Rapamycin Cycling (Time Off) - Who Is Right?

#61

Still, searching for that sweet spot. I have been doing 1 mg/day for 7 days and 7 days off.

I am still having trouble keeping my glucose below the high normal range.
Currently, I am taking 500 mg of metformin with rapamycin, a 50 mg acarbose tablets
before dinner. Also, I just added Linagliptin 5mg tablets four days ago morning and evening. “Linagliptin helps to control blood sugar levels by increasing substances in the body that make the pancreas release more insulin.” It is also sometimes combined with metformin in a single pill. So, far I have seen zero effect. Maybe it is still too soon to tell or I need to increase the dose. I have tried Jardiance Empagliflozin, also to no noticeable effect. Perhaps it is just because I am old.

The only insulin-sensitizing drugs that I can find have serious side effects and most of them have been banned in some countries.

So, my next plan is to reduce my rapamycin intake to 1 mg/day for 5 days then 9 days off.
I prefer to try this rather than increase my anti-diabetic drug intake.

As I have commented before: I don’t believe it is okay to have markers outside of the normal range even if you are taking rapamycin. Specifically, I believe that blood glucose should not be above normal. Glycation, from my readings, appears to be one of the most important things to reduce to prolong life span"

"Glycation, a deleterious form of post-translational modification of macromolecules has been linked to diseases such as diabetes, cataract, Alzheimer’s, dialysis related amyloidosis (DRA), atherosclerosis and Parkinson’s as well as physiological aging

“Hyperglycemia increases the glycation process, and is especially apparent in insulin independent tissues such as red blood cells, peripheral nerve tissue cells, endothelial cells, eye lens cells, and kidney cells”

“There is evidence to indicate that controlling hyperglycemia by antidiabetic biguanides prolongs life span in experimental animals. Caloric restriction, which appears to prolong life span by bringing about mild hypoglycemia and increased insulin sensitivity further strengthens the idea that glucose via glycation is the primary damaging molecule.”

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3257625/#:~:text=Hyperglycemia%20increases%20the%20glycation%20process,and%20kidney%20cells%20[44].

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#62

1 mg/day for 5 days then 9 days off, that’s exactly my dosage at the moment. So far, with this schedule, I’m feeling better and at the last blood test, my kidney function recovered (that was my main problem with weekly pulse dosing). Blood sugar levels are better too, but they’ve never been borderline. I’m younger (52), but I have other health problems, particularly heart problems

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#63

Hello everyone, newbie here. I watched an interview with Dr. Kaeberlein in which he mentioned taking it once weekly for 12 weeks. It’s on YouTube. Also, I guess it depends on each person’s goals. Younger women with infertility issues are told to use it for a few weeks to improve oocyte quality, but stop when trying to conceive for several reasons. From my understanding, Dr. Kaeberlein got all he needed from Rapa in 12 weeks, so he cycles. I just started back in August, and I’m at 3mg/week, and I’m hoping it’s enough for a 5ft, 109 lbs person. I’m considering doing the 12 week cycle suggested by Dr. Kaeberlein. I have a large number of Bosniak type II cysts in my kidneys, 1 nodule in my thyroid, 2 cysts in my liver, and I have medium size uterine fibroids, so I’m actually taking it in hopes that by decreasing mTOR may help keep my cysts from increasing in both volume and also in number. I just hope I’m on the right track.

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#64

That’s about my size (5’1/103) and I’ve been taking 3mg/weekly fwiw.

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#65

@desertshores what is your glucose control like if you’re not taking Rapa?

#66

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#67

That was off Rapa? On any Metformin or other glucose lowering medication?

#68

Yes, that was off rapa, but I have been taking metformin for many years as it was noted long ago to possibly have life extension properties.

#69

Sure. AFAIK the negative effects of rapamycin on insulin sensitivity are mainly caused by mTORC2 inhibition so that would probably be the best proxy here. Lipids might also be a proxy for mTORC2 but it’s not as clear. To test your insulin sensitivity it’s not enough to just test your fasting glucose and HbA1c. Although you will often see either fasting glucose or HbA1c get worse when your insulin sensitivity gets worse, it’s possible to experience a large change in insulin sensitivity without fasting glucose or HbA1c changing significantly. To get a better idea of your insulin sensitivity it’s important to measure insulin levels with glucose. For this I suggest getting a HOMA-ir test, which is simply a test of your fasting insulin and fasting glucose to calculate the HOMA index. If your HOMA index gets worse, you probably have poorer insulin sensitivity than before. Fasting glucose and HbA1c are good to measure also to give additional info but insulin is most important.

I’m not as sure about changes in lipids, that is, whether the worsening of lipids experienced by some people taking rapamycin is caused mainly by mTORC1, mTORC2 or both. It’s not as clear given the studies I have seen. But if your lipids get worse after taking rapamycin for a month or more, but not immediately after taking it (say in the first week) then that’s a good indication that mTORC2 inhibition is causing it. Basically any changes in insulin sensitivity or lipids that don’t occur very quickly but occur gradually over several weeks are likely caused mainly by mTORC2 inhibition while changes that occur in the first week after taking a dose of rapamycin are more likely caused by mTORC1 inhibition. This is because mTORC2 takes longer to be inhibited by rapamycin than mTORC1 so anything that changes in the longer term but not in the short term would be an indicator of changes caused by mTORC2 inhibition as opposed to mTORC1 inhibition.

As far as lipids go, the most basic test would be to test total cholesterol, LDL, HDL and triglycerides and see if they get worse. Optimally you would also test ApoB.

I doubt that’s a good sign of mTORC2 inhibition. The slowdown of wound healing is probably more a result of mTORC1 inhibition not mTORC2 inhibition since mTORC1 activation is necessary for wounds to heal fast. But it could also be both. In any case, that’s not an indicator that is particularly specific for mTORC2.

Yes. As I said above, a HOMA-ir test is good. Even better (if you can get that test) would be to take an oral glucose tolerance test with insulin measured at all time points. That would give you a very good indication of your insulin sensitivity. But that test is more time consuming and requires about four blood draws over 2 hours.

I don’t think the timing with respect to your dosing schedule matters much although I would probably avoid doing tests right after taking rapamycin. So I would suggest taking it maybe in the middle or end of your off week. The most important thing with respect to timing here is that you want to get your baseline values before taking rapamycin and then to test again after taking it for several weeks, maybe 4 weeks at least. So if you’re currently taking rapamycin you could stop taking it for a month or two, that should allow mTORC2 to get back to normal. Then you test the baseline. Then you start rapamycin and then 4 or more weeks later you test again to see if things have changed. FYI I actually did this test myself and discovered that I seem to be one of the lucky ones that is not sensitive to adverse effects on insulin sensitivity or lipids. I hope this helps.

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#70

Thank you for taking the time to respond. I appreciate it.
FWIW: I find it much easier to control my lipids while taking rapamycin than my glucose levels.
Probably due mainly to old age.

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#71

I took Rapa for about 3mths… mostly twice a week… unless I had functions or sport… as it gave me diarrhea, and I couldn’t risk being too far away… I have recently stopped… as I have an amazing immune/recovery system… but noticed if I cut myself it took longtime heal, normally I’d brush it off and it was gone in a couple of days … last time took two weeks…
I had been using it really for aches n pains, knees n feet. But no improvement… good luck

#72

That is a very frequent dosing of rapamycin (most of the people take it once a week or once every two weeks). And what is the dose you are taking?

When you get diarrhea with rapamycin it usually when you are taking very high levels. Have you reviewed the dosing thread: What is the Rapamycin Dose / Dosage for Anti-Aging or Longevity?

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#73

2 Rapa, one Metforin

#74

@Mary you Rapa taking is a tad concerning. You’re taking it twice a week, and for aches and pains? Maybe take some time to read through this great forum. As mentioned above, once a week is the current consensus.

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#75

what are your trend line on HBA1C?

#76

In my case, it seems dose-dependent on rapamycin, a lower dose means lower HBA1C

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#77

I wouldn’t really bother, but trying for pain… would rather have stem cells. But of course, even though they’ve used them for 25 years in Germany… it’s not going to be used properly here in Australia unless you pay thousands, and private health say it’s cosmetic surgery … obviously this doesn’t apply to footballers, or top athletes… which is pathetic,

#78

I’m just a person self medicating. I’m not a doctor.

I think it’s safe to say no one “knows” the answer to your question, because no one has done a proper study.

BTW - I’m taking 5 mg once a week (1 mg for every 30 lbs of body weight) and I’m on a 3 months on, one month off cycle.

According to the limited evidence I’ve found, there’s a concern that long term uninterrupted use of Rapamycin will down regulate mTor2 and this is NOT thought to be a good thing.

That’s why I’m taking a break every 3 months for a month and taking a conservative dose when I take the drug.

The evidence in favor of Rapamycin from mouse studies is based on relatively short term use. To my knowledge no one has given an animal an interrupted dosing regiment for a very long period of time, e.g years.

Taking a break might not negatively impact your desired outcome and it may help.

At this point everyone is guessing, so a bit of caution is probably warranted.

In the end, this is a personal risk/reward calculation based on very limited data.

Do you want to bet the farm on Rapamycin having absolutely no down side?

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#79

You make a good point about mTORC2 activation potentially requiring the concentration to be above some threshold that’s higher than 10 nM. That said, I disagree with your recommendation of measuring the level after 3 hours to try to catch the peak. I think it’s far better to measure at 24 or 48 hours, preferably 48 hours. My reasons for this are the following:

  1. The peak is so short lived that you won’t catch it accurately with a blood test. It’s a useful measurement but you could easily be off by a factor of 2 or more. Measuring at 24 or 48 hours you’ll get much more stable levels and a much better idea of the level you’re being exposed to for several hours.
  2. If rapamycin is inhibiting mTORC2 significantly at concentrations somewhere above 10 nM, it’s unlikely to cause much of an inhibition in just a short time unless it’s way above that. 1000 nM for 24 hours is a lot. If you were to catch a peak of say 20 nM after ingesting rapamycin, you would only be above 10 nM for a very short time, perhaps just 10-20 minutes. The fact that such concentrations might cause significant mTORC2 inhibition with 24 hour exposure in cell culture doesn’t mean they are likely to cause a significant inhibition with a much shorter exposure. Unless of course rapamycin causes some long term irreversible inhibition of mTORC2, but I have seen no evidence of that. This is a major reason why I think peak levels tell you very little about potential mTORC2 inhibition.
  3. If you test your level at 48 hours and get close to 10 nM, then you can be pretty certain (by extrapolating backwards from the pharmacological curves for rapamycin bioavailbility after intake in humans) that mabe you had 5-10 hours where you were above 10 nM. 5-10 hour exposure is more likely to be enough to cause some significant effects on mTORC2 and therefore is much more useful information than knowing whether you were above 10 nM for some 20 minutes around the peak.
  4. Last but not least, who is to say the peak is what’s important? If we extrapolate doses from animal longevity studies, they measure rapamycin levels after continuous dosing in the diet, not some peak levels after empty stomach dosing. Blood levels measured after 48 hours will give you a very good idea of what blood level you are being exposed to for a few days, which can then be compared to the animal studies and between humans. Peak levels tell you very little in this respect.

My opinion is that it’s most valuable to measure blood levels at 48 hours. If you measure at two time points, measure at 96 hours also. With that information you can calculate your half-life which will allow you to estimate your levels at other time points. Trying to catch and measure the peak is not that important, but can be interesting as an extra data point if people can’t’ test at 24 or 48 hours.

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#80

Would be more useful if we have some boomarks to gauge the dose calculations. Blood level of rapamycin is meaningless without the context of the said person’s own pathology?