We need an easy way to measure mTORC1 and a drug that selectively targets it
Context is important. He is talking about higher intermittent dosing in the passage you highlighted.
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I think there is no paper about that. All we really have is an ITP result that intermittent dosing has nearly the same effect as a lifelong treatment.
This just highlights that context is important. Intermittent dosing shedule is not the problem.
However, I use intermittent high dose regime but that way:
3 or 6 month cycle
start at 6mg once a week
go up to 14mg for a short period
lowering dose slowly to 6mg/week
then stopping at the end of the cycle.
its just a try to see if it works out for me. I cant recommend it to others. In short: its about immunology and the blood brain barrier.
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Perhaps a daily dosage will off set the mTOR rebound cycle?
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This was also fairly well discussed in this thread: Doses and Schedules of Rapamycin for Longevity - Blagosklonny - #15 by scta123
There is no evidence.
The theory is worth thinking about, unfortunately we can not always apply logical thinking to the response of the body because we do not know all of the variables and feedback loops. Until I see any evidence it is just a theory.
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I put little weight into anything Blago writes. Inconsistent, speculative, and transparent in his desire to become the ‘authority’ on Rapamycin.
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All my reading indicates mTORC1 cannot be targeted without also eventually down regulating mTORC2, because C2 depends on C1.
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I dont understand why you’re thinking this. Writing blogarticles isnt the key to boost a scientific career (except you want to make your carreer end). Please feel free to go more in detail here.
If that were the logic, wouldn’t there be mTOR rebound after CR as well? Has anybody had side effects from fasting?
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There is no such paper as regards the kind of intermittent dosing Blagosklonny refers to here and that is practiced by most on this forum: taking a dose (in B’s paper, a high dose) once a week or so. The only ITP paper that approaches that is this report that “Exposure to Rapa [at triple the dose of the original ITP] for a 3-month period led to significant longevity benefit in males only. Protocols in which each month of Rapa treatment was followed by a month without Rapa exposure were also effective in both sexes, though this approach was less effective than continuous exposure in female mice.” Either three months of continuous dosing or alternate-month lifelong dosing are quite different from intermittent dosing in our sense.
The only true intermittent-dose rapamycin lifespan study is this one, and it showed very small life extension effects and only tested it in female mice, who typically benefit more than males.
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I don’t know, no one knows, cells know how to adapt to stress, they can’t be fooled by rapamycin)
when choosing a dose, I focus on my own spermatogenesis
After being on a plant based diet for 2 years, and switching to high protein and intense hypertrophy workouts (x3 resistance bands) I experienced very quick muscle gains. I think the workouts are great but some kind of rebound effect from the previous low protein diet is happening. Just a personal theory.
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You equate plant based with fasting? How many calories did you take while on plant-based? How many now?
You equate plant-based with low protein, therefore low athletic prowess? The people below are vegans.
Our top vegan athletes include:
- Timo Hildebrand (Soccer)
- Venus Williams (Tennis)
- Novak Djokovic (Tennis)
- Lewis Hamilton (F1)
- Serena Williams (Tennis)
- Arnold Schwarzenegger (Bodybuilding)
- Lawrence Okolie (Boxing)
- Fiona Oakes (Running)
- Andreas Kraniotakes (MMA)
- Carl Lewis (Track & Field)
- Patrik Baboumian (Power Sports)
- Benedikt Höwedes (Soccer)
- Dirk Nowitzki (Basketball)
- Johanna Jahnke (Rugby)
- Kendrick Farris (Weightlifting)
I am not vegan, nor an advocate of any diet. I subscribe to George Foreman’s see-food diet. I see food, I eat it (except pastries). Am not a foodie either - 5’10", 132 pounds. (Friends say I eat like a bird). I am just lazy to choose. I eat any cuisine.
My post was a reaction to Blagosklonny’s comment, quoted above, that intermittent rapamycin dosing may cause harm, due to mTORC rebound:
However, intermittent therapy may have some disadvantages. Such schedules include drug-free periods. During these periods, mTOR can be overactivated in compensation and may, in theory, cause acute harmful events. (I believe that rebound of mTOR in endothelial cells may increase thrombosis, arterial permeability and arterial spasm).
Your plant-based diet was long-term (2 years), not intermittent. So Blag’s comment would not apply to you. Assuming it applies, you suffered no harm, but gained muscle. So your N=1 experience, actually proves Blag’s belief is misplaced.
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Many here have benefitted from intermittent dosing. It is the intermittent high dosages that cause problems, as Agetron and desertshores have shared.
Between Blag’s theory and belief, and the experience of the members here, I put greater weight in the experiential data.
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I was referring to the rebound effect, I think it exists in biology. My example is my low-to-high protein diet. My diet for 2 years was typical of plant based diets, which tend to be lower protein, especially lower in leucine and methionine. My diet was quite low total protein (< 50g). It’s certainly possible to eat a high protein plant based diet and of course many athletes do, but typically your average vegan is not eating a high protein diet and neither did I. So switching to a high (>120g) protein diet was a big change for me. It’s all n=1, but my belief is that my body sucked up the protein quite well after the change and that’s why I was able to gain muscle so quickly. My body fat levels have not changed. I could be completely wrong.
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Relevant to this discussion is this quote:
" Evidence indicates that non-responsiveness to mTORC1 inhibition results from the release of negative feedback loops whereby pro-survival pathways upstream of mTOR are activated, such as the activation of Akt (termed ‘Akt rebound’). To investigate these feedback loops in more detail Carracedo and colleagues analysed tumour biopsy samples from patients with metastatic breast or colon cancer or melanoma enrolled in a phase I trial of the rapamycin derivative RAD001. They found that tumours from all patients treated with a high weekly dose exhibited increased activation of extracellular signal-regulated kinase (Erk; indicative of mitogen-activated protein kinase (MAPK) pathway activation), whereas those treated with a low daily dose did not."
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The rebound effect on mTor I think is what has allowed many users to gain muscle even better than while not on rapamycin.
Theoretically that could be the case but I doubt it. The increase in mTORC1 between doses would have to be greater than the decrease in mTORC1 during dosing for the overall effect to be an increase in mTORC1 and increased anabolism. I think that’s highly unlikely. If there is some significant rebound, I think the mTORC1 level is on average lower with rapamycin. If it were not then the animal studies most likely wouldn’t show the benefits they do. Also anecdotally, while rapamycin doesn’t seem to be decreasing the ability of people to gain muscle, it isn’t improving it either. Any small perceived increase in the ability to gain muscle I would think are attributed partially to decreased inflammation in older people on rapamycin, which in turn allows them to train harder, which then leads to slightly improved results.
In any case. I’m not particularly concerned about the potential rebound effects of rapamycin. Any rebound appears to be either too small to be of major importance or to not matter much in the end for longevity. If that were not the case then we wouldn’t be seeing life span benefits in mice.
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I’ll let you know- I took a vacay from Rapa due to low MCV and increased RDW which have now stabilized. I am doubling down on strength training + protein =feel great! Not saying Rapa made me feel bad but I definitely feel a pump at the gym and more energy being off this month! Fasting, zone 2 exercise, ketogenic, (timing of more protein), sleep, supplements getting great results! Is Rapa the longevity elixir which will provide 5 years more of lifespan? Perhaps. Its a journey!I agree… you might not gain muscle… if anything for me, I am more shredded - but much stronger…no fat or marbelized muscles. In my 3-years of use, my muscle size has been consistent and considered large by peers who don’t workout.
Gains with rapamycin are in strength… not growth/size for me.
I am glad to be stable at 65 years - when most people at my age are losing both muscle size and strength.
No size change (increae or decrease) after the initial shredding of fat to my current size. Pic from last night at gym.
I do 1 hour 15 minutes of muscle resistance… a total body workout (arms, chest, legs) every other day. I just started taking 1 tablespoon of Taurine in my morning coffee this week.
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