mTOR activity levels

[mccoy]

Premise: as we all know, low mTOR activity (but not too low) has been correlated to longevity. This discussion on trying to find a rationale to downregulate mTOR, hence living longer, by adopting a specific dietary regime. Rapamycine downregulates mTOR regardless of dietary regime, but has the pretty serious drawback that it tends to downregulate it too much, possibly inhibiting the activity of macrophages hence weakening the immune system. Plus more undesired effects (hyperglycaemia, testiculat atrophy, cataratc...).

 

 

In the other thread in this same section on nutritional geometry, one of the articles cited is the following. There, I saw something which I didn't see anywhere else: the mapping of hepatic mTOR activity, in function of the macronutrients levels. Even though that's in lab rats, after so many theoretical considerations it's awesome to see the real deal.

 

Cell Metab. 2014 Mar 4;19(3):418-30. doi: 10.1016/j.cmet.2014.02.009.

The ratio of macronutrients, not caloric intake, dictates cardiometabolic health, aging, and longevity in ad libitum-fed mice.

Solon-Biet SM1, McMahon AC2, Ballard JW3, Ruohonen K4, Wu LE5, Cogger VC2, Warren A2, Huang X2, Pichaud N3, Melvin RG6, Gokarn R7, Khalil M8, Turner N9, Cooney GJ9, Sinclair DA10, Raubenheimer D11, Le Couteur DG12, Simpson SJ13.

[mccoy]

The illustration which captured my attention. The coloured surface displays contour lines of isovalues of hepatic phosporylated mTOR/mTOR, that is, mTOR activity in the liver

 

On the left-hand side, we have mTOR activity in function of protein and carbs intake. Red color is higher activity than blue color. It is evident that higher dietary protein increases mTOR activity, but only by a mere 1-2%. In real life, that's nothing. Ditto for fat vs protein, almost exactly the same effect. In thsi context, fats are not different from carbs. No neutrality. The change in activation is minimum though.

 

In this other illustration however, blood glucose versus blood BCAA are considered. It is evident that at lower quantities of glucose and medium to high quantities of BCAAs mTOR activity is high, with 55% to 65% and over of activation (phopsporylation). Whereas, with high blood glucosem even with medium-high BCAAs mTOR activity is pretty low, about 25 to 30%. This surface spans an increase of about two times mTOR activity.

 

Now, I'm slightly perplexed with both illustrations.

 

In the 1st one, there appears to be very little difference in mTOR activation with an increase of dietary protein, unlike what I knew. But in the second one we see that BCAAs are the key, so the total effect of dietary protein is not relevant if BCAAs are not included specifically. I'm not grasping it yet, but in the second graph would suggest that Leucine, Valine and Isovaline govern mTOR activation. The other amminoacids are ancillary to that.

Also, it would appear that higher blood glucose would downregulate mTOR. Notwithstanding the fact that hi glucose→hi insulin→AKt activation→mTOR activation, that's the right-hand side of the mTOR signalling cascade we see in all metabolic graphs. The message the authors want us to take home is that 

"The lowest activation state of mTOR is associated with a low ratio (blue line) [bCAA/glucose], and the highest activation state is associated with a high ratio (red line)"

 

 

So, an high glucose/BCAAs ratio is a consequence of hi carbs/protein ratio which governs mTOR activity. But the BCAA component in the dietary protein rules.

 

Any comments are very much welcome, if any of the above is applicable to humans we may have some very important concepts to play with in real life.

[mccoy]

Here are the illustrations on diets used. It seems like they are the quasi-artificial diets of lab rats: casein, methionine, soy oil, starch and simple carbs, supplements.

[Sibiriak]

 

second graph would suggest that Leucine, Valine and Isovaline govern mTOR activation.

 

 You've stressed that idea in numerous previous posts.  Is  higher blood glucose -->  mTOR downregulation  the perplexing notion?

[mccoy]

Sibiriak, 2 perplexing notions:

 

1. in the 'D' illustration, mTOR activity increases with increasing protein intake, but very, very little, I would say almost meaninglessly. This is contrary to the mechanistic hteory. Casein, the protein source fed to rats in this experiment, does contain BCAAs as far as I know. So that illustration is a big question mark ? to me.
2. In the 'E' illustration, I would have expected, again from the mechanistic theory, the blue area in teh response surface (lower mTOR activity) rotated anticlockwise by a little more than 90°to be located near the origin. In that way, low glucose AND low BCAAs→low mTOR activity (and the other way around, red area at high glucose AND BCAAs), perfectly according to theory. Whereas, as it was measured, if we increase both glucose (the insuline signal) and BCAAs (the leucine signal) we have almost a constant level of mTOR activity, to be precise a slightly DECREASING level of mTOR activity which is really surprising.

Maybe we should see that in the context of the 'B' illustration in the article, from which it is evident that BCAAs reach a saturation level in blood, an average of about 45 micrograms/ml, beyond which an higher P/C ratio causes no higher BCAAs concentration. 

 

Maybe the takeaway lesson is just the 'RATIO' lesson, that is, the blue line visualizes an increase in glucose/BCAAS ratio, which means higher carbs/protein ratio, whereas the red line is the opposite, and a diet with higher and higher BCAAs compared to glucose increases mTOR activity.

 

BUT, geoometrically speaking, the red line has a slightly lower angular coefficient, than the mTOR activity contours, this means that mTOR activity is increased by a little amount when increasing BCAAs (again, according to theory)..

 

Bottom line: in teh 'E' illustration, the blue region on the response surface, which visualizes significantly lower mTOR activity, corresponds to higher glucose concentrations. If we keep constant a high glucose concentration, increasing BCAAs, let's say we move horizontally along the glucose=7 horizontal line, spanning from BCAAS 20 to BCAAs80 we only increase mTOr activity of 5%.

 

In my dictionary, that means that GLUCOSE, not PROTEIN, has the greatest influence on mTOR. Strangely, an abundance of glucose would mean lower mTOR activity.

Again, we get back to the dietary contraint (in this experiment) that lots of glucose mean many carbs and little protein, so lots of glucose is correlted to low BCAAs.

 

Kind of confusing...

[mccoy]

Maybe the takeaway lesson, as an EVIDENCE,  from this rats study is that following the suggestions of Dr John McDougall, of the 'Starch solution' diet (Hi carbs, low protein), is favourable to longevity whereas following the suggestions of Dr. Atkins and similar low carb, hi protein diets is unfavourable to longevity. Ketogenic diets have low protein so they woudl be sort of in a middle ground.

 

The best natural therapy against diabetes would be that of the vegan doctors like McDougall And Barbard, many carbs, few protein, few fats. That would reverse the illness and ensure longevity.

 

If the results are applicable to humans.