T Cells are matured in the thymus (the very reason why they are called T cells).
That’s why thymus rejuvenation will be necessary/important.
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Yes, as destrider has pointed out, antioxidants and B vitamins can both prevent and promote.
More specifically, rapamycin and its effects on autophagy.
From the very knowledgeable Agingdoc
At some low doses rapa can be neuro protective , but the opposite at high doses, all dependent on degrees of autophagy.
There was a post on this thread showing the same problem with cancer.
Do I know that rapamycin can promote metastasis? Absolutely not! But I’m now considering the possibility enough to rethink the whole matter and reread the pertinent literature.
It’s certainly supporting my decision to remain at low dosing for the past 6 years.
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Well, as a doctor I’ve been an ardent supporter of Blagosklonny and rapamycin over the years,much to the derision faced by other doctors ,but this has caused me to stop and rethink. It’s reason to re-examine the evidence regarding rapamycin and cancer prevention. It would certainly be nice to have some decent human studies.
I’ve openly admitted that we don’t yet know the exact details, so I’m more than willing to change my view once the details emerge. After all, I’ve been on the drug uninterrupted for 6 years.
We need to be moved by whatever evidence is available at the moment. This isn’t a cult of personality. We should always remember Feynman when he essentially said:
Do not fool yourself- and you’re the easiest person for you to fool.
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I don’t think of the Soviet Union as a place that made a lot of effort to contain toxins.
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I see the added benefits of metformin as both an mTORC1 and AKT inhibitor
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Yes, but the meta analysis done several years later on over 20 RCT’s showed that the decrease in cancer incidence was primarily the rather benign non melanoma skin cancers, and even that may have been attributable to just substituting for cyclosporine. No effect on other cancer types.
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Im pretty sure I read in the past that the lifespan of Russians is lower then many other countries. Might have something to do with their love of Vodka. LOL Did find this: Life expectancy is the average age of death in each country. The global average is 72.8 years. Russia’s life expectancy is 69 against a global average is 72.8 years . Fairly sure its higher in US but since Covid the US age has dropped some. High Obesity in this country isn’t helping extend lives.
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Hello everyone, I’m new to the forum and have been lurking for a few months.
I’m not a physician but to me it looks like there are a lot of issues with this meta analysis. It would take me a significant amount of time to go through all the data but here are my biggest concerns:
- Most RCTs used in the meta analysis have extremely short maximum followups which is not good for cancer incidence tracking.
- RCTs that had longer than 2 year maximum followup are a mess (only 2 5). It’s really hard to ascertain anything regarding the efficacy of sirolimus. The longest RCT was 5 years by Lebranchu (2012) participants were taking cyclosporin + mycophenolate mofenil (MMF) for 12 weeks before either opting to continue taking it or to switch to sirolimus + MMF. The problem there is that you are continuing to take an immunosuppresant.
- The best observational study tracks for 14 years (Yanik, 2015). If we dig further into that observational study, there is some solid information that points to cancer incidence reduction. There is a clear 22% lower chance of getting all cancers (more so in lung, kidney and breast) excluding prostate cancer. The most surprising thing in this observational study was that a calcineurin inhibitor (CNI) was used by 72% of participants in the sirolimus-exposed group and 89% by the sirolimus-unexposed group. That is very telling by itself.
- It would be interesting to go over the dosage regimens to determine how much sirolimus participants were taking compared to their immunosuppresants. If whole blood trough levels of sirolimus were available that would also be interesting to go over.
- Participants involved in the RCTs and observational studies are all over (different sizes among groups). Some RCTs also have very small groups.
- Were participants taking sirolimus taking enough to inhibit mTORC2?
- Could combining other immunosuppresant drugs with sirolimus further inhibit mTORC2?
That meta analysis basically reveals nothing due to the large number of unknown variables. I’m still going through all the data. I’d also like to look at more recent and ongoing studies. However, it does seem that sirolimus may have anti-cancer and anti-proliferative properties that helped patients reduce cancer incidence while on immunosupressants.
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Thx. for more in depth look. I was just reading the study and had exactly the same questions and it is good to read your view.
I also understand that rapamycin MAY promote cancer. But using the word may in is too broad for a serious discussion on the matter of rapamycin IMO as it is remaining really speculative. It is the same as saying regular exercise may be bad for longevity. @rivasp12 and @DeStrider it would be good not to just speculate but discuss the possible mechanism that could promote or make cancer worse, more aggressive etc. without this we are just staying in the field of fear and feeling of threat maybe even paranoia. I understand that doctors need to act by “first do no harm” principle and caution is part of medical thinking and that using rapamycin on patients for preventative reasons poses ethical questions that can’t be answered unambiguously ATM or probably any moment.
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The best way, IMHO, to put this worry to bed is by talking to Dr. Green. He has a large cohort of patients on Rapa and could best gauge any increase in the cancer rate among his patients compared to the general population.
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This is my best guess as to why Rapamycin may promote cancer growth.
Rapamycin increases blood sugar levels. Higher blood sugar levels help cancer grow. Large doses of Rapamycin causes very high levels of blood sugar and IGF1. Cancer would love this. ITP results seem to support this with mice on Rapa and glucose control living longest. Remember mice mostly die from cancer.
Solution - Keep blood sugars in check with Acarbose, Canagliflozin and Metformin. Especially when taking Rapamycin. And probably avoid large doses of Rapamycin.
Russia has a lower than normal cancer rate. But this is deceptive as many Russians die of cardio events before they can develop cancer. You will find the countries with the lowest cancer rates also have the lowest life expectancy. But a Russian male should have a life expectancy just over 71. Dr. B drew the short stick and being an early Rapa adopter doesn’t seem to have helped him. 
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When it comes to delaying ageing and preserving health, I personally I think that metabolic health – caridovascular health is the first thing to focus on. This since, dysfunctions in that area is the main cause of early death. But then there is role for Rapamycin. The dog study will lead the way in translating animal studies to the complex human biology.
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Point well taken but I wouldn’t say that the analysis reveals Nothing. We’re grasping at straws because straws are all we have. We don’t have a good study on cancer prevention in otherwise healthy people using intermittent rapamycin.
The authors concluded that taking the studies as a whole, there’s no significant cancer reducing effects from rapamycin except for skin. The studies aren’t perfect, but even imperfect studies on humans > mice.
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I’ve taken rapa for 6 years and have been one of its most ardent supporters on this site, so to accuse me of paranoia and fearmongering is absurd.
I don’t need to know exact mechanisms of action to be concerned about a drug’s safety. I admit that we don’t yet have the details and that rapamycin may still be cancer protective, at least at some unknown dosage. But I’m not certain and I’m not married to it.
It’s smart to reevaluate it with each new bit of information- especially human information. It’s reckless not to.
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Being careful is the name of the game at this point.
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This is a good theory but remember that mice consistently get a longevity effect from rapamycin alone, even at very high doses.
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This latest article by Blagosklonny on protecting normal cells from the effects of chemotherapy reveals once again his incredible intellect.
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You need not be so defensive, I am only curious what ideas you have, why would or could be that rapamycin make cancer worse.
We all know that with an exception of few cancers (like smoking and lung cancer etc.) you get cancer mostly by chance. So in a way there is no prevention possible for many cancers other than spot it early before it spreads.
Rapamycin is used as a cancer medicine, it reduces new cell growth, it reduces some interleukins that are vital in spreading and growing of cancers. Studies show that in some animal models rapamycin is cancer protective and human studies don’t show at least the opposite that using rapamycin would make cancers worse. If anything they still show some degree of cancer protection… so I am just curious why are you thinking the opposite or proposing that in certain circumstances rapamycin could make cancer worse.
Because as I understand it may help and it worst case would not make much difference. So if you, that I like reading here and respect your opinion has this new ideas I would like to understand where is the fear coming from also to re-evaluate my decision to use rapamycin.
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Sorry, I tend to get a little fired up at times.
Take a close look at this study out of Taiwan published in Plos one. This was previously posted.
The authors acknowledge that rapamycin has been shown to inhibit the growth of skin, colon, and breast cancer. However, “ possible side effects such as promotion of tumor metastasis are serious concerns and this has not been thoroughly investigated to date”.
As for mechanism, “ for tumor cell invasion, regulatory T cells, Tregs, are known to play a key role in the metastatic escape of cancer cells…… rapa can enhance the expansion of Tregs…. which may promote the metastasis of mammary cancer in mice”.
More concerning:
A human database of cancer patients in Taiwan over 7 years showed a 2.79 fold Increase in cancer incidence in rapamycin users.! Granted, most were of course transplant patients. But still. Not perfect, but worrisome.
So where are we
- Rapa increases longevity in mice.
- In humans rapa can elevate lipids and glucose levels.
- Some mice studies, but not all, lean towards cancer prevention.
- A Human meta analysis shows no real cancer protection.
- A Taiwan study shows an actual highly significant Increase in cancer incidence.
- The most public and prominent promoter of rapamycin for longevity and disease prevention,most notably cancer prevention, himself comes down with a very aggressive cancer after years of rapamycin usage.
Because of points 1 and 3 above, I was willing to downplay point 2 as perhaps not being of great clinical significance in the context of rapamycin.
But points 4, 5, and 6, on actual humans, makes me re-examine the benefit/ risk .
We don’t have the necessary studies on rapamycin regarding human cancer and longevity in otherwise healthy individuals on intermittent dosing.
But the studies that we do have, albeit imperfect, are concerning, and this Blagosklonny case has made me look at this with a new perspective.
I’m being very consistent here. I’ve repeatedly said that I’ll look for option B if there’s even a slight risk of a very severe illness from an intervention. Maybe low dosing is option B. I don’t know yet.
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Іnhibition of mTORC1 with the mTOR inhibitor rapamycin may lead to an induction of Akt phosphorylation in cancer cells via mTORC2 activation.
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