Does something that activates AMPK necessarily inhibit MTOR? As someone who isn't an expert in metabolic theory etc. I keep seeing pathways AMPK and MTOR cropping up.
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Posted 29 January 2016 - 07:00 PM
Does something that activates AMPK necessarily inhibit MTOR? As someone who isn't an expert in metabolic theory etc. I keep seeing pathways AMPK and MTOR cropping up.
Posted 29 January 2016 - 08:09 PM
Yes, that's how the biochemical regulatory network around AMPK and mTOR is "wired".
Under conditions of low ATP or allosteric activation at the salicylate site, AMPK is phosphorylated, and in turn phosphorylates the mTOR complex protein raptor and the Tuberous Sclerosis Complex (TSC) tumor suppressor TSC2. Phosphorylated TSC2 inactivates the small Ras-like GTPase Rheb, which has been shown to associate with and directly activate mTORC1.
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Posted 30 January 2016 - 07:12 PM
Thanks for that! What is P13K, up near the top there?
I found as I read quite a lot about Maidenhair/GinkgoBiloba this: http://www.ncbi.nlm....ubmed/17312453
"Ginkgo biloba extract reduces endothelial progenitor-cell senescence through augmentation of telomerase activity. "
Also a similar finding was made for nicotine. Both were inhibited by something called LY294002, a P13K inhibitor. Also what does "phosphorylate" mean? Activate/inhibit/else?
Edited by Skyguy2005, 30 January 2016 - 07:14 PM.
Posted 31 January 2016 - 05:42 PM
Phosphoinositide 3-kinase (PI3K) is an important signal transducer in the chain between insulin & insulin-like growth factor signalling and and mTOR activation. More permanent activation of PI3K is common in many cancer lines, as are mutations to most of the other transducers in the IGF-1/PI3K/mTOR signalling chain:
⊣ autophagy (cell "recycling day")
It seems like most experimentally effective anti-aging interventions suppress this pathway.
Posted 01 February 2016 - 12:08 AM
http://www.ncbi.nlm....ubmed/21679734
So what exactly would you make of this Bilobalide study? Isn't autophagy (associated with activated AMPK and inhibited MTOR) supposed to be useful for degrading/digesting prion-ish things like amyloid-beta and its precursor proteins?
It says the degradation (by Bilobalide a well known neuroprotector) took place by a "P13K-dependent" mechanism, so how does that square with the AMPK and MTOR stuff?
Posted 01 February 2016 - 05:01 PM
You're link didn't work, but assuming that you're looking at the Shi lab studies, it appears bilobalide has its effects by reducing initial production of soluble amyloid. Its arguably a side issue to the possible positive effects of AMPK in inducing autophagy to clear amyloid aggregates, or possible negative effects of AMPK in neuroplasticity.
Cellular regulation is a tangled clusterf*** of wires. While experiments have determined the short regulatory pathways in isolation, we're a long way from being able to pick the first string in the knot to pull for given conditions.
Posted 01 February 2016 - 11:57 PM
You're link didn't work, but assuming that you're looking at the Shi lab studies, it appears bilobalide has its effects by reducing initial production of soluble amyloid. Its arguably a side issue to the possible positive effects of AMPK in inducing autophagy to clear amyloid aggregates, or possible negative effects of AMPK in neuroplasticity.
Cellular regulation is a tangled clusterf*** of wires. While experiments have determined the short regulatory pathways in isolation, we're a long way from being able to pick the first string in the knot to pull for given conditions.
(http://www.ncbi.nlm....pubmed/20333467) (1)
Sorry, that link should work I believe. A study on Ginkgolide where it activated P13K, inhibited GSK-3Beta and p-Tau: (http://www.ncbi.nlm....pubmed/22700047) (2) . Both activated P13K in these studies.
Yeah it seems analysing even a single herbal (Ginkgo Biloba) is complicated. In different study, it did not affect Akt in the same way as Ginkgolide/Bilobalide: (https://www.karger.c...FullText/381744) (3) (http://www.sciencedi...009279709001847) (4).
Instead Ginkgo Biloba is inhibiting Akt. Perhaps this is because of the different components of it in addition to Ginkgolide/Bilobalide, or perhaps in (3) it acted differently in what was a different setting (inhibiting platelet aggregation). In (4) it inhibited Akt but only in the presence of AB42, not when it was absent. .
Also there is a study analysing P13K and autophagosomes:
(http://www.ncbi.nlm....pubmed/22308354) (5)
"Class III PI3K Vps34 plays an essential role in autophagy and in heart and liver function "
In the study: "Starvation-induced autophagosome formation is blocked in both Vps34-null MEFs and liver."
So yeah it would seem rather complicated. It seems rather easy for simpletons like me to run into trouble by extrapolating simple logic.
Also this page lists autophagy inhibitors: (http://www.invivogen...hagy-inhibitors) and several are P13K inhibitors: 3-MA, wortmannin, and LY294002.
Edited by Skyguy2005, 02 February 2016 - 12:07 AM.
Posted 02 February 2016 - 12:10 AM
Caffeine has similar studies to the Ginkgo Biloba: http://www.ncbi.nlm....ubmed/18201823
"Caffeine activates the PI3K/Akt pathway and prevents apoptotic cell death in a Parkinson's disease model of SH-SY5Y cells."Inhibited by LY294002 and wortmannin (similar things seem to happen in Ginkgo Biloba).
Posted 03 February 2016 - 03:00 PM
Saturated fatty acids strongly activate AMPK.
Posted 03 February 2016 - 08:15 PM
That may depend on the tissue.
SFAs activate AMPK in skeletal muscle and fat cells.
Fediuc S et al. 2006. Regulation of AMP-activated protein kinase and acetyl-CoA carboxylase phosphorylation by palmitate in skeletal muscle cells. Journal of lipid research, 47(2), pp.412-420.
Pimenta AS et al. 2008. Prolonged exposure to palmitate impairs fatty acid oxidation despite activation of AMP‐activated protein kinase in skeletal muscle cells. Journal of cellular physiology,217(2), pp.478-485.
Hebbachi, A. and Saggerson, D., 2013. Acute regulation of 5′-AMP-activated protein kinase by long-chain fatty acid, glucose and insulin in rat primary adipocytes. Bioscience reports, 33(1), p.e00007.
SFAs inhibit AMPK in endothelium and liver
Wu Y et al. 2007. Activation of protein phosphatase 2A by palmitate inhibits AMP-activated protein kinase. Journal of Biological Chemistry, 282(13), pp.9777-9788.'
Barroso E et al. 2011. The PPARβ/δ activator GW501516 prevents the down-regulation of AMPK caused by a high-fat diet in liver and amplifies the PGC-1α-Lipin 1-PPARα pathway leading to increased fatty acid oxidation. Endocrinology, 152(5), pp.1848-1859.
As far as I can tell, no sensible authority is recommending SFA intake to AMPK phosphorylation.
Edited by Darryl, 03 February 2016 - 08:27 PM.
Posted 03 February 2016 - 09:33 PM
I don't recommend SFAs. I recommend high-fat, low-carb diet.
Posted 05 February 2016 - 04:30 AM
That may depend on the tissue.
SFAs activate AMPK in skeletal muscle and fat cells.
SFAs inhibit AMPK in endothelium and liver
As far as I can tell, no sensible authority is recommending SFA intake to AMPK phosphorylation.[/size]
Posted 11 December 2016 - 04:45 AM
There is a lot of talk about rapamycin and longevity but is anyone actually using it? I've only found to
researchers to admit to using it themselves.
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