mTOR inhibition can also be a double-edged sword

I’m interested by the work on mTOR and longevity. After trying 4 mg of rapamycin per week last year, I noticed a significant drop in mood, and a depressive state…so I stopped rapamycin after 3 weeks. I believe that rapamycin is an excellent product in aging and cancer prevention, but like everything else in nature, mTOR inhibition can also be a double-edged sword. Activation of the mTOR signalling pathway is implicated in many physiological processes of the nervous system, including neurogenesis, axonal sprouting, dendritic spine growth, ionic and receptor channel expression, axonal regeneration and myelination? Some study show that mTOR is good for your mood.

Also, mTOR inhibition is now widely accepted as a reliable protocol in lifespan extension…or is it?
Take this new study on mice with short telomeres. Using a standard mTORC1 inhibitor Rapamycin, caused decreased lifespan in those mice.
During the aging process, telomeres naturally become shorter, even in humans. mTORC1 is actually a pro-survival pathway in lifespan and healthspan extension. So its inhibition under certain contexts can have truly unexpected and devastating results.

There are some problems to elucidate for me before taking Rapa again…/2020-03-rapamycin-effects-telomeres…

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It’s interesting that you had a mood drop, many experience the opposite. Wonder if it’s a sensitivity issue. Maybe you should start at 2 or even 1 mg. Go slow.

I remember the telomere study. I believe those mice had genetically very short telomeres and while I don’t believe that that would translate well to humans, I still supplement with Centella Asiatica which is even more potent than astralagus for telomere maintenance. I really like that with rapamycin.

Of course you’re correct that we don’t want total inhibition of mTOR at all times, hence the intermittent usage regimens.

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Thank for your answer, may be start to low ! do you see the publication that mTOR enhancer decrease depression ? May be some people like me have a sensitivity for depression ! how much Rapa do you take per week ? Thank

I take 6 mg per week but I started at 2 mg and advanced slowly over years.

Sorry to hear of your experience.

From what I glean from the literature, rapamycin is not associated with depression.

“Chronic rapamycin decreased anxiety and depressive-like behavior at all ages”

Rapamycin, an Immunosuppressant and mTORC1 Inhibitor, Triples the Antidepressant Response Rate of Ketamine at 2 Weeks Following Treatment: A double-blind, placebo-controlled, cross-over, randomized clinical trial

CONCLUSION** Unexpectedly, pretreatment with rapamycin prolonged rather than blocked the acute antidepressant effects of ketamine

You might have to experiment some more to see if you can reliably reproduce your experience, to understand if truly rapamycin causative.

Once again, a mutant, transgenic mouse model.

The study does reference some human “shorter telomere” diseases, so perhaps one would have to be diagnosed with such to have some possible mTOR inhibitor therapeutic intervention contraindication.

“There are a number of human diseases, known as telomere syndromes, that are characterized by the presence of abnormally short telomeres caused by mutations in telomerase and other telomere genes. These diseases include cases of Dyskeratosis congenita, aplastic anemia, as well as pulmonary and liver fibrosis among other degenerative diseases”

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“total inhibition at all times”, that’s probably VERY unlikely with our low intermittent dosing regiment.

Chronic inhibition of mTOR by rapamycin modulates cognitive and non-cognitive components of behavior throughout lifespan in mice

Even these wild type mice, fed chronically DAILY, 2.24 mg/day rapamycin, equivalent to about 13mg/day for a 70kg human, the mice had only “approximate 30% reduction in TOR activity in brain

So the on/off/washout discussions and “fear or turning off TOR1/TOR2” relating to human dosing may not have ANY physiological relevance until MUCH higher doses administered?

Some other notable/interesting findings:

“It had been previously shown (Cloughesy et al., 2008) that rapamycin crosses the bloodbrain barrier. Similarly, mice fed a diet containing 14 ppm encapsulated rapamycin had rapamycin BRAIN concentrations of 8.65 ± 0.66 ng/mg wet weight, similar to the rapamycin levels found in plasma in the same animals”

“Of note, cognitive effects of rapamycin feeding were observed when mice were fed for 16 weeks or as long as 40 weeks, suggesting that the effect of chronic rapamycin treatment is sustained for
protracted lengths of time”

“High TOR activity in neuronal progenitors or in neuronal/glial precursors during development results in significant plasticity and memory deficits and aberrant excitability, suggesting that adequate plasticity requires that TOR activity be within a range that allows for appropriate regulation of protein synthesis at synaptic sites. While acute and complete inhibition of TOR abolishes plasticity required for long-term memory, chronically decreased TOR activity can improve learning and retention of a spatial task in young mice and improve memory of an aversive event in old animals. Even though rapamycin is considered to be a specific mTORC1 inhibitor, it was recently shown that longterm in vitro rapamycin treatment may result in the inhibition of mTORC2 as well. We observed no differences in the phosphorylation of mTORC2 targets in whole brain and in hippocampi of mice treated chronically with rapamycin” So no TOR2 activation even at these very high chronic doses.

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In fact, I am tempted to take it back, because I am convinced of the benefits of Rapamycin, believe me I am not here to destroy the benefits of rapamycin but I am trying to understand why certain studies are not necessarily encouraging. I’am 60 years old and I am in good physical shape, and I know that physical exercise also plays a role on autophagy… What do you think of natural substances like NAC, curcumin, green tea which are also mTOR inhibitors? I don’t think it’s comparable to rapamycin. Last thing, why the pharmaceutical industry is looking at mTOR agonists in depression ! so is it paradoxical? mTOR signaling in the neuropathophysiology of depression: current evid | JRLCR
MAC , how much of rapamycin who take ? Thank

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