12 replies to this topic

[Skyguy2005]

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. 

[Darryl]

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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[Skyguy2005]

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.

[Darryl]

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:

 

insulin & IGF-1 (whole body serum)

↓

IR/IGFR (at cell membrane)

↓

IRS 

↓

PI3K

↓

AKT → glucose uptake, ⊣ FoxO

↓

TSC2

↓

RHEB

↓

mTOR

→ 4E-BP (protein synthesis)

→ S6K1 (protein synthesis)

⊣ Foxa

⊣ autophagy (cell "recycling day")

 

It seems like most experimentally effective anti-aging interventions suppress this pathway.

[Skyguy2005]

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? 

[Darryl]

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.

[Skyguy2005]

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.

[Skyguy2005]

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). 

 

[BobbyDick]

Saturated fatty acids strongly activate AMPK.

[Darryl]

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.

[BobbyDick]

I don't recommend SFAs. I recommend high-fat, low-carb diet.  

[xEva]

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]

 
guys, all this is a so simple to understand once you understand "starvation". There are various requirements and pressures on different tissues during progressive stages of starvation. Muscles and fat become most active metabolically, endothelium thins and becomes more permeable, while the liver works its hardest supplying energy in its various forms to the rest of the body, mainly for the brain.
 
As fat brakes down, the skeletal muscles start ignoring both glucose and ketones and feed exclusively on fats-- while their least used fibers are catabolized to supply AAs to be converted to glucose. The liver keeps on churning out ketones at a constant rate throughout, causing their level to steadily rise -- until, about a week later, it reaches the point when the brain finally start feeding on them in earnest, quite suddenly, and thus lets go of a third of its prior glucose requirement -- causing its blood level to rise.
 
The whole brouhaha is regulated through, primarily, the relative concentrations of these main nutrients --glucose, AAs, FFAs, triglycerides, ketones-- floating around (+ pH and various hormones of course). But get this: SFAs and AMPK in various tissues merely respond to these changes in relative concentrations of the main nutrients in the immediate surrounding. That's all that matters. 
 
Once you understand the metabolism of starvation, metabolism in general becomes easy to understand, because in starvation, it's all clear and simple. Everything is geared toward one goal: to survive. It's different during  "feast times" when there are additional pressures and confounders in the form of exogenous nutrients coming from food. 
 
But get this: for a muscle cell --the way it is wired-- there is no difference why the level of FFAs is currently high. It is programmed to ignore ketones and glucose while FFAs are high and it does not matter why they are high. In reality those high FFAs could be either from lotsa recently consumed greasy food, or from the host being obese, regardless of food, or from starvation (its early stages when the fat brakes down).  


In other words, there is no "master regulator". Individual cells merely respond to the conditions in their immediate environment, and the main "condition" is the aforementioned varying relative concentrations of the main nutrients floating around.

I think we are confused by the complexity of our society and such and we sorta expect the same from our biology. Most of us are also largely ignorant of the complexities of other living things, like plants. But in basic metabolic terms, plants are not that different from us. In all cases the primary unit is a living cell that reacts to its immediate environment. No need for "higher nervous system" or "master regulators" that activate or inhibit this or that "pathway" throughout.

[david mount]

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.