mTOR activation, ATG13 inactivation and suppression of autophagy

belbyr

belbyr

Established Member (Voting Rights)
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That diagram from the video shows the rationale for the use of the Sim501 compound, in their attempt to make a drug induced model of PEM, which is the thing I wasn't sure about from my first listen.

When mTOR is inactivated, ATG13 participates in processes leading to autophagy.
When mTOR is activated, ATG13 is phosphorylated and inactivated, leading to disturbances in autophagy.
SIM50 is reported to activate mTOR. So the mouse model involves activating mTOR via this drug.

With the effect of the drug wearing off in the mice after a month, the question then becomes 'what is activating mTOR, and why does it remain activated?'.

I agree @belbyr, I'm happy that these researchers are working on this.

I don't think it is said, but I think SIM501 might be simvastin, a statin.
Statins, the inhibitors of the 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA), seem to be able to inhibit the mTOR.
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[deleted a bit that is an unnecessary diversion]
Does anyone here know for sure what SIM501 is?
 
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Hutan said:
I don't think it is said, but I think SIM50 might be simvastin, a statin.
Click to expand...

I would assume SIM501 is a code-name where SIM is chosen for "Simmaron Research". I haven't listened yet but from the above it sounds as if mTOR activation leads to ATG13 phosphorylation and badness, so simvastatin as an mTOR inhibitor might produce the opposite result?
 
SNT Gatchaman said:
I would assume SIM501 is a code-name where SIM is chosen for "Simmaron Research". I haven't listened yet but from the above it sounds as if mTOR activation leads to ATG13 phosphorylation and badness, so simvastatin as an mTOR inhibitor might produce the opposite result?
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Ah yes, that makes sense, I got tangled up in finding a statin referred to as SIM10 and making leaps from there. There's this paper https://pubmed.ncbi.nlm.nih.gov/23817226/
where the statin inhibits mTOR and increases autophagy. As you say, the opposite result from what these researchers did in trying to create a mouse model of PEM.

Some of our members will be on statins, I wonder if they have noticed any benefits.
 
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Yes, we have a few threads on rapamycin e.g.
Rapamune / Rapamycin/ mTOR
Results reported by members are variable but don't seem to be of the 'this cured me' type. And there's quite a lot of downside - an immune-suppressor in a pandemic...
 
From The Multifaceted Role of Nutrient Sensing and mTORC1 Signaling in Physiology and Aging (2021, Frontiers in Aging) —

In humans, susceptibility to respiratory tract infections (RTIs) increases with age, most likely because of a decline in immune function. Therefore, the fact that rapamycin can also function as an immunosuppressant seemingly contradicts its role as an anti-aging compound. Against this hypothesis, a landmark study showed that rapamycin treatment actually improved the immune response of elderly to vaccination against influenza. Furthermore, a recent clinical trial that tested the RTB101 mTOR inhibitor, alone or in combination with the rapamycin analog everolimus, showed a significant reduction in the incidence of RTIs in old individuals.
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Despite rapamycin being one of most promising anti-aging interventions, long-term treatment has been associated with significant side effects, such as hyperlipidemia, hypercholesterolemia, hypertriglyceridemia, glucose intolerance and insulin resistance, thus restricting its wide-spread use to tackle aging in humans. Of note, most of these side effects were later attributed to the concomitant inhibition of mTORC2, which occurs following chronic mTORC1 inhibition and as a result of rapamycin binding to mTOR, thus affecting mTORC2 formation.
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