“The median survival time of the everolimus-treated group (58.0 weeks) was significantly longer than that of the vehicle group (31.2 weeks)” That’s 85% on this metric
Interesting, mTOR and pMTOR don’t see as suppressed compared to vehicle in vivo? Wait what, not mTOR?
" Everolimus suppressed pmTOR and pS6 but not p4E-BP, and increased pAKT (via negative feedback) in vitro (Fig. 1C). Also, everolimus suppressed pS6 but not pmTOR and p4E-BP in vivo (Fig. 3B). Conceivably, everolimus may act on different signaling pathways in vitro and in vivo. Our results using transgenic mice suggest that marked suppression of pS6 by everolimus might be important in this respect"
DescriptionNeuronal mTOR signaling controls peripheral metabolismStacy A. Hussong1,2 and Veronica Galvan1,21University of Oklahoma Health Sciences Center 2Oklahoma City Veterans Health Care System, Oklahoma City, Oklahoma The mechanistic target of rapamycin (mTOR) is a central regulator of cellular and organismal metabolism. Reduction of mTOR signaling by rapamycin alters organismal metabolism and increases lifespan and healthspan. Neurons regulate many aspects of metabolism. To test the hypothesis that reducing mTOR signaling in neurons would impact critical aspects of metabolism cell non-autonomously, we genetically reduced mTOR complex 1 (mTORC1) by targeting its obligatory component Raptor in neurons of adult mice. Reduction of mTORC1 complex formation in neurons of adult mice by 35% or 60% did not impact body weight nor glucose and insulin tolerance, but increased liver gluconeogenesis and glycogen accumulation in skeletal muscle in association with enhanced exercise endurance and absent post-exercise hypoglycemia. While metabolic impact of mTORC1 attenuation could be partially recapitulated by mTORC1 knockdown in hypothalamus, exposure of muscle cells to serum from neuronal mTORC1 knockdown animals recapitulated in vivo changes in gluconeogenesis and glycogen metabolism, suggesting that circulating factor(s) mediate, at least partially, the cell non-autonomous peripheral impact of mTORC1 attenuation in neurons. Moderate (35%) but not profound (60%) mTORC1 knockdown in adult neurons also increased brain glucose metabolism and cerebral blood flow, enhanced spatial memory, and upregulated PGC1α. Thus, in addition to regulating cognitive function in a non-linear fashion, presumably in a cell-autonomous manner, mTORC1 signaling from neurons regulates basal and exercise metabolism cell non-autonomously in adult mice. Ellison Medical Foundation, Owens Foundation, Bailey Family Alzheimer’s Fund, VA 1 IK2 BX003798-01A1, NIA5T32-AG021890, 1 I01 BX002211-01A2, JMR Barker Foundation
Thanks. I attended AGE (virtually) and saw that poster.
Does anyone have solid info on the IC50 of rapamycin – for inhibition of either mTORC1 or mTORC2 – in neurons (or other parts of the brain)? Hussong’s work could help guide dosing.
Very interesting. Everolimus molecule size is about 5% bigger than Rapamycin. And there’s no difference in charge, so all other things being equal you’d expect rapamycin to cross the BBB marginally more easily
I started at 5mg/week with no amplifiers other than EVOO.
Then worked up to every 14 days at 20 mg. with ruby red grapefruit juice and EVOO. That proved to be too much as I got diarrhea every time at that dose. Since then after experimenting with doses that did no cause subjective side effects I settled on 5mg/ weekly with Bioperine, EVOO and RRGGJ. This I tolerate quite well and probably gives me an effective dose equivalent to 15 - 30 mg weekly.
The non subjective problem is my current ferritin levels are below normal. This may not be because of rapamycin, it may be because I am getting too old to give blood twice a year. Right now I am off rapamycin for awhile until I get my ferritin levels back into the normal rang.
Thank you for the reply. This is very interesting. I was on 24 mg every other week and just switched to 12 mg every week to experiment and see how I feel. I’m 58 years old and thinking of adding GFJ to the regimen. Interestingly enough my ferritin has been below normal the past two labs. I don’t each much iron in my diet but in the past year it has been in the lower end of normal but still in the normal range until my two most recent labs.
I’m not too worried given I have been following Mangan’s advice and wanting a ferritin number towards the lower end and I also donate blood every three to four months.
Question for you. What is your GFJ protocol? How much GFJ and when in terms of before/during/after you take the rapamycin?
I drink 8-10 oz of Florida’s Natural Ruby Red grapefruit juice at about 90 minutes before I take my rapamycin. I also swallow my pills in about 2 tbs of EVOO.
Just noticed this is a paper I was reading, where they were dosing as high as 4mg/kg of rapamycin the mother mice (not the pups they were later testing)… they talk about dose-dependent permeability of the blood brain barrier to rapamycin…
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Last time I dosed 1mg rapamycin (1st day of a 3 day fast) I got anxiety at night on the first day when driving my gf home. (Mild hallucinations in corner of eyes)
I did resistance exercise on day 1 and 2.
2nd and 3rd of the fast I was OK!
The reason I’m saying this is because it affected my behavior and I read in a paper that rapamycin treated mice had more anxious behavior compared to controls in a maze.
So did it cross the BBB for me, is it something else?
(I do not have an anxiety disorder.)
Have you had anxiety and mild hallucinations in corner of eyes previously?
If you want to know whether it is causal, you can do a self-blinding experiment.
Meaning you put rapamycin tab with a filler like creatine in non-transparent 00 capsules, and then just creatine in another one. Put the placebos in one bottle, and the others in an exact copy of the bottle. Mark the bottom of the bottles to say which contain rapa. Mix the bottles and randomly take one capsule. Look at the bottom of the bottle next day (or a few days afterwards) where you have marked if it is placebo or not. Then you fill up the bottles again so they have the same amount of capsules, or remove one from the one bottle you didn’t take.
