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Good interview.
Sabatini mentions some interesting stuff on future developments @ 26:34 (I might not be 100% quote correct)
“I do think there are interesting targets upstream of mtor. So that the sensing, nutrient sensing pathway. We originally thought was dedicated to mtor, that is was a very linear pathway. Nutrients, sensors, mtor.
But we now realize is that, that nutrient sensing pathway actually talks to many other proteins besides mtor.
Mtor is probably the most important to be fair. So if you really want to get closer to mimicking the impact of lower nutrients, you really can’t go after mtor itself, you have to go things upstream. So I think that is one very promising opportunity, and that’s something we are interest in looking at now. It’s hard because the targets in that pathway are not like mtor, which is a kinase. Which we know how to inhibit kinases.
Some of these other proteins we don’t know how to inhibit. So that’s the mtor space, and I’m excited to try to go after that.”
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Until then seems be another argument to also CR (at least sometimes) and for occasional fasting (and perhaps for shorter feeding windows each day)?
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https://www.nature.com/articles/s41392-023-01608-z/figures/3
Reduce glucose. Also reduce leucine and arginine.
Increase AMPK.
Low energy levels during glucose deprivation activate AMPK [81,82,83] through the phosphorylation of liver kinase B1 (LKB1) [84]. AMPK directly phosphorylates TSC2, increasing TSC2 GAP function [85]. In addition, AMPK phosphorylates mTORC1 component Raptor, increasing Raptor-14-3-3 binding and inhibiting mTORC1 [86]. During glucose deprivation, DNA damage response pathways lead to the inhibition of mTORC1 through the induction of tumor suppressor protein 53 (TP53) [87]. Other forms of stress, like hypoxia, result in mTORC1 inhibition. DNA damage and development 1 (REDD1) inhibits mTORC1 through TSC2, independently of AMPK [88,89].
How to increase AMPK.
AMPK: Metabolism & Insulin + Ways to Activate - SelfHacked.
- Exercise
- Caloric restriction
- Decrease inflammation
- Cold exposure
- Lipoic acid
The blog above also enumerates supplements to increase AMPK, among them, curcumin, bergerine, hydroxytyrosol (from olives), EVOO, fish oil, ginseng, and more.
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Another publication on AMPK activators.
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That’s what Sabatini seemed to allude to, CR.
However (If I recall correctly or not), in that podcast at another time, he did mention something about having enough vitamins (and maybe minerals, not sure) if one is doing CR.
So, who knows what supps/meds someone might need to use if doing CR to get max benefits.
He might have been thinking of doing a mixed approach like CR, occasional fasting, exercise, and use various supplements + medicines. It might depend on various health factors of the animal.
Or maybe those protein targets he mentioned will be so powerful of an intervention that CR/fasting won’t have to be used much if one can stay in a healthy weight range.
@JuanDaw Good info.
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