The Life Extension Pathway, Resveratrol etc. and Cancer Control: Mitochondrial Biogenesis Duality, the Metabolic Mechanism and Practical Applications

The Life Extension Pathway, Resveratrol etc. and Cancer Control: Mitochondrial Biogenesis Duality, the Metabolic Mechanism and Practical Applications.

Gregory S. Bambeck Ph.D. and Michael Wolfson  J.D., M.B.A.

Kent, Ohio U.S.A. 44240

SUMMARY STATEMENT: Cancer, heart disease and diabetes II, the three largest killers of the first and second world nation’s human beings (85%), and their disease antithesis, a healthy squirt from the fountain of youth, are finally defined under a singular unifying global hypothesis. Experimental molecular mapping proves that the regulatory pathway mechanisms define it as a true, real and clinically demonstrated system for the first time. Publicly available, practical and easily workable disease blocking and life extension implementation are readily available to anyone. There are three sections: ABSTRACT; PATHWAY MECHANISMS; PRACTICAL APPLICATIONS. Read on!

ABSTRACT

Full mitochondrial biogenesis is a two phase temporal process consisting of an early phase primarily associated with anabolism, cell replication and the making of over a thousand constitutive mitochondrial proteins that create new, but NADH to OX/PHOS inefficient mitochondria. Between these replication events, cell homeostatic controls up regulate a late phase set of mitochondrial respiratory chain proteins that create efficient NADH to OX/PHOS associated with a shift toward catabolism and autophagy of dysfunctional mitochondria and other cell debris. The early phase (neogenesis) supports cell growth, rejuvenation and whole body vitality in the short term, while the late phase (regenesis) supports cellular housekeeping and repair functions in the life extending long term. The immediate upstream effector of mitochondrial biogenesis is the mitochondrial proliferator co-activator (PGC-1alpha). Its up regulation institutes neogenesis and its down regulation institutes regenesis. Caloric restriction (CR) activates regenesis by up regulating adenosine monophosphate activated kinase (AMPK), while cancer activates neogenesis in the absence of regenesis by down regulation of the same AMPK pathway, upstream of PGC-1alpha. Recent ‘rediscoveries’ show that a cancer cell metabolism proposal of 1980, is correct in its many metabolic particulars. Most cancer cells are mutationally glycolytic fetal enzyme driven ‘sugar junkies’ supported by obligate mitochondrial ATP production inefficiency. Cancer cells are stuck in this cell growth drive state (metabotype), and become relentlessly replicative under the influence of mitogens. Recent genuine discoveries show that inhibition of the life extending CR pathway supports this ‘sugar junkie’ growth state by creating and maintaining inefficient and neogenic mitochondria in the presence of forced hyperglycolysis. Blocking fetal glycolysis and re-establishing the CR pathway pattern creates the regenesis of efficient mitochondria and halts cancer cell growth, and can sometimes even initiate cancer cell apoptosis. We describe the pathway mechanism as a unidirectional feedback loop starting with the CR target, AMPK, and how it regulates mitochondrial biogenesis, the reactive oxygen species (ROS) output, of which, feeds back to AMPK. We also make sense of CR mimetic resveratrol, and its bioavailability in this context, and further employ these understandings to envision simple nutriceutical and lifestyle synergies to fight cancer, the major diseases of aging and even aging itself.                                                                                                     

PATHWAY MECHANISMS                                                             

To make this easy to understand, we wish to start with some rules of the road. First, when we use the adjective ‘chronic’ or prefixes like ‘hypo’ or ‘hyper’, we are referring to aberrant, unnatural or man-made over impacts upon normal homeostatic systems or typical physiological shiftings in standard metabolic systems. These words are used to emphasize a principal or powerful effect of some kind. Second, since CR is the ‘gold standard’ of life extension, we will use it as a ‘home base’, or reference point, that most of our forays will diverge from, and then return to. Third, we will focus primarily on the unidirectional multi-toggle switch feedback cycle from AMPK to target of rapamycin (TOR) to PGC-1alpha to ROS to sestrin (SESN) and back to AMPK, with the up regulation of AMPK effectively down regulating every other component of the cycle downstream of it. Since the system is a closed feedback loop, everything is upstream of everything else as well as downstream of everything else, like the proverbial snake that eats its tail. However, extrinsic factors affecting any component can over ride their immediate upstream regulators, as we will often point out. Memorizing, or keeping a note pad with this simple AMPK, TOR, PGC-1alpha, ROS, SESN circuit, as a principal reference point, keeps the discussion grounded.

We will begin with a brief outline of the CR pathway. 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 PGC-1alpha 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 CR pathway. 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