I just submitted a very brief proposal to the ITP. My idea is to test rapamycin at a dosing schedule interval that minimizes potential side effects. Below is the main part of my proposal:
Background and Rationale
Rapamycin has been the most successful intervention tested at the ITP. It has been found to extend life span of mice in the ITP both in isolation and when combined with other interventions. As a result of the success of rapamycin, many people have begun to experiment with taking it for longevity. Yet the optimal dosing regimen for rapamycin for longevity purposes is unknown. Therefore, it is urgent to find out what is likely to be the optimal dosing regimen for longevity.
Different dosing regimens of rapamycin have been tested in the ITP, but this has only been done along one axis (the total daily dose) but not among a potentially equally important axis, which is the frequency of dosing.
Rapamycin has increased life span at different doses and the longevity benefits appear to be somewhat synergistic when rapamycin is given along with metformin or acarbose. Metformin and acarbose can both act to reduce blood glucose but chronic rapamycin exposure can induce insulin resistance which consequently results in elevated blood glucose levels that are harmful for aging. Thus, it is not surprising that they act somewhat synergistically with rapamycin since they have potential to reduce the negative effects of rapamycin on insulin sensitivity and blood glucose.
As an alternative to administering metformin or acarbose with rapamycin to minimize the harm rapamycin has on blood glucose levels, it may be possible to modify the schedule of rapamycin intake to minimize the negative effects on blood glucose levels while not interfering much with the longevity benefits. Here it is important to note that the main benefits of rapamycin for longevity are thought to derive from inhibition of mTORC1, but rapamycin inhibits mTORC1 strongly and directly.
While rapamycin does not inhibit mTORC2 directly and therefore short term exposure to rapamycin does not significantly inhibit mTORC2, chronic exposure to rapamycin can lead to indirect inhibition of mTORC2 by interference with the assembly of mTORC2. (Ref.1) This may cause problems since many of the side effects of rapamycin are thought to derive from mTORC2 inhibition. As an example, inhibition of mTORC2 by rapamycin has been found to be required to induce insulin resistance in the liver of mice exposed to rapamycin. (Ref. 2)
Given that most of the potential longevity benefits of rapamycin are attributed to mTORC1 inhibition while most of the potential side effects are attributed mainly to mTORC2 inhibition, it is reasonable to try to modify the rapamycin dosing schedule in a way to maximize mTORC1 inhibition while minimizing mTORC2 inhibition. This is most certainly possible to some degree by simply modifying the frequency of dosing.
In a 2012 study published in the USA the authors set out to determine the most frequent rapamycin dosing schedule that does not negatively effect blood glucose levels. They gave rapamycin to mice at a dose of 2 mg/kg body weight either daily, every 3 days or every 5 days. When given daily or every 3 days it had negative effects on glucose tolerance but this was not seen when it was given every 5 days. (Ref 3) These results suggest that giving rapamycin every 5 days may be a good way to maximize the inhibition of mTORC1 while minimizing negative effects due to mTORC2 inhibition. Hence this intermittent method of administration may be worth testing for longevity.
Note that this method makes sense if we consider the plasma half life of rapamycin (about 15 hours in mice). At that half-life and administration every 5 days it’s about 8 half lives between doses. That should be enough to get blood levels to almost zero for a short while between doses which, in turn, helps prevent the chronic exposure that ultimately leads to mTORC2 inhibition.
Suggested Treatment Protocol
Given the above results I suggest testing rapamycin by giving it to mice in their food every five days. Since rapamycin has already been found to extend lifespan in the ITP at doses of 14.7 and 42 ppm daily, I suggest testing it at the highest dose, or 42 ppm administered once every 5 days. This would result in an average daily dose of 8.4 ppm, which is on average around half of the lower doses that were found to be beneficial in the ITP studies. Hopefully, that will give some longevity benefits with minimal negative effects from mTORC2 inhibition. Treatment would optimally be initiated early in adulthood (4-6 months) and continued throughout life.
Mol Cell. 2006 Apr 21;22(2):159-68. doi: 10.1016/j.molcel.2006.03.029. Epub 2006 Apr 6.
Prolonged rapamycin treatment inhibits mTORC2 assembly and Akt/PKB
Science. 2012 Mar 30;335(6076):1638-43. doi: 10.1126/science.1215135.
Rapamycin-induced insulin resistance is mediated by mTORC2 loss and uncoupled from longevity
Aging Cell. 2016 Feb;15(1):28-38. doi: 10.1111/acel.12405. Epub 2015 Oct 13.
Alternative rapamycin treatment regimens mitigate the impact of rapamycin on glucose homeostasis and the immune system