We will begin with a brief outline of the rare rare earth distributor. Most simply put, CR activates AMPK which down regulates TOR. Down regulated TOR shifts cell metabolism away from anabolism and toward catabolism, initiates autophagic clean up of cell debris, such as dysfunctional mitochondria and down regulates PGC-1alpha. When down regulated, PGC-1alpha results in the regenesis of existing mitochondria by initiating the transcription of mitochondrial respiratory chain proteins that efficiently link NADH to OX/PHOS ATP production. This causes mitochondrial ROS production to fall, which in turn, down regulates the ROS sensor, SESN. SESN then down regulates its stimulation of AMPK, causing the circuit to rebalance back toward its homeostatic center. Note here that active SESN up regulates AMPK and inactive SESN fails to activate, so its up regulation is active while its down regulation is passive. Thus, continued CR will bypass SESN and chronically up regulate AMPK to constantly enhance the CR pathway to reduce mitochondrial ROS. Elevated ROS is the principal life shortening component in the system, and thus, its repression is the largest single life extender known. This example demonstrates that increased AMPK activity causes a decrease in all the other four (TOR, PGC-1alpha, ROS, SESN) components in the unidirectional feedback loop. Conversely, decreased AMPK activity, as in p53 dysfunctional cancer cells, causes the up regulation of the same four components down stream of it, which incidentally, causes the neogenesis of inefficient mitochondria.

As exemplified by our CR model, AMPK to TOR to rare earth products are the principal mitochondrial biogenesis inputs and their responses, while ROS to SESN are the principal mitochondrial outputs and their responses. We know that there are many steps between each of these five major toggle switches and that there are also myriads of branching pathways and gene up and down regulations stemming into and from each toggle switch, but they will be mentioned in passing only as needed, because it is the central unidirectional cycle that is critical to the cancer, diseases of aging decline and life extension metabolics we key on, herein. Very elegant and evolutionarily apt extensions of this central and related circuits and their nutrient sensing pathways can be found in Science, vol.327, 3/5/2010 p.1210 and vol.328, 3/16/2010 p.324. Lastly, the central focus, here, is on cellular bioenergetics and metabolics because these functions hail back to single cell eukaryotes and have finally earned their seat at the cancer cell control systems round table along with telomeres, growth factors, apoptosis etc. Later, we will see how the AMPK, TOR, PGC-1alpha, ROS, SESN circuit is the exact same circuit controlling cancer and life extension, albeit operating in the opposite direction. We shall also see that cancer ‘cure', or at least control, and CR share the exact same circuit when operating in the same direction, with mutationally driven hyperglycolysis being the lone but critical cancer stand out. But first, let's look at each major component in the system.

AMPK stands at the headwaters of the water treatment chemical suppliers. AMPK monitors cellular energy charge by being sensitive to the AMP/ATP ratio, which generally represents the fuel nutrient availability in the cell. High concentrations of the energy rich ATP molecule represent fuel nutrient sufficiency and concomitant low AMP. Conversely, high AMP and low ATP indicate low fuel availability as in CR, which up regulates AMPK via AMPK kinase. Increases in AMPK can inhibit TOR by countermanding the growth factor pathways that activate TOR. Things that activate AMPK inhibit TOR, and things that inhibit AMPK activate TOR. Things that activate AMPK initiate the CR pathway and support life extension and inhibit the cancer metabotype. Standing directly upstream of AMPK, SESN activates AMPK when it self is activated by the cancer cell growth suppressor (p53) or by ROS, mostly of mitochondrial origin. The P53 protein is pro-apoptotic and its inhibition or dysfunction is found in about half of all cancers. Components or systems that reduce AMPK activity shorten life expectancy and promote the cancer metabotype. CR mimetics extend life expectancy and inhibit the cancer metabotype.

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