AMPK is my new interest. I didn’t initially discover it from my usual CR and longevity channels, but after doing some quick reading, I learned that AMPK works with mTOR and SIRT1. I’m still trying to learn the details of AMPK activation, so I don’t know where this post is heading yet, but I am particularly interested in the effects of neuronal AMPK activation and how it affects a person. Peripheral AMPK activation, from an initial inspection, seems to be a good thing in relation to longevity, but apparently AMPK can be activated in a few different areas of the body.

Here is a quick overview of what AMPK is:
5′ AMP-activated protein kinase is an enzyme (hint: enzyme names end in “ase” for those that didn’t take biochem) that is expressed in several tissue types including the brain, skeletal muscle, and the liver and takes part in the cell’s energy regulation.

The recent article “AMPK and SIRT1: A Longstanding Partnership? ” that can be read in full on the CR Society Archives, is how I first discovered a connection between AMPK and SIRT1, then following a PubMed search, I found some mTOR connections too.

I have a lot to understand here, and have never read about these relationships before. While I am fascinated by the whole topic in general, I am momentarily interested in neuronal activation of AMPK, so my energy will most likely be initially focused on that subtopic. Any insight is appreciated since I am in a whole new area I am just now learning about. :-)

I might as well present a paper I found interesting, and summarize what I have gleaned from it. I guess that is my SOP. ;-)

The article highlights that AMPK and mTOR both function as regulators of cell metabolism that respond to changes in energy status (for example, think dietary restriction). With an increase interest in high protein diets (HPD), these researchers sought to understand the response of AMPK and mTOR in the context of a high protein diet.

The researchers found that increased Leucine was the major contributing factor in the effects of a HPD. Also, a HPD or high leucine diet both caused a decrease in AMPK and increase in mTOR in the hypothalamus.

Hypothalamic activated AMPK and mTOR are both recent focuses in the control of food intake and appetite. AMPK, activated by rising AMP coupled with falling ATP, “switches on ‘energy-producing’ pathways at the expense of ‘energy-depleting’ ones….mTOR is inhibited under conditions of low nutrients, such as glucose and amino acids, and low intracellular ATP levels.” Also, mTOR activation is affected by Leucine more than any other amino acid; a high intake of Leucine will stimulate the activation of mTOR.

Reported Findings:
*An HPD reduces food intake and body weight in rodents.
* HPD modulates the hypothalamic AMPK/ACC signaling pathway
*HPD activated mTOR in the hypothalamus
*HPD modulates AMPK and mTOR in the same specific neuronal subset and modulated   hypothalamic neuropeptides.

*Leucine reduces food intake and body weight in rodents
*Leucine decreases hypothalamic AMPK and activates mTOR signaling.
*Leucine modulates AMPK and mTOR in the same specific neuronal subset and modulated   hypothalamic neuropeptides.

Now for some of my ramblings:::::::::::

So, what does this mean in the context of CR? This paper was not focused on CR, but just on the effects of a HPD and high Leucine diet. However, my understanding is that we want to avoid activating mTOR for longevity purposes, and I would imagine that an increase of hypothalamic AMPK could very well be a good thing in the context of CR, but I need to do more reading. These findings do suggest that a high protein or high Leucine diet, as I have posted before, would most likely not be ideal for CR – but these effects may be minimized in a low calorie environment, but still not ideal. Calories do seem to be the trump card for longevity.

I am getting more resolved in my decision to keep my protein between 15-20% though. My intake has reflected a lower protein level for a few months now, and this very issue is a direct influence on my original vegetarian/vegan diet deviation.

My question though is this: If AMPK is activated in the hypothalamus via medication, and not diet, how will mTOR be affected? Also, what effect would/could this have on longevity or CR results?

On the other hand, for non-CRed people, this paper is more proof that a HPD or high leucine diet would be good for weight loss.

Decreased mTOR and the activation of AMPK, result in the opposite appetite effect from the HPD in the study. Which would be an increase in appetite. Seems rather counter productive to the goal here, eh? Grrrrr. Let’s see if I can find some papers on AMPK, mTOR, and CR….

Ok, so here is what I found:::::

This research paper’s findings “support a strong association between SIRT1 and AMPK
in mammalian cells, as demonstrated by concurrent regulation of both molecules in response
to varying concentrations of glucose and pyruvate. Additionally, exposure to SIRT1 activators
and inhibitors resulted in AMPK activation and inhibition, respectively.”

So, would the medication induced activation of AMPK correspond to an increase in SIRT1? Would it matter whether AMPK was being activated in the hypothalamus or skeletal muscle?

“In this study, we performed a side-by-side comparison of the role of different genes in lifespan extension elicited by a variety of DR regimens. Our results uncover the importance of the low
energy-sensing protein kinase, AMPK, in longevity due to some forms of DR and to resveratrol, a compound that extends lifespan and mimics some aspects of DR in many species……Importantly, our results show that DR is not a uniform condition that triggers a universal and linear genetic pathway. Rather, diverse DR regimens evoke mostly independent genetic pathways, depending on how DR is achieved“

So, the way DR is practiced could be a determining factor in how the DR triggers the genetic pathway? Now, this study was conducted the nematode C. elegans, but the importance of AMPK in DR and longevity here is very interesting.

I don’t have full access to this paper, but I wanted to post it anywho since the abstract was so promising. Maybe I be able to find it somewhere…

Ok, It’s 4am and I am getting too spacey to really be productive. I’m going to chop off my post here, and I’ll continue my research over the next few days and hopefully find some more interesting things. I need to tie together a few different perspectives on AMPK to maybe answer my questions. I am mainly trying to figure out if medication activated AMPK is a bad thing, a neutrual thing, or a good thing in the context of CR.