#1

Is it time to figure out dosing for safe, chronic use of Rapa?? or are mice just lucky?

Chronic rapamycin decreased mTORC1 but not mTORC2 activity in mouse brains.

  • Chronic rapamycin enhanced learning and memory in young adult C57BL/6J mice.
  • Chronic rapamycin improved memory in aged mice.

  • Chronic rapamycin decreased anxiety and depressive-like behavior at all ages.

  • Monoamines were increased by rapamycin in midbrain but not in hippocampus.
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#2

We are not mice. I think there are plenty of reasons why people should only take rapamycin intermittently. I personally think most rapamycin users take it too often.

I accept there is a valid disagreement about this. However, I think its main function is mitophagy and that having a higher less frequent spring clean of the duff mitochondria is better than weekly tidying.

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#3

Based on past forum activity, I’m guessing someone has already tried this or soon will.
I personally agree with John.

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#4

I thought about this while reading this paper: The mTOR Signaling Pathway in Cardiac Aging

The “rapamycin memory” discussed above is not limited to cardiac aging. Transient rapamycin treatment for 3 months, initiated for ~20-21 months-old mice, is sufficient to increase life expectancy by ~40%-60% and improve several measures of healthspan in middle-aged mice. A recent study reported a long-lasting geroprotection from brief rapamycin treatment in early adulthood. This was the result of a persistent increase in intestinal autophagy in Drosophila. This “memory” was confirmed by enhanced gut barrier function and Paneth cell architecture in mice exposed to short-term RP treatment.

Too high a dose can also be risky:

In the heart, the hyperactivation of mTORC1 leads to pathological growth (cardiac hypertrophy) and cardiac dysfunction, as seen in aging and in response to pressure overload stress. Moderate suppression of mTORC1 by calorie restriction, rapamycin or some genetic models of reduced mTORC1 has been shown to ameliorate cardiac aging and pressure-overload-induced heart failure. In contrast, cardiac-specific ablation of mTORC1 leads to dilated cardiomyopathy, as it may suppress protein synthesis required for adaptive cardiac hypertrophy. The role of mTORC2 in cardiac aging is less defined. In contrast to the detrimental effect of mTORC1 activation, overexpression of the mTORC2 component in Drosophila is cardioprotective; however, the role of mTORC2 in mammals remains to be elucidated.

What’s your rapa dosing schedule @John_Hemming?

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#5

I am working on about every 6 weeks. There is a detailed topic on my sep 23 dose

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#6

A strong argument against this is that young people have lower mTOR than older people and age more slowly. They don’t just have lower mTOR once or twice a month, they have lower mTOR every day. The best argument for taking it intermittently is to avoid mTOR2 inhibition. That can be achieved with a dose as frequent as once a week if the dose is not too high. But for very high doses a lower frequency would be needed to achieve that.

Another argument against this is that calorie restriction, the best proven intervention to extend lifespan, reduces mTOR every day, not just once a week or month.

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#7

I would be surprised if people on calorie restriction had low mTOR continually through the day. You would expect mTOR to be activated when they eat.

I am open to evidence that this is not the case if there is such evidence, but you need to continually measure mTOR rather than measure it at one stage during the day.

Similarly with young people I would not think mTOR is continually inhibited.

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#8

I agree that it’s going to be activated whenever they eat so normally it’s going to be activated for many hours during the day in people on calorie restriction, although the activation is likely to be a bit smaller and shorter after each meal since they eat less. However, it will most certainly be inhibited for more and for longer between meals, including during sleep in calorie restriction, so in that sense I think overall daily mTOR is going to be lower on average every day not just some parts of the week or month. I agree that mTOR isn’t going to be continually inhibited in young people. Young people are more sensitive to both anabolic and catabolic stimuli so they will most lkely have strong mTOR activation during meal times but lower mTOR between meals, so my guess is their 24h AUC is lower than in older people, because they drop to lower levels every time they are not stimulating mTOR by eating.