Switch mTORC1 off and not effect mTORC2?

#1

Has anyone done work on the question.

What would be the ng/mL required in blood to switch mTORC1 off and not effect mTORC2?

Looking for the black cat in the darken room.

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#2

I don’t think its exactly a blood level issue to inhibit mTORC1 but not mTORC2, its more complex and not exactly understood from what I’ve heard. Somewhere between a week and a month of continuous (daily) dosing of rapamycin starts to cause mTORC2 inhibition


Here is the best we have I think - from the Lloyd Klickstein interview with Peter Attia:

How much exposure to rapamycin before you start to see this dual-prong of inhibition of TORC1 and TORC2?

  • In humans, after a week to a month, you can start to see consequences of TORC2 inhibition with a rapalog alone and it’s reflected in hyperglycemia and hypertriglyceridemia
  • This happens in “normal” people as well—i.e., non-diabetic, non-immunocompromised
  • In one experiment—
    • Patients with polycystic kidney disease that were otherwise healthy, took the rapalog (RAD001) and a substantial fraction saw these biochemical changes in their blood
    • The dose was 5 to 10 mg a day (equivalent to 2-8 mg of rapamycin)
    • BUT
 not everyone has these effects and that it unclear why that’s the case

In summary :

  • Inhibition of TORC1 seems favorable (after the development stage)
  • Inhibition of TORC2 is generally not a good thing

⇒ David Sabatini’s has studied what happens when several components of the TORC1 complex are knocked out:

  • Inhibition of TORC1 extends lifespan and health span in rodents
  • But if you do that to TORC2, it accelerates death
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#3

Oh - I should also mention, that one of the ways to back into this calculation (of the blood sirolimus level that does impact mTORC2 (or not) is to look at the target blood levels of rapamycin used in transplant patients.

I’ve seen research that suggests it may be the mTORC2 inhibition that is key in the immune system suppression, that is desirable in organ transplant patients (to avoid organ rejection), but which we in the anti-aging community are trying to avoid. In this paper (immune regulatory functions of mTOR inhibition) it states:

Targeting Rictor has also established that mTORC2regulates the actin cytoskeleton through the small GTPase RHO and protein kinase C (PKC)14. TSC1–TSC2 has been shown to regulate cell adhesion and migration26, but it is not clear whether TSC1–TSC2 signals to and regulates mTORC2 directly. Regulation of cell movement and adhesion is an important feature of effective immune responses, so it is possible that mTORC2 might also be shown to modulate immune reactivity when specific inhibitors become available.

So, my thinking is that you can sort of identify the point where you get mTORC1 inhibition (but not mTORC2 inhibition) by looking at the doses used in organ transplantation patients as a guide.

I’ve not done extensive research on this, but this paper on doses for kidney transplant patients suggests:

The usual maintenance dose of Sirolimus in these patients is 2 to 5 mg/d and its optimal maintenance trough level is 5 to 10 ng/mL. The required Sirolimus doses may differ markedly from patient to patient. It is because of high inter and intrapatient variability in its pharmacokinetics.

And in renal transplants - this Medscape discussion seems to suggest:

The study by Oberbauer and associates[1] suggests, for sirolimus plus steroid-treated patients, sirolimus target concentrations of 20-30 ng/mL for months 3-12 after transplantation and 15-25 ng/mL thereafter.

and another opinion:

Our sirolimus targets are similar to tacrolimus targets: 10-15 ng/mL in the early phase, 8-12 ng/mL in the intermediate phase (3-12 months), and 6-10 ng/mL thereafter (in the absence of rejection or specific drug toxicity

So - obviously, lower than these daily dose ranges are going to result in lesser immune system suppression.

Interestingly, today at the American Aging Association annual meeting / conference, researchers were reporting on their clinical trial of rapamycin for cognitive impairment. They seem to be taking a dosing strategy similar to what you are discussing - high enough (on a daily basis) to inhibit mTORC1, but not so high as to inhibit mTORC2. See twitter discussion below:

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#4

“RAPA will be administered orally 1mg daily”

From the “REACH RCT with 40 participants” clinical trial, post above

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#5

Exactly - they seem to be doing what you are talking about
 they have the same goal, highest dose without mTORC2 problems


But I’ve seen no evidence that the daily lower dose is better in terms of results than the higher dose once per week.

#6

Thinking
2mg on Sunday’s, then 1 mg everyday till Saturday, repeat weekly.

8mg total per week

#7

This is a question for the AMA with Matt Kaeberlein - would 8mg spread out as you’ve suggested be expected to be better (for longevity, or side effect risk) than a single dose of 8mg one day a week?

I suspect he’ll say we don’t know, and don’t have any research to support one way or another.

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#8

If I recall correctly, in the Lloyd Klickstein interview with Peter Attia, it was mentioned that it’s the trough levels of rapamycin which were being kept above a certain level in transplant patients, in order to maintain their immunosuppression (i.e. TORC2 inhibition). So, presumably, we want to allow our trough levels to reach below the lab assay level of detection before dosing rapa again. This is one of the reasons why I have chosen to dose sirolimus every 14 days rather than weekly, given that its half-life is roughly double that of everolimus.

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#9

Yes, that is correct. But the new study using rapamycin for alzheimers mentioned above is using 1mg a day so they must have some data that it is safe.

#10

I came across an interesting paper last night that covers drugs for autophagy, but in the process mentions FDA approved drugs that target mTORC1 and not mTORC2.

Recently, Roberge and co-workers (31) reported a study in which they screened a library of 3500 chemicals with an automated cell-based assay to detect increases in autophagosome
numbers. The screen identified four compounds (perhexiline, niclosamide, amiodarone, and rottlerin) that stimulated autophagy by inhibiting mTORC1 (but not mTORC2) signalling (Fig. 2). Rottlerin inhibited mTORC1 signalling via TSC2 (tuberous sclerosis complex 2), whereas the other drugs inhibited mTORC1 signaling in a TSC2-independent manner (31). Interestingly, three of the identified compounds (amiodarone, perhexiline, and niclosamide) are drugs already approved for other therapeutic indications, thereby reinforcing the rationale for targeting mTORC1 activity in diseases in which positive modulation of autophagy may be beneficial.

The paper is here: https://www.jbc.org/article/S0021-9258(19)40552-8/pdf

And also uploaded
PIIS0021925819405528.pdf (577.9 KB)

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Multiple Sclerosis and Rapamycin
#11

Amiodarone? Wouldn’t touch it.

Keep an Eye on Amiodarone Patients.

The most serious potential unwanted effect of amiodarone is pulmonary toxicity (with a fatality rate of about 10%5); other harmful effects include visual disturbances as well as hepatic, cardiac and thyroid toxicities.

Niclosamide is an anti-helmintic, like the alleged COVID cure, Ivermectin, and the cancer treatment advocated by Joe Tippens (fenbendazole).

There seems to be a horde of benefits from niclosamide, as the article below details:

Your cited article reveals many other compounds. Just digesting it now.

This screen yielded eight compounds that trigger mTOR-independent autophagy and reduce expanded polyQ aggregates. These include fluspirilene and trifluoperazine (dopamine antagonists); pimozide, niguldipine, amiodarone, and loperamide (Ca2 channel blockers); and penitrem A (inhibitor of high conductance Ca2-activated K channels), which provide a number of potential therapeutic candidates for neurodegenerative disorders, as most of these compounds were FDA-approved drugs (Fig. 3) (54).

There it is again, loperamide (Imodium) the anti-diarrheal as anti-aging. I’ve seen it mentioned before.

The article also mentions rapamycin combos such as:

The existence of mTOR-dependent and mTOR-independent pathways regulating autophagy allows the combined use of different perturbations to increase the autophagic clearance of aggregate-prone proteins. For instance, although lithium induces autophagy in an mTOR-independent manner by inhibiting IMPase, it also inhibits GSK-3, which activates mTOR (47, 61). This mTOR activation acts to partially inhibit the autophagy-inducing effects of lithium action via IMPase inhibition (47). We have shown that treatment with rapamycin impedes the GSK-3-dependent activation of mTOR that occurs
with the simultaneous treatment with lithium, thereby eliminating the undesirable effects on autophagy resulting from mTOR activation. Combinatorial treatment with rapamycin and lithium enables greater autophagic clearance of mutant huntingtin in HD cell models and exerts a greater protection > against the neurodegeneration in HD fly models compared with either treatment alone.

We have further shown that simultaneous treatment with rapamycin and other mTOR-independent autophagy inducers, such as trehalose , calpastatin, and the SMERs, results in a greater up-regulation of autophagy than the single treatments alone (48, 50, 60).

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#12

I do rapamycin once a week and daily trehalose in my 100% cocoa morning drink.

#13

There are also other ways - Acarbose and 17 alfa estradiol increase mTorC2 - so they can cancel this side effect from Rapamycin to some extent

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#14

Interesting paper, it has some information on the action of some other supplements such as lithium that I wasn’t aware of.

Well, at least one, rottlerin is a natural product.
I missed the fact that polyphenols have the ability to suppress mTORC1 which may be the main reason for their health benefits. I think I might increase my polyphenol supplement intake.

The others are very problematic:

“Perhexiline is a coronary vasodilator used especially for angina of effort. It may cause neuropathy and hepatitis”.

“Niclosamide, sold under the brand name Niclocide among others, is an anthelmintic medication used to treat tapeworm infestations”

"Amiodarone is used to treat life-threatening heart rhythm problems called ventricular arrhythmias

“Rottlerin is a polyphenol natural product isolated from the Asian tree Mallotus philippensi
Medicinal properties: Every part of this plant has specific medicinal properties. It is used mainly in ayurveda to fight against intestinal worms in domestic and grazing animals. It is also used to treat kapha disorders, bleeding disorders, worms, abdominal tumors, stomach related troubles, and for quick healing of wounds and ulcers”

“Quarter-Century Explorations of Bioactive Polyphenols: Diverse Health Benefits”

For self experimenters berberine and/or quercetin + | Tyrosol + Salidroside | Rhodiola rosea, Salidrosol Quick Dissolve Tablets

Inhibition of mTOR/S6K1/4E-BP1 Signaling by Nutraceutical SIRT1 Modulators
“Therapeutic potential of polyphenols in cardiovascular diseases: Regulation of mTOR signaling pathway”

“Drugs targeting mTORC1 inhibition limit the atherosclerosis process”

“Therapeutic potential of polyphenols in cardiovascular diseases: Regulation of mTOR signaling pathway”

https://www.tandfonline.com/doi/abs/10.1080/01635581.2018.1446093
https://www.sciencedirect.com/science/article/abs/pii/S1043661819314306

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