article.
6 mg once a week. That’s the starting dose Dr Alan Green recommends and prescribes.
I am a Dog state licensed Rescuer. I have several older rescues that have Arthritis. How did you use in dosage for your dog and how large the dog? I need to try it as mine are in PT reg-but need more. I also have all the maladies listed in this article. Does your insurance cover just Brand name for your use?
Thank you for your input.
I don’t see any reference to how long he took the drug, or if he takes it weekly and expects to do so indefinitely?
“I decided to use a low dose of rapamycin once weekly.” I believe he is still taking it.
I still take Rapamycin weekly. I stayed on 6 mg weekly for four months. Subsequently, I raised the dose Following comments by Dr. Green and Dr. Blagosklonny podcasts. This was due to Rapamycin‘s use for longevity.. I am afraid to stop it and though I don’t know if it’s necessary to take it at this point..
Jeremy, have you noticed a difference? Or is that why you are uncertain is is necessary to continue? Thank you for your input.
How about a week long fast mimicking diet fast? That will also boost rapamycin.
I’m glad for those that these drugs have helped, but it’s totally frustrating for just regular people who have trouble even finding a doctor for normal stuff, let alone willing to experiment with our condition. So far, none of this is of practical value for most of us. But somewhere down the line, we hope that a breakthrough is coming whereby we can simply given a prescription or a shot to help.
We need doctors to write their case reports and we need studies. I was told by a researcher how important case reports can be. For one, they provide the evidence researchers can use to get funding for clinical trials. They’re not difficult – they simply chart the patients history, provide diagnosis and then chart the treatment progress. I wish more doctors would take the time to do this.
A story like this may prompt doctors to give this a try, write up a case report and get it published. These things can move fast at times. We have two oxalacetate studies going! That’s really something for this field.
Some doctors will also just give this stuff a try before that if they have some evidence it works and its safe.
Health Rising is going to provide a way to find good doctors. It should be up soon.
Cort, I am so grateful for what you’ve done with your thorough website and blog, and really appreciate that you’ve found doctors who’ve had CFS/ME. Being that pre-COVID many doctors believed CFS was all psychological, it seems that afflicted physicians are the gateway to raising awareness among researchers. Even if I try none of the remedies, I still find everyone’s success story an essential piece of the puzzle. Thanks again for all you are doing!
Cort, Dr. Jose Montoya, now at Palo Alto Medical Foundation, worked on transplants at Stanford before becoming an ME specialist. It would be interesting to hear what he thinks about the use of Rapamycin. When I hear of one or two stories of something that seems to give great improvement, it seems prudent to me to wait to see if some numbers of additional patients report similar outcomes over time.
What was this drug used for in the beginning? What Maladies, what disease?
I don’t get how one Dr or 2 DR can come up with even trying this on very sick people.
I am now having severe dizziness and eye issues. Also weakness. Had MRI it is ok. Still think something else is going on with CFIDS.
Carole, find a Functional Medicine Specialist. They are more open to try things. They have an association that you can find online that has quite a few docs listed by areas of the country.
Very interesting and promising, in several ways.
a) Rapamycin has indeed been tried by ME/CFS patients before, see here: “I just started taking Rapamune (Sirolimus) which is an mTOR inhibitor, about a month ago and have experienced SIGNIFICANT improvement in both physical and cognitive functionality.” (https://www.healthrising.org/blog/2017/03/08/davis-strategic-approach-chronic-fatigue-syndrome – comment by Marcia Adelman)
b) Also, Rapamycin seems to also modulate the immune system of the brain, i.e. the microglia (https://pubmed.ncbi.nlm.nih.gov/27279283/)
So yes, this could be a plausible candidate for more research!
That’s great info, thanks for posting the link. I suspected that when I read immuno-suppressant property of it. Dopamine is also known to down-regulate activated microglia. Perhaps without any side effect of rapamycine, if you can juice the brain to naturally produce it.
I thought this was an immune modulator rather than suppressor?
I indeed did have a remarkable but temporary reprieve from all of my symptoms, most strikingly – PEM and severe fatigue and cognition. I was taking 2mg daily for around 6 months and then reduced to 2mg every other day. The dosage change did not immediately seem to affect my extreme progress – but after a month I gradually moved back down in functionality. Increased dosage again but did not improve and ultimately stopped the rapamycin altogether as I was back down to baseline functionality and insurance change made it unaffordable. That was in 2017. Now in 2022 at 68 years old, I want to try this drug again. My functional medicine GP is not inclined to prescribe off label so I will pursue other avenues, including Dr. Green. Thanks for this story and I look forward to hearing from others who have tried Rapamycin.
Marcia, you may want to read through Dr. Green’s vebsite, and the references he quotes. You might opt to try it out longer intervals between dosings.
Good luck!
Also interesting: This Australian study has found “chronic elevation of TORC1 activity” in the lymphoblasts of ME/CFS patients:
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7036826/
This may render pathobiological plausibility to treating ME/CFS with a TORC1 inhibitor like rapamycin
As it’s also said to help with aging I’m going to update on my experience with hyperbaric oxygen therapy here. I’ve done 5 treatments at the shallowest dive level the centre provides. My first reactions were that it was noisy and the mask (some places use hoods) stank and is noisy. When they reduce pressure you feel cold and afterwards you will feel hungry sooner than usual as your blood sugar drops. I have problems with my ears on flights and they are having to pressurise more slowly than usual for me. Next week I try a deeper dive, I’m not sure I’ll manage the deepest level they offer so may be unable to complete my course of treatment.
I was warned I might initially feel more tired and I do. I’m switching from morning to afternoon sessions and expect to be going to bed early afterwards. I am sleeping more and hopefully this is more restorative sleep.
Even if people can afford it/ had insurance to cover it this would probably be impossible for those with severe ME. I’m glad I have the chance to try it though.
Yes, please do keep us updated! Hyperbaric therapy was recommended for my husband and daughters, but we have yet to try it.
I was on low dose rapamycin for about 9 months. I kept having HSV2 outbreaks and then, an EBV reactivation. We concluded that even at a low dose, twice weekly, it was suppressing my immune system.
Can you please share what dose of rapamycin you were on?
.5mg twice weekly.
Maybe you needed an even lower dose, less frequency, etc.
But also, one has to eat and give the body nutrition, as its metabolism starts to improve
My doctor, a top ME/CFS specialist, and I decided it was not a good fit for me and we’ve focused on other things. I eat a very healthy diet and am on a high quality supplement program, which is how I’ve improved, in addition to treating infections and dealing with immunodeficiency.
Alternatives https://medicalxpress.com/news/2017-11-scientists-natural-mimetics-anti-cancer-anti-aging.html
Have you tried any of these tatt? I notice that EGCG is derived from green tea which is also thought to be beneficial.
Dear Jeremy, would you consider writing out a case report including more information on dosage and dosage/body weight used? It may enable patients to forward this information to their treating physicians for consideration, or spark further research. As an ME/CFS patient, I would not be able to review the extensive medical information on rapamycine or come to conclusions about dosage for myself. I think some physicians might be open to trying off-label medications with their patients when presented with a document on treatment, but do not have the time for extensive literature review themselves. Thank you!
I don’t have the energy to decipher much of this but it seems like rapamycin may not be safe for those with Alzheimer’s risk. I can’t post the link for some reason. ?
Journal of Neuroscience
Rapamycin increases Alzheimer’s-associated plaques in mice, study finds
Research also reveals a novel way to decrease the plaques — a potential drug target
Date:
June 7, 2022
Source:
University of Texas Health Science Center at San Antonio
Today, in response to a tweet about research on plaque-like findings in LongCovid, someone posted a fascinating article from 2018 on new Alzheimer’s research by Moir re-interpreting plaques as a microbial defence of the brain, blaming inflammation for more neurotoxicity than the plaques themselves: https://www.statnews.com/2018/10/29/alzheimers-research-outsider-bucked-prevailing-theory/ I wonder how this research went since then.
That’s a remarkable story. We should establish Anecdotal Recovery CRT program and trial plausible success stories. Rapamycine could be working by suppressing hypersensitive immune cells somewhere that’s causing CFS havoc.
I can attest to the deconditioning after 10 years inactivity. When I got on the ski slope in 2018 after 10 years in CFS, I was cramping all over just to get to the ticket booth from my car. 3 years after, I just completed 24 miles day-hike in the Teton. 79 yo is not that old the day and age, especially for someone on the longevity drug, LOL. I’m sure you’ll get to live healthy life for another 10-20. Congrats and good luck to you.
Congratulations TK ! How did you accomplish all this?
sorry if i missed out on details.. hard time to keep up with all.
I would be willing try try the rapamycin if i could find a dr willing to RX it.
Thank you, cb. As far back as 2008 when I moved to SF, I knew that I could walk twice as far without triggering PEM when I’m in a new exciting place. I came to call it “novelty effect”, probably caused by extra dopamine. That would last for a few weeks and then I’d be back down to same old CFS self. I kept moving around for that temporary boost. Then, in 2017, I went on the road and I’ve been improving leaps and bound since then. I’ve been living in my car and tent for the last 2 seasons.
It could’ve been just a coincidence and it’s not for everybody for sure: not too many CFS patients can travel or exert to the extent that I did. But occasional travel, or whatever activity that boosts your dopamine level, might help you temper down the exercise intolerance.
TK, your “novelty effect” observation is helpful for me. I think I’ve experienced the opposite, now I’m tempted to test more intentionally. Thanks.
Anne, if you are going to try, I’d recommend “getting lost” in a new place for a few days. Just day-tripping may not work, in my experience.
TK on July 7, 2022 at 11:54 am
Thank you, cb. As far back as 2008 when I moved to SF, I knew that I could walk twice as far without triggering PEM when I’m in a new exciting place. I came to call it “novelty effect”, probably caused by extra dopamine. That would last for a few weeks and then I’d be back down to same old CFS self. I kept moving around for that temporary boost. Then, in 2017, I went on the road and I’ve been improving leaps and bound since then. I’ve been living in my car and tent for the last 2 seasons.
It could’ve been just a coincidence and it’s not for everybody for sure: not too many CFS patients can travel or exert to the extent that I did. But occasional travel, or whatever activity that boosts your dopamine level, might help you temper down the exercise intolerance.
—————————
This is exactly the same story I told to Dr Paul Cheney in 1984.
I was falling apart in San Francisco but improved by living in my camper and going on the road.
I told Dr Cheney I was pretty sure that I was getting better by avoiding mold, but he didn’t believe me and never looked into it.
Links to my story are in the comments section of this blog.
https://www.healthrising.org/blog/2022/07/02/iacfs-me-international-conference-2022/?fbclid=IwAR0AFg_Gjo-1z4BeGFmyivws_9zZBatmuQ2aL0THxZHvZXtZXzWH7AAg_pc
Maybe the “novelty effect” is the reason that I always seem to improve and my CFS sometimes completely disappears when I’m away on holiday in the Canaries. It then returns a day or two after I get home. This is very interesting
TK probably has something to say on this subject 🙂
I believe rather than novelty effect, it relates to the humidity of the place. The more humidity, the worse the symptoms of cfs/me. I have witnessed this many times. Humidity is also a big factor in worsening autoimmune diseases according to research.
Some random thoughts inspired by the “novelty effect” you’ve reported:
– Sometimes it helps when I am able to “drift aimlessly” and associatively through a day. It’s the opposite of “forced activity by pushing with adrenaline”. I still think adrenaline/pushing is also under-researched in ME/CFS. If I had enough energy for traveling, I might like the “drift & explore” part of it.
-“Novelty effect” I think is also experienced by people with ADHD, I believe it relates to dopamine? I’d like to read an article on ADHD as a co-diagnosis in ME/CFS ( I remember Jaime Seltzer mentioned this). I think it’s possible that I might have a late-onset form of it. I’ve read that in (not specifically ME/CFS) people with ADHD it can add a layer of fatigue, as far as I understand because the brain needs to maintain extra activity all of the time to compensate for some specific ADHD related low metabolism (unless the proper activity comes along that produces dopamine?). If on top of ME/CFS one had a type of nervous system that really likes novelty, or some form of ADHD (I am just speculating here, not saying you would have this), living in a novelty-rich way (if possible within the energy envelope) might reduce overall stress on the system. Interestingly, ADHD has recently been mentioned as a risk factor for Covid 19 severity & hospitalisation https://journals.sagepub.com/doi/pdf/10.1177/10870547211003659. In a German database on ADHD research I’ve seen ADHD linked to neuroinflammation (among other factors), might this explain it as a Covid 19 severity risk factor from an inflammatory point of view?
One reason why I think I might have ADHD is the interest-fueled “hyperfocus” flow state/concentration tunnels that “happen to me”. They have 2 sides to them: One the one hand, they seem to temporarily mobilise extra energy similar to adrenaline, temporarily calm the mind, and I find the “getting lost in time” part of it relaxing. (Interestingly, someone on this blog mentioned dopamine might calm migroglia). On the other hand they carry me over energy limits without noticing and make me crash later.
Cort, how about a blog some day on ME/CFS with ADHD, with Jaime Seltzer? 🙂
Kind regards!
Cathode Ray Tube?
Critical Race Theory?
Cardiac Resynchronization Therapy?
What is CRT?
Guessing Clinical Research Trials
Rapamycin and Alzheimer’s Disease.
A large body of preclinical studies especially on APOE4 transgenetic mice shows rapamycin is extremely effective in prevention of AD, especially in those at high risk, APOE4 carriers.
The UT study from San Antonio was extremely mischievous. The used 5x transgenic mice. This is mice genetically engineered to greatly overproduce amyloid. The problem is that the amyloid theory of AD is bad science. Amyloid is the downstream byproduct of the upstream disease process. Unfortunately, the amyloid theory has dominated AD research for the past 30 years and prevented proper understanding of AD, the most important disease of our time.
Amyloid overproduction is not the cause of AD in the 99.9% of cases that are NOT caused by familial genetic AD.
The UT study noted by Kira Moore ONLY applies to 5x transgenetic mice; not the 99.9% of people that don’t have those genes.
!!!
We do have cures in our midst, just the medical industry complex doesn’t ‘allow’ us get to them!
I was reading your site and interviews: aspirin, the sartans to keep angiotensin down (salt and progesterone could also do here, via their effects on aldosterone?) and rapamycin. I surmise one of the key ways they are all helping is by keeping inflammation down – directly/indirectly.
Six weeks to remission!
Here we are like idiots minimizing our lives, our minds, our emotions, our social bonds, pacing to slowly hopefully gain semblance of some life.
Six weeks it took the doctor to put his ME/CFS in remission and start expanding in to life again!
The amyloid plaques as source of disease, the kill the cancer approach, the use of mice to study humans by proxy, etc – all proven to be baloney A1. There are enough scientist and researchers writing about why it’s baloney. Was just reading Soto and Sonnenchein’s articles on cancer and organicism.
I saw the Univeristy of Washington is working with you in a study. Coincidentally, isn’t Gerard Pollack there too?
Thank you Dr Green for sharing your knowledge here. Meeting with you and you being so generous with your time yesterday 3 hours uninterrupted is greatly appreciated by my wife and myself. Your detective like manner to try and pin down a possible cause of my initial infection has never been done before. I was surprised at what you had me recall going back 40 years!
I have tried methylene blue (50 mg daily) and noticed some benefit in energy levels and cognitive function. Luckily I have an anti-aging doc familiar with rapamycin and he is willing to write it. Dose 2.5 mg once weekly. I’ll keep you posted on any benefit.
Hello Carol,
do you know why the protocol is to take a certain dosage once a week, rather than taking a lower dosage every day?
What made your doctor decide on the 2,5 mg for you, rather than the 6mg, that Jeremy took?
I’m so very tempted to try this, but it’s very expensive here, so I’m hesitant.
Any shared information would be so appreciated : )
Warm regards,
Suj
It can be very dangerous to take an anecdotal report from someone who has had a remission from drug and apply it to your own health condition. First, since a cause for ME/CFS has not be identified, we have no idea if we all have the same illness. It is very likely that we don’t.
I almost killed myself trying to self treat. I was determined that the many unusual allergies I had were symptoms of mast cell disorder. I went to local allergists for testing and on scratch testing, I was reactive to a range of chemicals and other substances. The doctors decided to give me a trial of several medications used to treat mast cell disorder. These were in very small doses and given all at once.
The next day, I woke up with blurry vision. I thought I must be having a reaction to one or more of the meds so I stopped everything. My vision did not improve.
I went to an optometrist who panicked because my eye pressure was so high. He sent me immediately to a glaucoma specialist. The meds had triggered narrow angle glaucoma. The specialist recommended laser surgery. All seemed to go well for two weeks.
Then we flew in a pressurized plane for 13 hours to see our daughter in Maui. After we arrived, my left eye turned bright red and began to droop. I also had the worst headache of my life.
When we sent a picture of my eye to the glaucoma specialist, he became very upset and sent me to a former partner of his who lived on Maui. He put me on pressure control eyedrops..
When I got back to Orlando, I was rushed into surgery. The artery behind my left eye had ruptured and attached to the vein. It is called cavernous carotid fistula and can result in fatal stroke or loss of vision in the affected eye.
I went in for a seven hour surgery where a specialist went up the veins in my groin into the brain and separated the artery and vein with platinum coils.
It took me two months to regain vision in both eyes and I will have narrow angle glaucoma for the rest of my life. Fortunately, it is controlled by eye drops right now.
While it is tempting to try treatments that seem to have helped others, it can have devastating consequences in a vulnerable person.
I am glad that rapamycin has helped the doctor, but it is a serious medicine that could have severe adverse effects in the wrong patient.
Betty, thanks for sharing your story, a valuable contribution to the discussion.
In response to M’s comment about having cures in our midst, well, yes we do, but unfortunately we have no way to know for sure what is a cure for ME in which person. A cure for one person might only be a cure for that one specific person. The medical industry isn’t preventing other PWME from trying rapamycin. However, if you gave the drug to 100,000 PWME, how many would it actually cure? Quite possibly none. There probably is a reliable cure for ME somewhere out there, but we don’t at this point know which chemical it is.
As to how rapamycin worked for Jeremy, we don’t know. We know some ways that this drug interacts with the body, but we don’t know whether it was one of those known mechanisms that was responsible. It might have killed off a specific gut microbe that was triggering an immune response. It might have interacted with some other chemical reaction in the body which changed some ratio that had been keeping him in the ME state.
I think that in cases where a chemical does provide a significant benefit for a PWME, it should be reported, and hopefully other people will try it, and maybe one of these treatments will end up getting multiple reports of “It works great for me too!” which will lead to it being a general treatment.
I’ve tried plenty of treatments that others have reported success with, which did nothing useful for me. One report of success with rapamycin isn’t enough to convince me to rush out and ask my doctor for a prescription for it, especially since it can have adverse effects.
I live in a country where the health ministry does not allow for off-label use of prescribed medications. It’s very traditional when it comes to this, doctors can lose their license if there is no lab tests to prove the need for it. ME/CFS is not recognized, there is no evidence to prove it so you see where this leaves us.
I know of other countries with more draconian systems – i.e. you are stuck with the doctor in your area, ME/CFS is treated as a mental disorser / people get interned in psych wards against their will, taking away from their parents etc.
This is what the evidence-based model of medicine looks like. It removes agency not only of the patient – the doctor cannot use the wisdom gathered from years treating and interacting with diseases and humans. It’s geared to the tests, algorithm, statistics and protocols set forth by the ministry. Drs spends most of the appt staring at the screen and typing.
This is in ‘developed’ nations…
Even in the States though, off-label use usually makes it harder to have the medication covered by insurance, nons?
M, can you share what country you are from? France? Canada?
This is EXACTLY why I would never advocate for a centralized healthcare system like the UK’s NHS; everything is reduced to the lowest common denominator. The furthest the US should ever go is a centralized insurance system with guarantees of Doctor independence. Often the system is far behind individual doctors.
I have been on Rapamycin since December 2021. I am age 70 and my treatment goal was improving CFS symptoms.
I started at 6 mg once a week and after about 4 months, I went to 10 mg once a week and now I’m at 12mg every 10 days.
I was trained in a behavioral medicine psychology program and worked with physicians in clinics for many years. I can read and understand most of the scientific articles about rapamycin. My primary care provider is a nurse practitioner who I’ve worked with for years. Once she determined I’m competent, she’s been willing to give me prescriptions for the unusual meds I’ve asked for. Not only that, she and her medical assistant are goddesses of coding and my rapamycin and unusal labs are paid for by insurance.
Energy levels are a little higher. My BPH has gone away. I suspect my insulin resistance is better based on how I feel. I’m getting labs soon
My mast cell activation syndrome symptoms have been gone for months.
There is still some fatigue which I suspect is from deconditioning.
I also have an HSV2 outbreak. This is my third one with the first at age 69.
To clarify, are you saying that you have had three HSV2 outbreaks since starting the Rapamycin amd had never had an HSV2 outbreak in the past?
Robert Lawson, please post again as the weeks go by. And – congratulations on connecting with Dr. Green. I’m sure I’m not the only one, I would love to follow your rapamycin story, with huge interest! Hope this works out!!
Chronic fatigue syndrome has been one of the great medical mysteries for the past 150 years. First called Neurasthenia, by Neurologist, Dr Beard in 1869; over the last 150 years various names have been applied including: myalgic encephalomyelitis, chronic fatigue syndrome, fibromyalgia, Raggedy Ann Syndrome, chronic Lyme disease, post-viral fatigue syndrome and most recently long-haul Covid. Due to absence of positive physical finding, positive ordinary laboratory test, specific autopsy finding; it is very difficult disease.
For the most part, it has been up to patients with CFS to try and sort things out. I was very fortunate to have received a telephone call from person who self-identified himself here as “Dr Jeremy”. He started telephone call by saying “I have had long-haul covid for 40 years”. All I can add is “Dr jeremy” is an extremely intelligent person and I hope by sharing his experience this will be helpful to other CFS patients and physicians trying to provide treatment. A person who has a disease for 40 years, studies everything known about that disease, figures out a treatment, tries the treatment and goes into remission and then decides to share his experience; is maybe a good place to start.
The 1955 Royal Free Hospital was compared to neurasthenia and to Iceland Disease, and found to have distinguishing characteristics that warranted a new name to reflect the narrowing focus on these specific clues.
To refer to ME as if it is congruent with neurasthenia is to remove the very reasons this term was coined.
Same for Lake Tahoe “Raggedy Ann Syndrome”
This outbreak had evidence that could not be found in ME for the simple reason that the new testing employed by Cheney and Peterson had only just been invented.
CFS represents an even more specific dataset than ME.
I realize people don’t know this. They were fooled by the silly name.
What are you thoughts that with Rapamycin down regulating the innate immune system, it could possibly put someone at higher risk for Covid?
Tracy asks: If rapamycin downregulates the innate immune system, is this bad for Covid. 2 and 1/2 years and 1000 patients later showed that weekly Rapamycin was spectacular for Covid protection. The people at high risk are those with high activity of innate immune system and chronic inflammation. This group includes older people, insulin resistance, diabetes, chronic disease, overweight all at high risk. What is needed for protection is a healthy acquired immune system (T-cells). People on Rapamycin just had a mild to moderate viral syndrome. People on weekly Rapamycin did not have cytokine storm, respiratory failure, need for hospitalization and ventilation and death. They also did not develop Long Haul Covid. There was a large body of evidence to suggest in March 2020, that weekly Rapamycin would protect against death from Covid, etc. The failure of the medical system to not look at rapamycin and ways to downregulate the innate immune system for Covid protection; but rather just focus on anti-viral efforts was a catastrophic failure. However, in March 2020, my website advised that rapamycin was protective. 2 1/2 years later proved this was good advise.
Alan … thanks for your detailed response regarding the innate immune system! Makes much sense to me. Something else I thought was interesting with all the research done on mice worms, etc. I find it interesting that apparently there was a study suggesting that it rapamycin extended the life of yeast? Yeast is a fungus and they’re also studies that report rapamycin can serve as an antifungal. These two statements seem contradictory?
“Dr. Jeremy had long -haul Covid like symptoms for 40 yrs”. This article mentions 10 yrs since diagnosis of ME/CFS and climbing an 18k peak the year prior?
I just shot off an e-mail to Dr. Bonilla at Stanford with a link to this article. I hope it ‘plants a seed.’ Told him I would be willing to try Sirolimus (Rapamycin).
Last visit he prescribed low dose Ketotifen and I didn’t notice much of an effect but he did want my feed back, so I included the above link.
I discontinued Oxaloacetate a while ago and have noticed that my energy has gone down and so now I’m wondering if it really was helping. Effects can be subtle. Darn, that supplement is so expensive!
The new ‘diet’ prescribed by U.C.S.F.’s alternative medicine department has been a big flop. Too restrictive with no noticeable benefits so I’ll be adding stuff back. Apparently food isn’t my problem.
P.T. for pain is slow going. Ouch! Poco a poco…
This is interesting: take a look at a prior post, covering Paul Fisher’s latest mitochondrial studies – mTOR is mentioned. And rapamycin.
https://www.healthrising.org/blog/2022/03/27/novel-approach-mitochondria-chronic-fatigue-syndrome/
I do wonder if other antibiotics from the tetracycline family could also have a similar effect. Have they been studied for their other efects on immunology/ mtor / lifespan / etc?
Nice! I had forgotten about that. Thanks, M!
This reminded me – doxycycline was used in an experiment invitro on that-disease-that-looks-like-EDS-but-is-not tissue samples. It seemed to do something positive, invitro.
https://pubmed.ncbi.nlm.nih.gov/34831458/
Just heard back from Dr. Bonilla and he nixed my suggestion of trying Rapamycin. Said a clinical trial was needed first (isn’t that what he is doing at Stanford???) and that it was too dangerous a drug.
Oh well… I tried.
You might try ordering your own here from India. I heard they do the wrong assays for purity although likely from China.
https://www.oddwayinternational.com/rapact-5mg-everolimus-tablets-exportindia/
Dang, I said their own Assays.
Hi Tracy,
How do you know Evermil or Everolimus are the same as rapomycin. I cannot find anything to say they are the same. I found my own answer.
Sirolimus is a macrocyclic lactone antibiotic produced from Streptomyces hygroscopicus. Everolimus is a derivative of sirolimus. Both bind to the same intracellular immunophilin as tacrolimus (FKBP12), but instead of inhibiting calcineurin, the drug-receptor complex binds to the mammalian target of rapamycin. This causes inhibition of a multifunctional serine-threonine kinase, preventing both DNA and protein synthesis, resulting in an arrest of the cell cycle
Oddway International quoted me $11 a tablet for 5mg of Evermil. Minimum order 30 tablets shipping to US $25. If you were to take one 5 mg tablet a week which is slightly less than the 6 mg recommended it would be @ $45 a month. Supposedly it’s manufactured in India. Personally, I would feel more comfortable with something from India than China. Good portion of the medication being prescribed in the UK comes from India. Although a little scary to start on the path like this without the help of a doctor! Perhaps one could only take a half a pill and wait a week just to make sure we didn’t have a reaction to it before we take the full 5 mg dose?
Start low and slow = name of the game
Is a good ME/cFS motto
Lower than what you think is low. Much lower. Observe how your body reacts. Wait and then wait some before a second dose. Don’t try more than a new th8ng at a time, etc.
For every substance, even new foods
Is a good idea
Read everything there is about a substance first before ye gets to know it intimately. Get a feel for it etc
Hi Tracy,
How do you know Evermil or Everolimus are the same as rapomycin. I cannot find anything to say they are the same.
I can’t see any match between Rapomycin & everolimus. Could you please elaborate about Rapomycin active ingridient? If it’s Sirolimus then you can try ordering from them https://www.medixocentre.com/
They are legit pharmaceutical of generic medicine from India.
Yes, I can’t see any match between Rapamycin & Everolinus. Both are different ingrdient.
Omission
There is data to suggest that Rapamycin and Lithium work by different mechanisms and are synergistic. It is possible that my low-dose lithium, 300 mg, played a role in my dramatic response.
A triple drug combination targeting components of the nutrient-sensing network maximizes longevity
Jorge Iván Castillo-Quana,b,c,d,1, Luke S. Taind,1, Kerri J. Kinghorna,e, Li Lia,2, Sebastian Grönked, Yvonne Hinzed, T. Keith Blackwellb,c, Ivana Bjedova,f, and Linda Partridgea,d,3
aInstitute of Healthy Ageing, Department of Genetics, Evolution and Environment, University College London, WC1E 6BT London, United Kingdom; bSection on Islet Cell & Regenerative Biology, Joslin Diabetes Center, Boston, MA 02215; cDepartment of Genetics, Harvard Medical School, Boston, MA 02115; dDepartment of Biological Mechanisms of Ageing, Max Planck Institute for Biology of Ageing, D-50931 Cologne, Germany; eDepartment of Molecular Neuroscience, Institute of Neurology, WC1N 3BG London, United Kingdom; and fDepartment of Cancer Biology, Cancer Institute, University College London, WC1E 6DD London, United Kingdom
Edited by Joseph S. Takahashi, The University of Texas Southwestern Medical Center, Dallas, TX, and approved September 16, 2019 (received for review August 1, 2019)
Increasing life expectancy is causing the prevalence of age-related diseases to rise, and there is an urgent need for new strategies to improve health at older ages. Reduced activity of insulin/insulin- like growth factor signaling (IIS) and mechanistic target of rapamycin (mTOR) nutrient-sensing signaling network can extend lifespan and improve health during aging in diverse organisms. However, the extensive feedback in this network and adverse side effects of inhibition imply that simultaneous targeting of specific effectors in the network may most effectively combat the effects of aging. We show that the mitogen-activated protein kinase kinase (MEK) inhibitor trametinib, the mTOR complex 1 (mTORC1) inhibitor rapamycin, and the glycogen synthase kinase-3 (GSK-3) inhibitor lithium act additively to increase longevity in Drosophila. Remarkably, the triple drug combination increased lifespan by 48%. Furthermore, the combination of lithium with rapamycin cancelled the latter’s effects on lipid metabolism. In conclusion, a polypharmacology approach of combining established, prolongevity drug inhibitors of specific nodes may be the most effective way to target the nutrient-sensing network to improve late-life health.
aging | polypharmacology | trametinib | rapamycin | lithium
Aging is a complex process of progressive cell, tissue, and systemic dysfunction that is involved in the etiology of age- related diseases (1). Genetic, dietary, and pharmacological in- terventions can ameliorate the effects of aging in laboratory animals and may lead to therapies against age-related diseases in humans (2–4).
In organisms ranging from invertebrates to mammals, re- ducing the activity of the nutrient-sensing mechanistic target of rapamycin (mTOR) and insulin/insulin-like growth factor sig- naling (IIS) network can promote longevity and health during aging (2, 3). Lowering network activity can also protect against the pathology associated with genetic models of age-related diseases (1, 2). The network contains many drug targets, in- cluding mTOR, mitogen-activated protein kinase kinase (MEK), and glycogen synthase kinase-3 (GSK-3) (Fig. 1A). Down- regulation of mTOR activity by rapamycin, GSK-3 by lithium, or MEK by trametinib can each individually extend lifespan in laboratory organisms (5–11), and brief inhibition of mTOR has recently been shown to increase the response of elderly people to immunization against influenza (12). In addition, both mTOR and MEK inhibitors have been shown to reduce senescent phe- notypes in human cells (13), while increasing concentrations of lithium levels in drinking water correlate with reduced all-cause mortality in a Japanese population (10). An advantage of phar- macological interventions is that the timing and dose of drug administration are relatively simple to optimize, and drugs can be easily combined (4, 14–16). Combination drug treatments also have the potential to counter resistance from feedback and to reduce each other’s side effects (17). Rapamycin, trametinib, and lithium each target different kinases and transcription factors to
extend lifespan (5, 8, 11), and therefore their effector mechanisms are at least partially different from each other. Simultaneous inhibition of multiple targets within the nutrient-sensing net- work may hence be needed to optimize effector outputs and health benefits. Here, we measure the effects of combination treatments of rapamycin, lithium, and trametinib on lifespan and other traits, using Drosophila as a model organism.
Results and Discussion
Rapamycin treatment, from Caenorhabditis elegans to humans, is
associated with altered metabolism, including hypertriglyceridemia and obesity (5, 18). Alone, a lifespan-extending dose of lithium (11) did not alter triglyceride levels, but simultaneous treatment with both lithium and rapamycin reversed the dyslipidemia caused by rapamycin (Fig. 1B). To confirm that this change in lipid levels was physiologically relevant, we pretreated (14 d) flies with lithium, rapamycin, or a combination, and assessed their survival under starvation. Lithium did not alter survival under starvation conditions, while rapamycin increased it (Fig. 1C). Consistent with their effects on lipid levels, combining lithium and rapamycin treatment resulted in control levels of starvation resistance (Fig. 1C). Lithium can therefore reverse metabolic stor- age alterations associated with mTOR inhibition.
Lithium inhibits GSK-3 activity to extend lifespan (11), im- plying that activation of GSK3 is likely, if anything, to shorten lifespan. Inhibition of IIS in the canonical PI3K pathway can extend lifespan and health span, but reduces inhibitory phos- phorylation of GSK3 by Akt (Fig. 1A), and hence activates GSK3 (4), a potentially deleterious side effect of lowered IIS (19). We therefore tested whether lithium could have additive effects in combination with genetic inhibition of IIS upstream of Akt. Lithium was able to further extend the lifespan of flies lacking the insulin-like peptides 2, 3, and 5 (dilp2-3,5) (Fig. 1D) (20). In contrast, rapamycin or trametinib, neither of which inhibit GSK3, were not able to extend the lifespan of dilp2-3,5 flies (Fig. 1 E and
Author contributions: J.I.C.-Q. and L.P. designed research; J.I.C.-Q., K.J.K., L.L., S.G., Y.H., and I.B. performed research; J.I.C.-Q. and L.S.T. analyzed data; J.I.C.-Q., L.S.T., and L.P. wrote the paper; T.K.B. provided input in manuscript writing; J.I.C.-Q., L.S.T., and L.P. interpreted data; and T.K.B. and L.P. supervised experiments.
The authors declare no competing interest.
This open access article is distributed under Creative Commons Attribution License 4.0
(CC BY).
1J.I.C.-Q. and L.S.T. contributed equally to this work.
2Present address: Department of Neurosurgery, School of Medicine, Stanford University, Palo Alto, CA 94304.
3To whom correspondence may be addressed. Email: l.partridge@ucl.ac.uk.
This article contains supporting information online at http://www.pnas.org/lookup/suppl/doi:10.
1073/pnas.1913212116/-/DCSupplemental. First published September 30, 2019.
DEVELOPMENTAL
BIOLOGY
Downloaded by guest on November 26, 2021
http://www.pnas.org/cgi/doi/10.1073/pnas.1913212116
PNAS | October 15, 2019 | vol. 116 | no. 42 | 20817–20819
BRIEF REPORT
Downloaded by guest on November 26, 2021
explain the greater longevity observed with the triple drug B
A
dILP3 dILP2
combination.
dILP5
dInR
***
******
Given the complex nature of the aging process, it is unlikely 200
cytoplasm
Chico
Control
150
Ras
Rapamycin PI3K
Lithium
that the most effective preventative antiaging therapy could be achieved by a single compound with a single target. We have Rapamycin
MEK acids mTORC1
Amino Lithium Akt
100
Triglyceride levels Rapamycin + Lithium
Trametinib shown that simultaneous inhibition by 3 components of different 50
Erk
S6K Atg1 Sgg
nodes in the nutrient-sensing network using a combination of 0
drugs already approved for human use is a viable strategy to nucleus
Aop
CncC FOXO
maximize animal longevity and to reduce a side effect. Rapa- CD
mycin treatment results in insulin resistance and dyslipidemia in 1.0
Starvation 1.0
patients and mice (4, 18, 22), and this disturbance manifests as 0.8
0.8
hypertriglyceridemia in Drosophila (5). Lithium reversed this and 0.6 0.6
Survival Survival Control the starvation resistance associated with rapamycin treatment. dilp2-3,5 0.4 Control 0.4
Taken together, our results highlight a potential therapeutic –
Lithium
*** Lithium avenue to promote longevity, coadministrating compounds that +
0.2
Rapamycin 0.2
Rapamycin + Lithium
*** ***
act on different nodes of the nutrient-sensing network, to max- 0.0
0.0
0 2 4 6 8 10 12 14 16 0 20 40 60 80 100 120
imize their beneficial effects while minimizing negative side Time (d)
Time (d)
effects.
F
E
1.0
1.0
Methods
0.8
0.8
Fly Stocks, Husbandry, and Lifespan Analysis. For all experiments, a wild-type 0.6 0.6
white Dahomey (wDah) stock, or, when noted, dilp2-3,5 mutant flies Survival
Control
dilp2-3,5
Survival
Control dilp2-3,5 0.4 –
Rapamycin
0.4
Trametinib
(wDah backcrossed), were used, and raised as previously described (20). LiCl –
+
(Sigma) in ddH2O, trametinib (LC laboratories) in dimethyl sulfoxide, and 0.2 +
0.2
rapamycin (LC laboratories) in 100% ethanol were added to sugar−yeast− ***
0.0 ***
0.0
agar (SYA) medium to a final concentration of 1 mM, 15.6 μM, and 50 μM, 0 20 40 60 80 100
0 20 40 60 80 100 120
Time (d)
Time (d)
respectively (5, 8, 11). Equivalent volumes and concentrations of vehicle were added to SYA medium for control treatments. Drug treatments were started 2 d posteclosion. Female flies (n = 130 to 200, 15 to 20 per vial) were Fig. 1. Lithium blocks negative side effects of mTORC1 and IIS inhibition.
sorted onto SYA medium that was replaced every 2 d to 3 d throughout life. (A) A simplified diagram of the Drosophila nutrient-sensing network
showing the target kinases of rapamycin, trametinib, and lithium. Lithium
reversed the (B) hypertriglyceridemia (n = 6 replicas of 5 flies per condition,
1-way ANOVA) and (C) starvation resistance induced by rapamycin (50 μM)
(n = 75). (D) Lithium treatment significantly extended lifespan of both wDah
Maximum lifespan B
A 1.0
and dilp2-3,5 mutant flies. Neither (E) rapamycin (P = 0.58) nor (F) trametinib
Trametinib Rapamycin Lithium Median lifespan
(P = 0.14) further extended lifespan of dilp2-3,5 mutant flies [log-rank test (n =
0.8 +++
(274/7) 150)]. Cox Proportional Hazard analysis showed a significant genotype by
++-
(444/3) treatment interaction for rapamycin (P = 0.002) and trametinib (P = 0.0018).
Control
Error bars represent SEM. ***P < 0.001 (1-way ANOVA or log-rank test).
0.6
+ – +
(440/3) Lithium
Survival
Rapamycin
(482/10) – + +
(599/2) Trametinib
0.4
Rapamycin + Lithium
+ – –
(620/7)
–
+
–
F). Lithium thus reverses an adverse side effect of inhibition of the
****** ***
Trametinib + Lithium
(636/5) 0.2
***
Rapamycin + Trametinib
+
–
–
canonical IIS pathway.
(793/10) Rapamycin + Trametinib + Lithium
–
–
–
Because rapamycin, lithium, and trametinib extend lifespan by
0.0
at least partially independent mechanisms, we investigated the
60 80 100 120
0
20
40
60
80 100 120
effects on lifespan of their double and triple combinations. Double
Time (d)
Time (d)
C 1.0 1d
combinations of lithium and rapamycin, lithium and trametinib, or
D
E
Trametinib
25
rapamycin and trametinib produced a reproducibly greater life- 0.0
40
Feeding
behavior
15
span extension than controls, on average 30%, compared to each
0.5
15d
30
compound alone, which extended lifespan by an average of 11% 0.0
5
Systemic levels (ng/fly)
(Fig. 2 A and B and Dataset S1). Importantly, the triple com-
0.6
Rapamycin
Fecundity (Eggs/fly/day)
20
120
bination of rapamycin, trametinib, and lithium promoted lon- 0.4
80
Food intake
(mg/mL)
** ** * 10
** 40
gevity beyond that of the double combinations, extending
0.2
0
0
median lifespan by 48% (Fig. 2 A and B and Dataset S1). Thus,
0.0
Rapamycin – – + – + – + +
– – + – + – + +
– – + – + – + + each compound independently displayed an additive effect on Trametinib – – – + – + + +
– – – + – + + +
– – – + – + + + Lithium -+–++-+ -+–++-+ -+–++-+ lifespan. The additive effect of rapamycin, trametinib, and lith-
ium on lifespan is unlikely to have been due to changes in
Fig. 2. A triple drug combination maximizes longevity. (A) Representative feeding behavior, because feeding frequency, food intake, and
survival curve and associated pairwise log-rank tests. (B) Replicated median/ drug uptake were unaltered by the treatment regimens (Fig. 2 C
maximum lifespans plotted for all single (n = 4), double (n = 3), and triple (n = 2) combinations of rapamycin, trametinib, and lithium treatments. Each and D). Fecundity is often reduced in interventions that promote
lifespan contained 130 to 200 flies per treatment. Numbers in parentheses lifespan extension (21), and this could provide a potential ex-
show (total number of flies/number of censors). (C) Proboscis extension feed- planation for the greater longevity with drug combinations.
ing behavior assay (1 and 15 d of treatment; Top and Middle) and quantifi- However, at the concentrations used, only trametinib and
cation of ingested nonabsorbable (Bottom) blue dye (n = 8 replicas of 4 to 5 combinations containing trametinib significantly reduced fe-
flies 15 d old, 1-way ANOVA with Dunnett’s test). (D) Mass spectrometry of cundity (Fig. 2E). Importantly, the triple drug combination did
systemic trametinib (Top) or rapamycin (Bottom) levels when other drugs were coadministered (n = 5, 1-way ANOVA). (E) Fecundity of treated (15 d) flies not reduce egg laying below that achieved with double
within a 24-h period (n = 8 replicas of 4 to 5 flies). Error bars show Tukey trametinib-containing combinations, or trametinib treatment
whiskers, and outlying data points are shown as dots. *P < 0.05, **P < 0.01, alone (Fig. 2E). Thus, a trade-off with fecundity is unlikely to
***P < 0.001 (Kruskal−Wallis test and Dunn’s pairwise tests).
20818 | http://www.pnas.org/cgi/doi/10.1073/pnas.1913212116
Castillo-Quan et al.
Lifespan raw data are provided as Dataset S1. Starvation assay was per- formed as previously described (11).
Food Intake, Fecundity, and Triglyceride Measurements. Feeding behavior (proboscis extension at 1 and 15 d of treatment) and food intake (quantified by dye-calibrated feeding) (4 to 5 flies per replicate, n = 8 to 10) were measured as previously described (23). Fecundity was quantified as number of eggs laid within 24 h (15 d), and triglyceride measurements (5 flies per replicate, n = 8) were performed as previously described (5, 11).
Mass Spectrometry. Flies (n = 5, 15 flies) were treated with drugs (15 d), their digestive system was allowed to void (1 h), they were snap frozen, drugs were extracted as previously described (5), and they were resuspended in 100 μL of acetonitrile/isopropanol 70:30 for measurement with an Acquitiy UPLC I-class System/Xevo TQ-S (Waters) with MassLynx and absolute quantification.
1. C. López-Otín, M. A. Blasco, L. Partridge, M. Serrano, G. Kroemer, The hallmarks of aging. Cell 153, 1194–1217 (2013).
2. J. Campisi et al., From discoveries in ageing research to therapeutics for healthy ageing. Nature 571, 183–192 (2019).
3. C. J. Kenyon, The genetics of ageing. Nature 464, 504–512 (2010).
4. J. I. Castillo-Quan, K. J. Kinghorn, I. Bjedov, Genetics and pharmacology of longevity:
The road to therapeutics for healthy aging. Adv. Genet. 90, 1–101 (2015).
5. I.Bjedovetal.,MechanismsoflifespanextensionbyrapamycininthefruitflyDrosophila
melanogaster. Cell Metab. 11, 35–46 (2010).
6. D. E. Harrison et al., Rapamycin fed late in life extends lifespan in genetically het-
erogeneous mice. Nature 460, 392–395 (2009).
7. S. Robida-Stubbs et al., TOR signaling and rapamycin influence longevity by regulating
SKN-1/Nrf and DAF-16/FoxO. Cell Metab. 15, 713–724 (2012).
8. C. Slack et al., The Ras-Erk-ETS-signaling pathway is a drug target for longevity. Cell
162, 72–83 (2015).
9. G. McColl et al., Pharmacogenetic analysis of lithium-induced delayed aging in Cae-
norhabditis elegans. J. Biol. Chem. 283, 350–357 (2008).
10. K. Zarse et al., Low-dose lithium uptake promotes longevity in humans and metazoans.
Eur. J. Nutr. 50, 387–389 (2011).
11. J. I. Castillo-Quan et al., Lithium promotes longevity through GSK3/NRF2-dependent
hormesis. Cell Rep. 15, 638–650 (2016).
12. J. B. Mannick et al., mTOR inhibition improves immune function in the elderly. Sci.
Transl. Med. 6, 268ra179 (2014).
13. Z. N. Demidenko, M. Shtutman, M. V. Blagosklonny, Pharmacologic inhibition of MEK
and PI-3K converges on the mTOR/S6 pathway to decelerate cellular senescence. Cell Cycle 8, 1896–1900 (2009).
ACKNOWLEDGMENTS. We are grateful to Prof. David Gems and Drs. Helena Cochemé, Natalie Moroz, and Filipe Cabreiro for advice and comments, and to Rachel Beltzhoover for proofreading. We thank Drs. Fiona Kerr, Anna Tillmann, and Giovanna Vinti for technical advice and assistance. We ac- knowledge funding from University College London Scholarships (J.I.C.-Q.), American Federation for Aging Research/Glenn Foundation for Medical Re- search Postdoctoral Fellowship (Grant PD18019 to J.I.C.-Q.), Max Planck So- ciety (J.I.C.-Q., L.S.T., S.G., Y.H., and L.P.), and National Institutes of Health (Grants AG54215 and GM122610 to T.K.B.). This project has received funding from the European Research Council under the European Union’s Horizon 2020 research and innovation program (Grant Agreement 741989), Euro- pean Research Council Starting Grant (Grant 311331 to I.B.), Research Into Ageing (I.B. and L.P.), Parkinson’s UK (L.L. and L.P.), Wellcome Trust Clinical Career Development Fellowship (Grant 214589/Z/18/Z to K.J.K.), Wellcome Trust Strategic Award (WT098565/Z/12/Z to L.P.), and Academy of Medical Sciences (K.J.K.).
14. T. D. Admasu et al., Drug synergy slows aging and improves healthspan through IGF and SREBP lipid signaling. Dev. Cell 47, 67–79.e5 (2018).
15. P. Dakik et al., Pairwise combinations of chemical compounds that delay yeast chronological aging through different signaling pathways display synergistic effects on the extent of aging delay. Oncotarget 10, 313–338 (2019).
16. K. Evason, J. J. Collins, C. Huang, S. Hughes, K. Kornfeld, Valproic acid extends Cae- norhabditis elegans lifespan. Aging Cell 7, 305–317 (2008).
17. B. D. Levine, R. L. Cagan, Drosophila lung cancer models identify trametinib plus statin as candidate therapeutic. Cell Rep. 14, 1477–1487 (2016).
18. V. P. Houde et al., Chronic rapamycin treatment causes glucose intolerance and hy- perlipidemia by upregulating hepatic gluconeogenesis and impairing lipid deposition in adipose tissue. Diabetes 59, 1338–1348 (2010).
19. K. Tanabe et al., Genetic deficiency of glycogen synthase kinase-3beta corrects diabetes in mouse models of insulin resistance. PLoS Biol. 6, e37 (2008).
20. S. Grönke, D.-F. Clarke, S. Broughton, T. D. Andrews, L. Partridge, Molecular evolution and functional characterization of Drosophila insulin-like peptides. PLoS Genet. 6, e1000857 (2010).
21. M. Jafari, Drosophila melanogaster as a model system for the evaluation of anti-aging compounds. Fly (Austin) 4, 253–257 (2010).
22. D. W. Lamming et al., Rapamycin-induced insulin resistance is mediated by mTORC2 loss and uncoupled from longevity. Science 335, 1638–1643 (2012).
23. R. Wong, M. D. W. Piper, B. Wertheim, L. Partridge, Quantification of food intake in Drosophila. PLoS One 4, e6063 (2009).
BRIEF REPORT
Downloaded by guest on November 26, 2021
Castillo-Quan et al.
PNAS | October 15, 2019 | vol. 116 | no. 42 | 20819
DEVELOPMENTAL
BIOLOGY
Hi there.
How is your recovery going? Have you thought more about the low dose lithium added to the rapomycin? When did you start the lithium?
If you are getting HSV2 outbreaks have you tried to control them with valcyclovir?
I’d like tot try Rapamycin.I asked my own docter to prescribe it,but he won’t do it.
Does anyone know a docter in The Netherlands of Germany who’s willing to prescribe it ?
All the best,
Ben
You can order it from India, Oddway Imyernational w/o Rx.
I just saw Dr. Green last Friday and was prescribed rapamycin. I am starting off at a low dose as I am very small–2mg once a week. I will update if I notice any improvements! My main symptom is extreme mental fatigue. This began 9 years ago at the age of 19 after getting sick with a bad virus. Prior to getting sick, I was very active running marathons. I am very hopeful that rapamycin will help, as I’ve tried SO many things that haven’t made a difference.
Good luck to a former marathon runner! Please let us know how it goes 🙂
How are you getting on Meghan?
Any updates? I’m thinking of trying this, possibly along with ss31. Hope you’re doing well!
How are you getting on Meghan?
Could his remission have to do with rapamycin’s effect on EBV? Important caveat- Rapamycin lowered EBV lytic replication on a one level but increased on a different level
https://virologyj.biomedcentral.com/articles/10.1186/1743-422X-11-110
“We determined that treatment of cells with rapamycin, which is an inhibitor of mTORC1 activity, led to a reduction in the ability of B cell lines to undergo lytic replication. In contrast, EBV-positive epithelial cell lines underwent higher levels of lytic replication when treated with rapamycin.”
Therefore, its complete treatment may cost around 1-1.5 lakhs. We can help from web platforms including Lybrate to know about the exact price of the treatment in different parts of India. You can speak with Lybrate’s Hepatitis C doctors for further information https://www.heptopic.com/
Nice article, it is very useful to me. If you are suffering from a man’s health problem use vilitra 20 mg for better health.
These circumstances cause significant distress. It is perplexing to comprehend how one is expected to discover a solution amidst these seemingly disparate anecdotes, each presenting a distinct narrative.
Regrettably, I lack the necessary resources, both in terms of expertise and financial means, to pursue the multitude of emerging pathways that surface on a weekly basis. Nonetheless, it is evident that certain individuals achieve remission through methods that are not feasible for me to pursue.
You can try to order rapamycin at lower cost from India from here.
https://www.medixocentre.com/
You can check with Medixo Centre about availbility of Rapamycine. They have quite good price.
It appears that both LDN and Rapamycin suppress IL-6. But that IL-6 helps in the suppression of Herpes Zoster. It’s all a puzzle piece and everyone is different. Reading the comments I saw that Jeremy had an HSV outbreak following treatment. I had an HSV outbreak following treatment w LDN. Found this in the literature. Now I know enough to be dangerous.
Naltrexone Inhibits IL-6 and TNFα Production in Human Immune Cell Subsets following Stimulation with Ligands for Intracellular Toll-Like Receptors
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5504148/
Interleukin-6 and type 1 interferons inhibit varicella zoster virus replication in human neurons
https://pubmed.ncbi.nlm.nih.gov/29979960/