#61

I don’t think whether they are essential or not really matters here.

Let’s use Astaxanthin as an example. We know that it isn’t essential, but it looks like it improves our health. Therefore, why would we benefit from purposely discontinuing it for a certain period of time? It seems logical to think that we benefit from it as long as we are taking it. I certainly don’t think stopping it and then re-starting it is going to be better than just taking it continuously.

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#62

you’re conflating fundamentally different biological systems. Circadian light cycling serves a specific regulatory function - entraining molecular clocks that coordinate cellular processes. This isn’t analogous to nutrient availability, not adaptive optimization. your hibernation example actually contradicts your thesis. these animals maintain steady vitamin D levels through endogenous synthesis precisely because stable concentrations are optimal. They’re not cycling, they’re maintaining homeostasis through alternative pathways. Fasting benefits stem from specific molecular mechanisms: AMPK activation, autophagy upregulation, metabolic switching. This isn’t intelligent pauses, it’s hormetic stress with defined dose-response curves. The core flaw is assuming evolutionary constraints represent optimal design. evolution satisfices for reproductive success under resource limitations, not longevity optimization under abundance. take the example of acarbose ITP study in mice, the consistent dosing maintained optimal glucose levels, which extended lifespan about 15 percent.If cycling acarbose had been superior, the mice would have lived even longer. They didn’t test that because pharmacologically it makes no sense - you’d get glucose spikes during off-periods, which accelerates aging through glycation and oxidative stress & mice will age faster. Same logic applies to rapamycin. If mTOR hyperactivation drives aging, and rapamycin inhibits mTOR, then maintaining consistent inhibition within the therapeutic window should be superior to cycling. The cycling approach would allow periodic mTOR reactivation - exactly what we are trying to prevent

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#63

Jack, what I’m doing here is only telling you that from all the research done till this day, we are still only scratching the surface. We just don’t know yet. If you “believe” in favor of chronically ingesting the same molecule, rain or shine: OK.

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#64

Luke, if some protocol is doing good for you, keep doing it.
Pauses may or may not benefit systems and what can work for someone may not work for others.
We just don’t know yet to affirm things like there’s already solid evidence or proof… humbleness is needed, which biology is very good for that.

#65

Can you mention how much rapa you take and on what schedule? I’ve been taking 4mg a week with a high-fat meal (heavy cream in coffee), as I’m concerned about not getting down to zero before taking the next dose. A few times I’ve taken up to 6mg with the coffee, but the following week I take 2mg so I’m for sure zero’d out before the next week. (Every other week dosing gets too complicated for me as far as making a habit.)

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#66

Because I started later in life (80+ years), I take a larger dose than I would if I were younger.

Back when I began taking rapamycin, Dr. Blagosklonny was recommending taking the maximum dose that didn’t cause serious side effects.

My current regimen is as follows (once weekly dose): I drink 12 ounces of ruby red grapefruit juice with 10 mg of piperine two hours before taking 6 mg of rapamycin, which I have put into enteric-coated capsules. I take the capsules with an additional glass of grapefruit juice.

I hope that this regimen results in an effective dose of at least 12 mg. The effective dose falls within a wide range, ~12-30 mg. I am unsure about the effective dose because I have not measured it.

I plan to increase the dose to 10 mg with this regimen.

I have no discernible side effects from this dose. My lipids and glucose are under control.

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#67

I agree. I’ve never cycled supplements/drugs or recommended it. It makes no sense IMO. If you need to cycle it, you’re probably doing something wrong.

Yes but the solution to that is just to take it at a lower dose or less frequently. As an example, if you’re taking such a high dose weekly that it eventually results in considerable mTORC2 inhibition then instead of taking it weekly one month on and one month off, you can just take it all the time every two weeks. Taking too frequently and needing a break seems stupid when you can just take it less frequently and never need breaks.

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#68

I have been taking relatively high doses of rapamycin for over three years, and I have found no evidence that it is suppressing mTORC2 in me, at least in a statistically meaningful way based on my bloodwork for the last three years.

I found no credible evidence that rapamycin inhibits mTORC2 in any significant way through weekly intermittent dosing. Indeed, Dr. Blagosklonny didn’t think this a factor in his recommendations of high weekly dosing.
If anyone can furnish any credible evidence that weekly intermittent dosing suppresses mTORC2, I would like to see it.

Gemini:

“mTORC2 is resistant to acute, intermittent dosing of rapamycin. Most evidence points out that mTORC2 is mainly inhibited by chronic, continuous rapamycin exposure, rather than by high single or once-weekly doses.”

Ditto-Perplexity:

“mTORC2 is resistant to acute, intermittent dosing of rapamycin. Most evidence points out that mTORC2 is mainly inhibited by chronic, continuous rapamycin exposure, rather than by high single or once-weekly doses.”

DeepSeek:

"Once-weekly doses ≤10 mg are generally mTORC1-selective in humans, while daily dosing ≥1 mg/day often suppresses mTORC2

Consensus AI:

“It should be noted that although rapamycin does not exert acute effects on mTORC2, long-term treatment of some cell types with the drug has been shown to prevent mTORC2 assembly.”

"Rapamycin and mTOR kinase inhibitors - PMC

Healthspan Research Review | How to Navigate Dosing Rapamycin for Longevity and Anti-aging"

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#69

In most people taking typical weekly doses it doesn’t seem to inhibit mTORC2 much, but it definitely will inhibit it if the dose is high enough since with a high enough dose, you won’t get low through levels. We know that in some people taking it weekly it has effects that can be attributed to mTORC2 inhibition, but those are the minority.

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#70

“taking typical weekly doses it doesn’t seem to inhibit mTORC2 much, but it definitely will inhibit it if the dose is high enough”

I concur and have two biological markers showing this in a spike at heavy rapa use… then at reduction the graft shows a return to normal slowly over a period of 8 months.

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#71

Dr B unfortunately died of cancer. He was taking pretty high doses weekly.

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#72

While this may not apply to Rapamycin and whether or not it should be cycled, I do frequently opt in favor of cycling other substances or supplements. Here are the reasons that come to my mind:

Someone mentioned the idea of eating seasonal foods, for example, suggesting that we may be evolved to eat certain foods at certain times. I could imagine that to be true.

The other reason is receptor down regulation. When certain substances are abundant in our bodies, there are sometimes mechanisms to down regulate the necessary receptors thereby slowing the impact or inflow to the system. That could certainly be the case for certain supplements, I would think. This leads me to a more relaxed approach to what I take and a belief that cycling may be beneficial, in general.

Finally, cycling also allows me to evaluate and periodically reevaluate what is working. My system does change from time to time whereby a formerly ‘holy grail’ supplement gets relegated to the supplement drawer in favor of something different.

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#73

Rapamycin didn’t hasten his death. He was a lifelong heavy smoker. Jogging didn’t kill Jim Fixx; his underlying heart condition did. Taking supplements didn’t kill Durk Pearson. Nobody believes that rapamycin is a panacea for everything.
My age suggests that my chances of living longer diminish each year.
When I die, it will be because of some illness or accident, not because I took rapamycin.

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#74

[quote=“desertshores, post:73, topic:20551”]
Rapamycin didn’t hasten his death

We don’t know that. What if his extremely high dosage expedited it? Or contributed? We simply don’t know.

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#75

Rapamycin is used in chemotherapy treatments and is anti-cancer in general. Saying Rapamycin hastens cancer development is like saying drinking water hastens dehydration.

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#76

It goes without saying that it could not cause cancer, but the wrong dose (like too much.water) could be damaging. We all know that the dose is everything.

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#77

True, but I think his lifestyle was a more likely contributor to his death than rapamycin.

Is there any evidence that rapamycin causes brain cancer?
The most likely cause of his brain cancer, IMO, is an unfortunate case of cell mutation. It could have even been some random exposure to something.

Rapamycin would be far down my list of probable causes.

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#78

Could be random exposure, even like Chernobyl in 1986. Very unfortunate.

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#79

I’m not sure if you are aware, but Dr. B was diagnosed with cancer decades (I don’t recall the exact year) before he actually died of cancer, and he credits Rapamycin for not dying sooner.

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#80

In “My battle with cancer. Part 1,” published January 3, 2024, he revealed:

“a small vague mass in the lung was seen by X‑ray in the Summer of 1991, and it had changed very little eight years later. Therefore, it was decided to ignore it. … Subconsciously, I may have been anxious and suppressed any thoughts of the asymptomatic harmless mass. I never looked at any X‑rays until 2023.”

He was sure it was benign otherwise he wouldn’t had ignored it for so long. Something made it turn into malignancy unfortunately.

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