Hello, i was wondering if anyone had heard of this approach for CLL stage 0 (wait & see) there is multiple study showing that it might be beneficial to combine Rapamycin - Metformin and fasting to induce autophagy ... any advise or link would be appreciated .
youtube.com/watch?v=Eg1GbyO...
Rapamycin - metformin and fasting are being used today by many people in profilaxis to stop age related diseases.
Being in good health and just waiting ... would this approach be beneficial ?
There are over 1000 studies listed at clinicaltrials.gov regarding rapamycin, for a number of disease states, so I think there is quite a bit of interest. It looks like the potential effect for rapamycin was noted in the early 2000's as scientists worked on cancer pathways
pubmed.ncbi.nlm.nih.gov/160...
clinicaltrials.gov/ct2/resu...
With a recent study looking at potential ways to pharmacologically decrease the effects of aging on cells, looking at these compounds to maintain "good health" is also on the radar
pubmed.ncbi.nlm.nih.gov/358...
It looks like there are a number of studies being done specifically regarding CLL and rapamycin or similar agents
pubmed.ncbi.nlm.nih.gov/160...
There are a few studies looking at CLL and metformin interactions. The US U of Michigan doc hasn't yet gotten all his patients, I last spoke with him before Covid, I was interested in joining it. Then Covid hit and no way was I traveling. And it seems folk in London have looked at both at the same time in CLL
clinicaltrials.gov/ct2/resu...
There are some studies looking at metformin for other cancers as well, among the thousands including other disease states
clinicaltrials.gov/ct2/resu...
Whether or not it is desirable to take them in Watch and Wait, is hard to say. Remember not all cancers involve all the same metabolic pathways, and some agents that are considered "good for immune boosting" generally, are specifically bad for CLL pathways.
If you posted a video, I am not seeing the link, so I can't comment on it.
Ok thank you very much for replaying ... The current literature on anti-anging medicine is that the main benefits of drugs like metformin - rapamycin and fasting is the boosted autophagy... rapamycin is a Mtor-1 inhibitor = boost autophagy + decrease WBC, metformin up-regulate AMPK = boost autophagy and lastly fasting both inhibit Mtor-1 and up-regulate AMPK. So my thinking was : while on a wait and see protocol ... why not help my body eat this CLL 
Perfercly healthy researcher in this field are taking Rapamycin - metformin and fasting.
sinclair.hms.harvard.edu/pe...
Peter Attia : podcastnotes.org/high-inten...
No, its fine your not raining on my parade
FYI english is not my 1st language so excuse me in advance if i make errors !
1-It dose not uptake mTOR-1 but rather suppress it without affecting m-TOR-2 it has to be taken 1-5mg every 7 to 14 days... NOT on a continus basis.
pubmed.ncbi.nlm.nih.gov/173...
Previous reports demonstrated that rapamycin, which inhibits mTOR activity, sensitizes certain resistant cancer cells to chemotherapeutic agents. These facts have made mTOR to be viewed as an important target for anti-cancer therapeutics development. Evidence suggests that the rapamycin derivatives CCI-779 and RAD001 could induce G1-S cell cycle delay and eventually apoptosis, depending on inner cellular characteristics of tumor cells.
2-Yes if taken every day it will act as an immunosuppressor, it was initially only used for this.
3-like i stated earlier, in a comment : The current literature on anti-anging medicine is that to live longer and in good health, the #1 solution is to boost autophagy.
The main benefits of drugs like metformin - rapamycin and fasting is the boosted autophagy... rapamycin is a Mtor-1 inhibitor = boost autophagy + decrease WBC, metformin up-regulate AMPK = boost autophagy and lastly fasting both inhibit Mtor-1 and up-regulate AMPK. So my thinking was : while on a wait and see protocol ... why not help my body eat this CLL
Perfectly healthy well establish researchers in this field are taking Rapamycin - metformin and doing fasting. What would be the downside of trying it ?? I dont know ? im asking here because people have a-lot more experience in this forum than me.
sinclair.hms.harvard.edu/pe...
Peter Attia : podcastnotes.org/high-inten...
have a good day
spare75 - You have ID'd 2 of the leading MDs looking into longevity & senolytics, David Sinclair and Peter Attia (The Drive Podcast). Sinclair is fully into research at Harvard and Attia runs a clinic that is focused on both healthspan and lifespan. YouTube has numerous podcast interviews with each of them.
Attia's The Drive Podcast covers a wide range of issues related to health and fitness and his knowledge is very deep and wide. Most important, his clinic provides continuous feedback, ever expanding that impressive knowledgebase. Highly recommended!
Sinclair published a book in 2019 that covered the status of his research into aging and longevity at that time. He basically views aging as a disease that can be treated. That book, Lifespan: Why We Age – and Why We Don't Have To, is an excellent read and I also recommend it to you or anyone else that wants to understand the complex medical aspects of aging.
I first became interested in the use of senolytic compounds (that act on certain of the 7-member family of sirtuin proteins involved with regulating metabolism and clearing out senescent aka "zombie" cells) after reading an article in the NYT. Then several years later I saw Sinclair interviewed on the RichRoll Podcast. (He has done two there and both are very good.) That interest was and remains mostly related to my "other cancer", PCa. Since it is as yet unclear if, in addition to extending the life of normal cells, senolytics might also do that for some types of cancer cells, I became a bit cautious. However, I do know of an MD with PCa who is fully on-board with the use of rapamyacin, quercetin, fisetin, pterostilbene, and resveratrol. His current protocol calls for high once-a-month dosages (hit and run), as there is evidence that low dosages may act as a cancer agonist, while high doses act to clear out accumulating "zombies" and defective cells, like cancer. Minus the rapamyacin, I am now doing something similar, expecting to gain some clearing of defective calls that would prove beneficial to both cancers.
Good luck to you - and BTW, I wouldn't worry much about your command of English!
Stay Well - Ciao, Capt'n cujoe
PS As for intermittent-fasting/time-restricted eating, Valter Longo (Fasting Mimicking Diet) is a leader in research on the metabolic benefits of fasting. We don't have to look very far back in evolutionary time to see that scarcity of food (and, thus, forced fasting) was a regular occurrence in life. Similar to senolytics, fasting provides a clearing of senescent cells along with many other metabolic benefits . . . and we haven't even gotten to the many benefits of exercise . . .
Fascinating! Do you have any idea what is considered a high (monthly) dose, or any idea how I can find out what is so considered, as I have been taking these supplements but not at some super high dose level.
It'll take me a few days to track that down, but i'll get back to you later.
Oh, thanks so much!
Vlaminck - see my recent reply to your request for more info - posted to spare75 main post. It should at/near the bottom.
In these Podcast Notes, Peter mentioned he’s been taking 5 mg of rapamycin for the last 3 months (he doesn’t specify how often, but it sounds like every 4-7 days)
podcastnotes.org/high-inten...
Thank you for the article. Interesting to read but boy, this fellow must spend every waking moment focused on his health. That is part of the balance I guess we all must weigh, how much time in our day to spend focused on this stuff, and how much to forget it and just to try to live healthy, maybe take some basic nutriceuticals (quercetin?) and multivitamins, oils, etc. Plus, so much of this is based on suppositions as he admits re autophagy. But the 4-7 days idea by someone this into the weeds is useful, given the prior article about high doses once a month, since I've been basically an every day or two person.
Interesting. However I do wonder about this treatment. I have type II diabetes. I have been taking 500 mg of metformin for a long time. Whatever might be said please remember that the primary purpose of metformin is for type II diabetes. I take 500 mg of metformin with my evening dinner. I record my glucose daily. One must watch out for hypoglycemia.....feeling faint, heart racing, tiredness. If that happens you need to have some sugar....maybe orange juice or a glucose pill. I wonder if one does not have type II diabetes and takes this drug what are the possible reactions and how would they be handled? BTW I was diagnosed with CLL 5 years ago and am W&W. My A1C usually stays below 6 which is optimum.
I too take metformin, for Type 2 diabetes, I have been taking it for nearly 25 years now, 500mg morning and night. I know it is also used to treat polycystic ovaries in women of all ages regardless of whether they are diabetic. I don't know how it works, for that. I am coming up to 5 years W&W, no idea if metformin is linked to that in any way.
I never heard about this combination but thank you for bringing it to my attention. Looks like another rabbit hole I can happily dive into. Fasting - by all means, I've been doing it for a long time and feel no detrimental effects. Quite the contrary. The other two agents I have to check out.
Since I started intermittent fasting, about 2 1/2 years ago, I lost about 20 pounds and my WBC has improved since then. On my last blood check about a month ago, the total WBC went below 10,000, this is the lowest number since I was diagnosed in 2004. I am still in W&W, mutated. I don’t know if the intermittent fasting was the reason for my low WBC, but it obviously didn’t have any negative implications for my CLL. For me, the 16/8 schedule works well with my lifestyle, fast for 16 every night and feed on an 8 hour window. I have two meals a day and avoid snacks in between meals. I take allopurinol to keep my Uric Acid in check. My oncologist supports my protocol, and he indicated that my body eliminates more white blood cells that it produces for some unknown reason. That’s why I need to take the allopurinol. I would strongly advise anyone to check with their doctor before embarking on an intermittent fasting protocol. Peace 🙏
Those are great results! Very motivating. Unless one is diabetic, I would advise what Mr. Nike said: Just Do It! 😁 Never mind the naysayers. Doctors or else.
Please note that you need to track your absolute lymphocyte count, not your WBC, to get a more accurate measure of what is happening to your CLL tumour load in your blood. Otherwise it can be changes in your other white blood cell types, usually your neutrophil count, that may be responsible for a fall in your WBC. (What was your highest and lowest absolute lymphocyte count? A WBC of around 10,000 is really not that high when you have CLL and seriously, variations in your neutrophil count and lymphocytes, including quite typical changes in your CLL count, can be responsible for what you report).
Also, your lymphocyte count is the total of your good B lymphocytes, CLL lymphocytes, helper T cells, cytotoxic T cells and Natural Killer cells. CLL typically causes an increase in your cytotoxic T cells. In my case, that increase has persisted for 3 years after the start of treatment. You need a special (immunophenotyping) blood test to tease apart the contribution of the different lymphocyte types to the total lymphocyte count, including the contribution to that count of your monoclonal B cell population, that is your CLL tumour load in your blood. Finally, you haven't determined whether your intermittent fasting might be changing the distribution of your CLL tumour load between your blood and your lymphatic system and bone marrow. CLL cells engage in complex signalling with their environment in the lymph nodes (including the spleen) and bone marrow to support their survival. What will be very interesting to know, is whether intermittent fasting affects that process. For you to state that "My oncologist supports my protocol, and he indicated that my body eliminates more white blood cells that it produces for some unknown reason. That’s why I need to take the allopurinol." implies that your CLL cells are undergoing apoptosis at a higher rate than normal. I hope that's the case, but from what I've read, some caution is needed before we can be sure that CLL can be slowed by intermittent fasting. Extraordinary claims require greater evidence and you also are IGHV mutated, where this type of variation in your ALC and hence your WBC, is more typical. Remember, CLL specialists don't particularly worry about doubling time of the CLL tumour load in the blood until the lymphocyte count (not the WBC) exceeds 30,000, because with a lymphocyte count below 30,000, there is a great deal of noise in the count due to variations in all of the contributing factors - and that's before including the changes in 4 other white blood cell types due to infections, allergies and just natural variations.
Sorry to come across as negative, but I've seen similar claims for other attempts to slow CLL progression and sadly, they ended up being due to inadequate reporting. 
Neil
Absolutely, I really can’t claim that’s the intermittent fasting that helped control my blood counts. It could be due to other factors that I don’t really know… Regarding the other counts they were as follows. WBC 8.5, RBC 5.1, Neut 3.1, Lymph 4.9, PLT 235, HGB 16, HCT 49. The Lymphocytes were 13.1 about 5 years ago, or 88%, now they are 57.5%. What’s important to me is that they are going on the right direction… As I said, I don’t claim the IF is the reason for my improvement, it just makes me feel better and with more energy. Peace 🙏
Yes indeed, I was very surprised… I can’t say it was because of the intermittent fasting, but I am certain it didn’t hurt… my numbers never been this low in 18 years…
My takeaway from this is that a good old water fast in and itself is enough and does not need to be coupled with rapamycin and metformin. For those who cannot fast for one reason or another perhaps a fasting mimicking diet adhered to for five days coupled with rapamycin and metformin could be a suitable substitute and perhaps could achieve similar results. But I have my doubts. Who knows what adaptation mechanisms other than the ones we know about does fasting trigger. The reaction of the body to a good old water fast is complex. Protein sparing mechanisms and other stuff comes to mind. So I think that there is no need to pour gasoline (metformin and rapamycin) on the fire. Just keep it going and feed it with twigs (not eating) 🙂. I'd probably run into problems trying to secure prescriptions for these drugs not to mention then having to think about what the correct dosages are and having to pay for them. All these problems fall away with a simple fast. Plus it's one up to the food industry and saving the planet at the same time 😁
Doubt you would be able to find a reputable CLL specialist to prescribe this regimen. Rapamycin for lack of a better word, is a bad a— medication with strong immune suppressing properties. Additionally, some bad side effects such as elevated blood sugar, hence metformin which has its own side effects. Additionally, rapa results in poor wound healing and increased infection risk.
Personally, I would rather stay on watch and wait, especially at stage zero. Or if need treatment, would rather go with one of the basically miracle drugs such as BTK inhibitors. I call them miracle drugs because, just 10 years ago people with CLL did not have many treatment options.
spare75 & Vlaminck
This was put together as a reply to Vlaminck's request for more info on senolytics. It has taken me a bit longer to get to it, so I am replying to the main poster, spare 75, so that others interested in this topic can benefit. The latter references are recent posts done at HU's Fight Prostate Cancer. The links below are not in any specific order, but all are recent papers focused on cellular senescence.
This first paper is a good primer on cellular senescence, including the processes involved and the targets for interventions.
Cellular senescence: the good, the bad and the unknown
ncbi.nlm.nih.gov/pmc/articl...
This introduction to a recent issue of Mechanisms of Aging and Development (the science of aging now has its own journal) outlines the contents of an issue dedicated to senolytics and cellular senescence. It was edited by two researchers from the Department of Physiology and Biomedical Engineering at the Mayo Clinic. Some of the articles listed are behind paywalls, but others are full access. The References section indicates which are "PMC free" articles.
Mechanisms of Ageing and Development,
ncbi.nlm.nih.gov/pmc/articl...
And for a very deep dive into the science of cellular senescence, here is a long, technical overview paper from earlier this year. It was done by researchers at the Institute of Molecular and Translational Medicine at Palacky University in the Czech Republic. Pretty deep, but very comprehensive. (I have provided a graphic from this paper as an attachment that you might find useful.)
Cellular Senescence: Molecular Targets, Biomarkers, and Senolytic Drugs, Internationa Journal of Molecular Science, Published online 2022 Apr 10
ncbi.nlm.nih.gov/pmc/articl...
Here is an article by one of the doctors mentioned in the Men's Health Article:
Anti-aging: senolytics or gerostatics (unconventional view), Oncotarget, Mikhail V. Blagosklonny, Published online 2021 Aug 31,
The story of the discovery of rapamycin is a true accidental miracle, as it was the result of a researcher unintentionally deciding to return with soil samples from a failed research at Easter Island. This article from 2019 in Men's Health is a good overview of Rapamycin. One major consideration for its use by CLL patients is its dampening effect on the immune function - after all, it is a drug that was developed to do just that in organ transplants. (Along with the possible life extending benefit to cancer cells, that was the other reason, esp. in our time of COVID, that I became less enthusiastic about the deep end of the synolytics pool, i.e., rapamycin, dasatinib, etc.)
This Obscure, Potentially Dangerous Drug Could Stop Aging: Is rapamycin a miracle drug? Or is it just killing men slowly?, By Michael Easter, Published: Jul 19, 2019
menshealth.com/health/a2844...
**********************************************
You might also find some useful insights by reading through these Posts at HU's Fight Prostate Cancer forum, esp. the links therein. None of these are "locked", so you should be able to view them without adding FPC to your HU "My hub".
The first describes a possible bi-polar action of senolytics based on tissue types and hints at the "hit & run" approach I mentioned in my earlier reply.
Just in time for Halloween: Not so fast when zapping all those senescent Zombie Cells, as some might actually be your friends. - cujoe•2 months ago•2 Replies
healthunlocked.com/fight-pr....
And this is an earlier post that is specific to cellular senescence and discusses possible drug+supplement combos and dosage schedules.
PCa Heterogenity and cellular senescence - new info on the nature of 'The Beast" - cujoe•2 months ago•15 Replies
healthunlocked.com/fight-pr...
Dasatinib and Rapamycin are frequently mentioned as the more powerful senolytic agents to use, but as both require scripts, I am having to go with the supplements for the time being.
Lots to unpack in the above, but in approaching unproven treatment options, caution is always advisable. Also, of primary importance would be the possible interactions (+ or -) with any current treatment programs. Tread lightly - or wait for further evidence of efficacy.
Hope this helps broaden your understanding of the subject. Best of Luck To You Both & Happy Holidays.
Keep It Safe & Well, Ciao Captain K9
Wow, Cujoe, you remembered! Thank you so much. Must say that this is a huge compilation of (slightly over-my-head in parts) info! About this hit and run approach, I am wondering -- would the hit and run approach apply also to intermittent fasting? -- meaning that it could be bad to try to trigger fasting's senolytic effects every day rather than every few weeks, etc? Or would the reasoning in these articles so far as I understood them apply differently to drugs/supplements? After all, the fasting provides relief to a whole part of our system. And where would reservatrol come in, since it has been touted for supposedly producing the senolytic effects of fasting (all to different degrees, of course). No red wine every day, just gallons every few weeks? Just some thoughts. Haven't totally digested all of this info (not even just that which I can understand) but will be trying to do so.
That's a darn fine question - and I don't remember ever seeing it tested? I'm not the sort who sticks with a rigid routine, so some days I time-restrict my eating and others, not so much. I also have started a three-day (minimum) "water-only" fast and will expect to do one every quarter or so. (*) Maybe that sort of extended fasting would qualify as a "hit & run" technique. There is good clinical research on extended water-only fasting at the TrueNorth Clinic in Santa Rosa, CA. Here is a link to the Water-only Fasting info page at their website:
healthpromoting.com/water-o...
One of the advantages that we all gain from some sort of fasting is a sense of disciplinary control over our native eating urges. With all the food product manufactures pulling at our sensory levers, the notion that you can regularly go for even 15 hours without stuffing some sort of foodstuff in your mouth can be a liberating experience. Make it to three days and it makes an 18/6 routine look easy.
Eat Well to Be Well,
Ciao - Capt'n K9
(*) It is usually recommended that fasting beyond 3 to 5 days should be done under medical supervision.
Impressive, cujoe. The only time I've gone one 24-hr water only (well, unsweetened tea also) was the day before colonoscopy. Felt proud of myself, but not sure I have the will power for a 3-day fast. When you say once a quarter, assume you mean every three months? I've been always doing at least 12/12, but today second day doing 15/9. May not be that effective, but doesn't seem it could hurt! Not sure how to do more since I take some meds and supplements and don't want to do on empty stomach!
Have a great holiday season. Deborah
Deborah - Getting a diet and lifestyle that works (and we can comfortable/enjoyably live with) is a perpetual work-in-progress for each of us. The appeal to me personally of fasting (in any form) is that it should provide equal benefits to rapamycin, without any of the risks of a pharma product; i.e., Nature doing what she does best - by connecting with bio/metabolic functions that were probably at work on a regular basis in our evolutionary history.
Multi-day fasting sounds difficult, but once you eliminate all the food cues and make it past the first day, it is not really that hard to sustain. In fact, once your digestive system is cleared, you can actually feel an energy boost - as you no longer are using it to digest food. (15-30% of our calories go to just running our digestive system.) That said, I live solo and imagine that having a partner who continues to eat while I try to fast, might not work out so well. It would be a bit like try to quit smoking with a pack-a-day smoker in the house.
All, of course, JMHO. Everyone should do their own research and reach their own conclusions. With the Holidays upon us, we all need to cut ourselves some slack and enjoy the shared joys of the communion with family and friends around a table filled with seasonal delights.
Make it special, whatever you do! Ciao - Capt'n cuJoe
CLL & Fasting in Ramadan
Newly diagnosed too, stage 0
Stage 1/2 CLL and no follow-up visits?
Vaccinations - advisability of having Shingles vaccination at stage 0?
