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Life Extension Metabolic Pathway Map Reveals New Phytonutrient Candidates- Part 1

Life Extension Metabolic Pathway Map Reveals New

                     Phytonutrient Candidates

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

Summary

The three most common and deadly diseases of aging are atherogenic cardiovascular disease, the cancers and diabetes II. The metabolic pathway conferring life extension has just recently been outlined. The three disease metabolic pathways run in direct opposition to the life extension pathway. We have generated a metabolic flow chart (map) that shows both systems as a dynamic singularity. We make sense of these diseases and life extension in the text, in terms of the metabolic map. From a compendium of phytonutrients, we discovered a small handful of them that satisfied a very stringent set of criteria for fighting these diseases and accomplishing genuine life extension. The three most successful candidates form a remarkable fit in terms of our metabolic map, while the five runners up are very close fits. Used singly, or in combination, all eight have found efficacy in treating many dozens of age related diseases beyond the three main killers we describe, herein.

 

Introduction

 

The most common and deadly diseases of aging are the 1) atherosclerotically induced cardiovascular disease group, 2) middle age onset type II diabetes and 3) the multitudinous array of cancers. Obesity might be considered a fourth disease, but since its morbidity usually manifests its outcome as a consequence of one or more of the first three diseases, it will only be treated in an ancillary fashion, as a   condition. All these diseases share, at their causative core, a metabolic pattern of imbalances that are remarkably similar. Viewed superficially, this does not appear to be the case, because they operate in different physiological compartments and at different levels of cellular organization. For instance, in cancer, the metabolic pattern operates at the intracellular level, and in fact, can begin in a single cell. Extracellular physiological manifestations of cancer become evidenced at the multicellular level, much later, as mesenchymal and metastatic 3D tumor invasion and dispersal. Diabetes requires the mobilization of trillions of cells working in concert at the tissue and organ level of integration. Atherosclerotic cardiovascular disease also involves the participation of gaggles of cells operating at the level of the vascular tree. The common denominator includes mal adaptations to carbohydrate metabolism that become fixed and self exacerbating, ultimately leading to each disease having characteristic forms of outcomes.

 

Recent developments give us three great proofs that the aforementioned statements are true. First, the same metabolic pathways and/or their downstream destructive outputs are evidenced in all three disease situations. Second, and more importantly, pharmaceutical or phytonutrient metabolic pathway differential rectifiers prevent, delay onset, delay progression, and in some cases, actually reverse all three disease states with a single therapeutic regimen. Lastly, pushing the metabolic system in the reverse direction of its multiple disease manifestations actually extends life beyond its normal time span limit. This is multi-serendipity enough to induce a lustful search for an Occam's razor.

 

We have developed an essential skeletal outline of the entire regulatory metabolic system with its most salient inputs and outputs. This ‘map' is provided in Figure 1. To simplify matters, it is presented from the standpoint of a single cell. After describing its functions, we will probe its perturbations manifest as cancer cell growth, followed by those of diabetes II and atherosclerosis. Throughout the discussion, we will contrast these disease pathways with the opposing life extension pathway.

 

First, the system will be articulated from the perspective of the single cell and disease perturbation at the single cell level. Then, we will branch out to the somewhat more obscure and less obvious whole body physiological manifestations evidenced by perturbations at the organ and tissue level. Finally, we use these understandings, and the map itself, to speculate on the mechanisms of action of both well and poorly understood phytonutrients that are known to have had a beneficial impact on all three disease states, but have not had the benefit of the cell growth and life extension pathways, to be matched to, until the present time. 

 (Figure 1 is available at http://www.scribd.com/doc/61407739/Life-Extension-Metabolic-Pathway-Map-Alternate#fullscreen:off)

 Figure 1. The cell growth (CG)Icancer metabotype (CM) vs. caloric restriction (CR)Ilife extension (LE) pathway flow system (map). Circled ovals represent the core elements of the CR/LE system. Boxes are used to contrast the mitochondrial CG neogenic state from its CR driven regenic state, as shown in ovals. Stars

represent very recently discovered or described phenomena which made this map possible for the first time. All other (unboxed and uncircled) tenns represent knowledge gained prior to star affixed knowledge. Most solid lines represent responses to stimulation, while dashed lines show downstream impacts of a special core catabolic interaction. TSC2 and TOR are the heart of the input/output tree. A listing of abbreviations is provided in the text. Arrows represent up regulation and blocking end plates represent down regulation. All components are to be thought of ‘as if in the activated state, when upstream effects are ignored and down stream effects are followed. The map should be kept at the ready when reading the text, because they are inextricably co-dependant.

         

The CG/CM and CR/LE System

 This segment of our narrative is presented in a rather concentrated and rapid fire fashion. A thorough understanding of metabolic pathways and a reasonable familiarity with their regulatory elements is absolutely required. For those less inclined, we recommend that you skip forward to the three disease type examples or to the phytonutrient candidates section. For those who wish to brush up a bit before jumping in, we recommend that you read the metabolism Special Section found on p.1337 in the 12/03/10 issue of Science, Z. Feng, Cold Springs Harbor Laboratory Press, p.199, 2010, and Seyfried and Shelton, Nutrition and Metabolism, 7/7,1/27/10. This is up to date review material that is highly focused around the subject of this article, but without the unifying metabolic pathway system. It is helpful if one has a copy of the Figure 1 CG/CM and CR/LE metabolic map on the side, as a reference guide, when reading this paper, as we refer to the map throughout the narrative.

 

In the mid twentieth century, it was discovered that calorically restricted (CR) mice lived longer than their normal maximum life expectancy, which we term as true life extension, just life extension or LE, (LE) for short. Since then, research has reported the CR/LE phenomenon throughout all major branches of the proto-animal and animal kingdom, from fungi, worms, insects, spiders, fish, rodents to primates. The field lay fallow for decades, until just recently, when LE was also noted to occur when using the anti-tissue rejection drug rapamycin and the anti-diabetic drug metformin. Knowing their molecular targets provided the first inklings of a pharmaceutically induced up regulation of the same pathways activated by CR. We call these drugs CR mimetics.

 

Even more recently, cancer investigators found powerful tumor cell growth (CG) inhibiting properties in the molecules that strike at the catabolic core glycolytic pathway downstream and common to all known CG upstream target of rapamycin (TOR) pathway factors. Similarly, CR pathway activation increased insulin sensitivity, reduced hyperglycemia, slowed CG and inhibited the whole downstream gene transcription output of the CG pathway, allowing us to connect the CR/LE and CG systems into a singularity. A new and dawning realization in the cancer research community, that mutations in the CG proteins controlling core metabolism caused cells to remain ‘stuck' in CG, resurrected a long forgotten thirty year old hypothesis. We call this CG ‘stuck' state, the cancer metabotype (CM). Thus, we were enabled to connect CG, CM, CR, LE and diabetes II into a more global unification. Atherogenesis was less obvious, but became an easy fit, when understood from the CG/CM-CR/LE context, as described later. Results published in the March 2010 issue of Science, helped integrate this singularity by knitting an antioxidant sestrin redox containing active domain protein (SESN) to the tumor suppressor protein P53 and into the CR/LE pathway. We will describe, later, how it was necessary to divide mitochondrial biogenesis into two functionally discrete domains in order to render the pathway unification hypothesis consistent, coherent and realistic. The December 2010 admission, in Science, referred to earlier, that the denial of the notion that core catabolic metabolism as a requisite control element in cancer, had been a thirty year dogmatic blunder of major proportions, did not surprise us. The Science Special Section cancer metabolism discussion acts as an excellent primer for our paper. All of this combined to yield the metabolic flow diagram shown in Figure 1.

 

The system provided in the flow chart is a skeletal outline of the regulatory control pathways monitoring, responding to and governing catabolism, anabolism, nutrient availability, cell energy status and cell damage and repair integrity; all being in terms of the cell's ‘decision' to grow and divide under CG drivers or to hunker down and wait out a famine. The map is basically shown from an intracellular cytoplasmic perspective, because that is where the core system initially evolved, and is still housed, even in modern eukaryotic cells. The chart does not include wholesale nuclear gene system activation and deactivation, as they are described, as needed, in the narrative. The plasma membrane is provided to relate the core system to the extracellular milieu, which evolved from being the world at large for single cell organisms, to being the many integrated tissue trafficking interstitial fluid systems of modern multicellular organisms. Being the ‘vertrebrate chauvenists' that we are, we will bias our description from the standpoint of human physiology.

 

Viewed superficially, tuberous sclerosis complex 2 (TSC2) and target of rapamycin (TOR) act like the trunk of a tree with two input ‘branches' feeding in from the protein kinase AKT (AKT) and the adenosine monophosphate  kinase (AMPK). On the left side, AKT is the major CG/CM input, and AMPK, on the right side, is the major CR/LE input. Like a tree, finer branches feed into the two major branches. TOR outputs represent the ‘roots' of our metaphorical tree. Arrows represent component activation, while blocking plates represent inhibition. All components in the system are represented in an ‘as if poised' for activation state. For instance, if AMPK is activated, then it activates TSC2. Conversely, if AKT is activated, then it blocks TSC2. The opposing deactivated state causes the passive lifting of its activated dynamic. For instance, a blocked TSC2 lifts its block on TOR, thus allowing its activation by other factors such as AMPK etc. For the most part (except for PGC1 alpha and mitochondrial neogenesis), the right hand side of the chart represents the CR/LE pathway, while the left hand side of the chart represents the CG/CM pathway. The top half of the chart represents TOR inputs, while the bottom half represents TOR outputs. The big take home lesson is that the chart shows that the CG/MS and CR/LE systems operate in direct opposition via TSC2/TOR. What is not shown in the chart is that there is considerable reinforcing regulatory self-talk and counter reinforcing cross-talk between the two pathway systems. For instance, activating regulatory stimulators of one pathway synergistically co-stimulate multiple components in the self-same pathway, while inhibiting control elements in the opposing pathway. Thus, not only are the pathways in opposition, but they operate in self reinforcing and in oppositional inhibition. By acting as a dual function toggle switching system, TSC2 and TOR help to mitigate self-reinforcing vicious cycles, mostly via outside the pathway external inputs such as mitogenic growth factors or internal energy status sensors. This permits the system to invest in massively sweeping gene sets controlling giant pathway circuits, such as anabolism or catabolism, and to sustain them until they complete their processes.

 

 As we shall see later, mutational flaws in the system, as present in cancer cells, initiate vicious cycles by short circuiting plasma membrane signaling, cross-pathway dampening, genotoxic feedback loop monitoring and response, and fix the catabolic processing of fuel into a mostly ‘stuck' fetal-like state. We will also show how diabetes short circuits the system at the physiological level of a liver, adipose and muscle tissue triad, with the pancreas mostly being enslaved to the triad. To articulate the general overview of the systems, we will start with the CG/CM system, and follow with the CR/LE system.

 

Cell growth and division is critical for life, as organisms need to manifest it, explosively, during fetal development and wound healing, while utilizing a more leisurely rate for worn out cell replacement. We represent it, here, mostly from the perspective of a fetal cell, because it so closely resembles cancer, but in a regulable form. For instance, cell growth and replication, in the fetus, advances at a furious pace, is in a hypoxic environment, needs to invade surrounding tissues, requires vascularization and parasitizes the fuel and nutrient base that is provided ‘carte blanche' by the mother (or host), similar to an aggressive cancer.

 

Growth factors, like growth hormone (GH), transforming growth factor (TG), epidermal growth factor (EGF) and, to date, more than twenty others, stimulate either the rat sarcoma virus oncogene protein (RAS) and/or protein kinase C (PKC), via their activated kinase and tyrosine phosphatase cascades to up regulate the protein kinase AKT (AKT) to block TSC2, to TOR activate hypoxia inducible factor HIF, ribosomal S6 protein kinase (S6K) and the mitochondrial neogenesis portion of mitochondrial biogenesis. S6K activates the thousand, or so, genes that up regulate the whole of the anabolic system. Lipid catabolism is shut down, in favor of lipid synthesis and is replaced by heightened anaerobic glucose metabolism via transcription of the low Km fetal glycolytic enzyme set ordered by HIF. In essence, the cell becomes a sugar fuel ‘junkie' so as to preserve amino acids, fats and nucleotides as new cell construction material. Glycolytic end products, such as pyruvate, pile up and cannot be assimilated by the OX/PHOS incomplete neogenic mitochondria. Glycolytic intermediates and feedstocks, like glyceraldehyde 3 phosphate, dihydroxyacetone phosphate and glucose 6 phosphate, pile up and are diverted  to the pentose phosphate shunt (PPP) to generate pentose for nucleotide synthesis and NADPH for anabolic reduction and cytoplasmic defusion of reactive oxygen species (ROS) arising from respiration complex protein deficient neogenic mitochondria and elevated substrate phosphorylation. HIF also blocks the apoptotic mechanism, which would normally be poised for activation by the elevated mitochondrial ROS output. Importantly, HIF also activates vascular endothelial growth factor (VEGF) that is exported from the cell to mitogenically stimulate vascular endothelial cells to grow capillaries, then arterioles etc. to feed the growning and dividing cells with oxygen, fuel and nutrients, in a process called angiogenesis.

 

To support the growth system for impending tissue invasion, PKC and TOR stimulated S6K activates the release of cytoplasmic bound nuclear factor of kappa chain activated B cells (NF-kB) to the nucleus, where inflammatory cytokines such as cyclo oxygenase 2 (COX 2), tumor necrosis factor (TNF) and interleukins (ILs) become transcribed and exported to initiate extracellular edema, interstitial matrix breakdown and a furthering of the inflammatory cascade. In the interests of speed, the system sacrifices cleanliness and efficiency by inhibiting flawed self-component recycling via autophagy, and by delaying the transcription gene set for nuclear mitochondrial respiratory proteins until well after the CG driver system has been shut down. These respiratory proteins render inefficient neogenic mitochondria into efficient regenic mitochondria. Under CG activation, hexokinase II associates with the external surface of mitochondria to highjack mitochondrial ATP to entrap phosphorylated glucose within the cell and to reinforce hyperactivation of the glycolytic/PPP system. Mitochondria can also adapt to anaerobiasis by importing  deaminated glutamine for substrate phosphorylation via the succinyl CoA synthetase step, therefore, bypassing citrate synthetase, which normally utilizes the glycolytic post end product, acetyl CoA to prime the Kreb's cycle. Thus, we can see how the core catabolic systems complement the anabolic drive state initiated by the CG/CM pathway.

 

Mitochondrial participation in CG has always been a bone of contention, particularly in the case of cancer cells. The recent elucidation of the CR/LE pathway interaction with the CG/CM pathway, by our selves and others, has helped to resolve this debate.

 

Mitochondrial biogenesis has long been thought of as a singular process, initiated principally, via PGC1-alpha. It has been known, for over two decades, that mitochondrial biogenesis consists of two transcription phases, aptly named, the early phase and the late phase. The early phase begins immediately after TOR activation of PGC1-alpha, and produces the bulk of the thousand, or so, proteins that make up the vast majority of the proteins constituting the mitochondrion. Indeed, from all outside appearances, a whole new mitochondrion is born; but, in fact, such a mitochondrion is very functionally incomplete. The late phase proteins are a small, but vital set of deactivated TOR block lifted eukaryotic transcription initiation factor 4E binding protein (4E-BP) mitochondrial respiratory chain proteins typically produced some 24 to 48 hours after mitosis, and have been traditionally thought to ‘complete' the mitochondrial biogenesis process. This mitochondrial second phase ‘lag' is seen throughout fetal development, and has traditionally been thought of as a mere consequence of rapid proliferation and, therefore, as a component in a singular biogenic process. We see it as a dual process with the first phase requiring the absence of the second phase if cell growth and proliferation is to be able to occur at all.

 

The elucidation of the CR/LE system, its ROS activated SESN component, TOR as a toggle switch oppositely activating the early and late phase aspects of mitochondrial biogenesis and the different roles of mitochondrial catabolism during CG opulence and CR starvation, forced us to split mitochondrial biogenesis into distinct functional phases we call mitochondrial neogenesis and mitochondrial regenesis. Neogenesis is driven by CG, makes new OX/PHOS inefficient mitochondria and participates in CG metabolically. When CG shuts down and/or CR turns on, regenesis creates late gene mitochondrial OX/PHOS efficiency, and switches to functioning in the between replication cell quiescence, cleaning and maintenance phase. Our CG pathway implied as much, and its oppositional CR pathway, described below, further illustrates the point.

 

The CR/LE pathway upstream of TOR is best described by starting at AMPK. Until a mere year ago, AMPK was primarily viewed as a cell energy status sensor, being up regulated by elevated concentrations of energy poor AMP and NAD, and being down regulated by their absence, as a result of high concentrations of their alternative energy rich forms as ATP and NADH. AMPK is now also known to participate as a powerful reactor to ROS and genotoxic stress from ROS effects via P53 to SESN, or other SESN activation, as shown in our chart. This acts both as a mitochondrial neogenic or regenic function feedback sensor as well as a nutrient availability, CG drive state and energy status sensing and response cluster. 

 

When activated by cell energy depletion, SESN or P53, AMPK activates TSC2 and, thereby, inhibits TOR, which lifts its block of 4E-BP and initiates transcription of late phase mitochondrial regenesis respiratory complex genes. These regenerated mitochondria become efficient in OX/PHOS and dramatically cut ROS production, which in turn, reduces genotoxic stress, which shuts down p53 induced DNA repair mechanisms. Of course, this deactivates AMPK if and only if  the cell is energy rich, and not CR driven. A CR to AMPK drive state eventually lifts TOR inhibited autophagy, causing the cell to engage in frugally scavenging its own defective parts. If ROS damage becomes too severe for scavenging and repair, an already cross pathway sensitized apoptotic mechanism due to activated p53, cytochrome c efflux from ‘dying' mitochondria, a down regulated CG pathway and others, institutes cell suicide.

 

Lastly, mitochondria and glycolysis ‘talk' to each other through metabolic intermediates, not yet fully understood factors, mediated in part by NF-kB and COX2, in a complex system called the retrograde response (RTG). This helps facilitate the switching back and forth between mitochondrial metabolic states associated with regenesis and neogenesis in the context of up and down regulation of glycolysis. In general, the RTG response is utilized in the ‘on' position by hypoxic neogenic mitochondria with poor oxygen utilization when cells are highly dependant on anaerobic glycolytic substrate phosphorylation for ATP, as is found in fetuses and in the core of neoplastic tumors. Interestingly, in cancers, mitochondrial telomerase can relocate to the nucleus to initiate immortalization. It is intriguing that the central elements of both cell suicide (apoptosis-cytochrome c) and immortality (mitotic index-telomerase) were both evolved to be released from mitochondria. Suicide vs. immortality, WOW! In teleological terms, that seems like a rather god-like position to be in, for such a lowly organelle. A much deeper treatment of mitochondrial function is provided by Seyfried and Shelton, as referred to previously.    

 

It would be so easy if everything just feeds into and out of TOR as a simple toggle switch. However, nothing in biology is simple. There are many TOR molecules in a cell, and they can be geographically and microsomally compartmentalized in the cell, with some in the ‘on' position in one compartment, while others are in the ‘off' position, elsewhere, as is revealed in the 5/20/11 issue of Science. Both TOR conditions can be operating in a pseudo homeostatic condition, when there is no clear cut drive state, or, probably, during circadian rhythms, when the system ‘leans' CG during post prandial states or ‘leans' CR during temporary, light fasting, sleep states. In clear cut drive states, like starvation or ad libitum fetal growth, the TOR system is caused to respond wholesale to the preponderance of the inputs. Such is the case in the diseases of aging we describe below.

 

The Cancer Metabotype and Some Therapeutic Logics

 

As we saw from the previous section, the glycolytic and mitochondrial metabolic pathways form a catabolic core system driven by CG and CR. Furthermore, these systems make coherent and consistent requisite changes depending on the cell state in all animal organisms and all of their cell types. No matter what the status of myriad regulatory elements superimposed on the ancient core system, it must respond in a flexibly limited fixed manner, or the global system collapses. Apoptosis and novel cancer therapies show some of the bounds of this limited flexibility. In normal cells, the core system can toggle back and forth between the CG and CR states. It cannot do this, either easily, or at all, in the cancer cell, as a result of mutations in the core system or in the regulatory elements of the core system. We distinguish this mutationaly ‘stuck' cancerous growth state from the normal CG state by referring to it as the cancer metabotype, or CM, for short. It has long been felt that the core system was a mere normal handmaiden to cell growth factors and other regulatory elements, and therefore, unworthy for investigation as a means of chemotherapeutic attack. (The sad tale of this 54 year drought can be search engined under Bambeck cancer: Mainstream Science Dogma Reversal, on the internet.) Recent developments show that many types of cancer cells can be growth arrested, killed or even differentiated by direct attack on the core system, its most intimate regulators or nearest neighbor/function partners. However, cancer cell kill therapies are neither the thrust, nor the scope of this paper, albeit the logic behind such therapies is well within its purview. Our primary focus is to define the basic CG/CM and LE/CR systems and to conduct a search for phytonutrient regulators which rectify the system in a way that helps to prevent or renormalize the three major diseases of aging, and which promote life extension. Thus, we will give a cursory overview of cancer in terms of our metabolic flow chart, and some of the therapeutic logic that can impact cancer.

 

The cancers are a madhouse of mutagenic realities in terms of both their many cell variations and types, and the myriad ways they can convert CG to CM. For instance, there are over twenty growth factors, and even more growth factor receptors and downstream cascade components that are specific to different tissue types and cancers, each of which would need a different ‘magic bullet' if attacked at this level. As an example, Herceptin blocks the up regulated growth promoter estrogen receptor on breast cancer cells and is, therefore, a magic bullet for this kind of flaw. This receptor is not the error for most breast cancers, or virtually any other types of cancer, for which, Herceptin is useless. The amount of research time, cost and testing to develop such a vast target specific array, is mind boggling. Later mutations in the cascades down stream of growth factors and their receptors can, and do, eventually circumvent such therapy. Even insulin dependence and resistance can be skirted by up regulation of non-insulin dependant glucose transport proteins, such as GLUT 4, to feed CM hyperglycolysis. We must note that the high ROS index of cancer cells fosters further mutagenesis to enhance selective survival of individual cells from the tumor cell population. Many tumors contain several, or more, clonal subpopulations in a tumor mass. However, all of these CG errors facilitate the core metabolic CM system.

 

On the CR/LE side, the P53 protein is defective, in one of many possible ways, in about half of all cancers, being far and away, the single most common gene product function defect in all of cancer, but we have yet to figure out how to fix defective proteins or how to target gene therapy to the cell type of interest. In addition, too much of a good thing might be a bad thing, as mice with extra copies of P53 genes die prematurely. Back on the CG/CM side, RAS function is also elevated in a plurality of tumors and provides a reasonable therapeutic target, but can be circumvented by P13K. Attacks at this level are more like cancer management than cure strategies, as they basically renormalize metabolic flow into a non-growth dynamic, which might sometimes initiate differentiation into a less mitotic form, or delay disease progression rate by slowing growth, which is a good thing when one has a lethal disease. HIF and the VEGF response family, which lie closer to the core metabolic system of glycolysis provide much more tempting targets, and are a hotbed of research today. Blocking HIF would shut down the whole fetal enzyme driven glycolytic pathway while the rest of the TOR activated anabolic drive state would still be operating. This would really throw a monkey wrench into the whole CM metabolite flow dynamic. As a bonus, this blocks angiogenesis downstream of VEGF, which shuts down the tumor fuel supply, in addition to down regulated HIF already having diminished its ability to use a fuel supply. The closer we get to the CM core system of metabolism, the more general the impact across a broader array of tumor types.

 

Some recent developments in core systerm attack logics have really raised a lot of eyebrows. Blocking Hexokinase II with 3-bromopyruvate eradicated a hepatoma in all cases of a rat tumor model. Attacking fetal puruvate kinase II with dichloroacetic acid has shown merit in a broad array of tumors. It would seem wise to broaden our assault further up the glycolytic chain and its input branches to the PPP. These are simple molecules to mimic and there should be thousands of inexpensive candidates. We could have begun all this research thirty years ago, had we only listened, so for the present, this ‘new' area of research has only a few weapons. The good news is that we have robotic micro-array tissue culture and automated fluorescent cell status and cell apoptosis monitors that allow testing thousands of molecules and dozens of cell types, daily.

 

Interesting synergies between glycolysis and mitochondrial therapies can be envisioned. TOR up regulation of both systems keeps mitochondria spending most of their existence in a neogenic default state. In some cases, this is concomitant with a large glutamine importation increase, but it always includes a programmed OX/PHOS deficiency/insufficiency. Glutamine deamination inhibitors or Kreb' cycle blockers downstream of oxalosuccinis acid, could inhibit glutamine pathway flow and assist glycolytic disruptors in further catabolic substrate flow disregulation with TOR activated anabolism. Used judiciously, respiratory chain blockers or OX/PHOS to ATP uncouplers could also disrupt CM flow integrity. These glycolytic/mitochondrial therapy strategies were first presented, in much more detail, in the Bambeck dissertation of 30 years ago, and as referenced in our January 2011 Mainstream Science Dogma Reversal paper.

 

Robert Weinberg is hailed as creating his, supposedly independent six hallmarks of cancer, these being: 1) growth signal self-activation, 2) growth suppressor inhibition, 3) anti-apoptosis, 4) immortalization, 5) angiogenesis and 6) metastatic tissue invasion. Why he did not include avoidance of immune surveillance as a seventh hallmark, is mystifying to us. With our new understanding, as discussed throughout our paper, we would list 1, 3 and 5 under the single hallmark of CM pathway activation, with 4 as a mitochondrial corollary to our first hallmark. His number 2 hallmark could stand alone, mostly in terms of the CR/LE pathway. His number 6 hallmark would definitely stand alone at our present stage of understanding. Thus, we would reduce his six hallmarks to three and add immune avoidance as a fourth. Being of a strongly anti-Warburg and anti-metabolic bent, like his predecessor Sydney Weinberg, probably prevented him from being able to see what scientists so clearly understand today. From a purely scientific standpoint, the anti-Warburg story is shameful.      

 

Everybody admits that preventing cancer, in the first place, is the most preferable. A proper Spartan diet, plenty of exercise, anti oxidant supplements, not smoking, avoiding glucose/fructose, etc. can reduce cancer incidence by a whopping, age-indexed 70%, far in excess of the cure rate. Such horror avoidance is a good thing. However, if CR is included for life extension, it represents a Draconian, near anorexic life style, and people, just flat out, won't do it, especially during this age of pre-fab food and lounge lizard Hi-Def flat screen toys. It appears that a moderate life style and CR mimetics just might be the ticket. The problem is that there are only two prescription requiring and relatively expensive pharmaceutical candidates available, and a foreign tissue immune system suppressor, like rapamycin, is just too TOR direct, bypasses all input pathway cross regulation, and just plain sounds, too immunologically scary.

 

Type Two Diabetes and Metabolic Syndrome

 

By analogy, diabetes II is unnervingly similar to the supply and demand conundrum that plagues the present American (July 2011) economy. The bank, corporate and wealthy citizen investment/production/supply side is engorged with some $6 trillion in hard cash while the consumer/demand side is unemployed and cashless. Supply fails to invest in domestic (but not foreign) employment, goods and services because its domestic demand side customer base dwindles, while a polarized government remains gridlocked and does nothing to alter the bulk of the cash flow dynamic. One side of the aisle robs the cash input side of the treasury to juice the enfranchised elite, while the other side of the aisle spends the treasury, so as to keep the highly weaponized, but job and home dispossessed from starving and rioting. A continued widening of the economic gap is unsustainable. In retrospect, we seriously doubt that even a mentally challenged Marie Antionette would suggest that we repeat history before learning from it.

 

Similarly, diabetes has been called ‘a disease of starvation in the midst of plenty'. It disrupts the carbohydrate balance of the whole cell population of the body. It does so by coupling massive carbohydrate intake, over a long time, with a muscular lassitude that fails to burn the carbohydrate fuel and creates a catabolic lipid oxidizing collapse, a metabolic condition called metabolic syndrome (MS)  that not only maintains, but exacerbates the condition. Thus, in the preponderance of cases, diabetes is preceded by obesity. The over all physiological response is rather slow to develop, but has recently been revved up by a childhood obesity epidemic. The MS state is both a hyperglycemic and hyperinsulinemic state, before developing into full blown diabetic insulin deficiency due to exhaustive pancreatic collapse in insulin producing capability. Simply put, diabetic end stage glucose is in abundance, and the cells can't take it up. Many now feel that diabetes progresses from a disorder of muscle/adipose origin. These tissues occupy about half of the metabolizing ‘wet' tissue weight of the body in normal, non-obese individuals, thus is a disease process facilitating bulk flow mismanagement of the whole carbohydrate/lipid economy. In the end elevated glucose, increased insulin resistance and insulin insufficiency cause starvation in addition to hyperglycation, elevated ROS, widespread inflammation, and with a massively elevated cancer incidence and cardiovascular system collapse risk, instituting a total body rebellion that burns the organism's ‘cell city' to the ground, i.e. death. We describe the physiochemical process, below.

 

Early in the twentieth century, type I diabetes was discovered to result from loss of pancreatic insulin production. Insulin replacement dramatically reduced lethality, albeit with an over all reduced life expectancy. Middle age onset type II diabetes also responded to insulin replacement, and was most pronounced in the obese. Thus, initial research focused around a food intake (intestinal), liver and pancreas metabolic triad. In the late twentieth century, the growing obesity epidemic, the growing fatty liver (steatosis) epidemic, increased muscular lassitude, a massive upsurge in fructose in the diet and a few key discoveries have shifted our focus toward a muscle, adipose and liver triad, with the pancreas as mostly a response element to the triad.

 

The metabolic syndrome (MS), in modern developed nations, begins from a combination of over indulgence of prepared convenience and ‘junk' foods, coupled with a physically lethargic life style. These foods contain astronomical amounts of rapidly absorbed simple carbohydrates, because these carbohydrates are almost dirt cheap on a $ to weight ratio, making great ‘filler' and they also foster an eternal ‘sweet tooth' addiction in humans, as described below. There are three main rapid absorption carbohydrates in these foods, and they are: 1) high fructose corn syrup (Hi FCS), which is composed of the simple sugar monomers fructose and glucose in a 55/45 ratio, 2) sucrose, mostly from sugar cane, is a sugar dimer composed of fructose and glucose in a 50/50 ratio and 3) simple starch, a mostly linear sugar polymer composed of nearly 100% glucose. Hi FCS, being monomeric, enters the blood stream fastest of all, achieving bulk transfer concentrations in about five minutes, while sucrose must be cleaved into its monomers by the enzyme sucrase, to also achieve similar to Hi FCS blood levels, in about twenty minutes. Simple starch, as found in potatoes, rice, white flour etc., is partially cleaved into large chunks by salivary amylase, then, converted to monomers by further amylase treatment in the digestive tract. It is bulk transferred to the blood over about an hour. Although all three are rapidly absorbed, Hi FCS is, by far, the worst offender, due to its prodigious and rapid uptake, so we will use it to demonstrate our MS to diabetes II conversion. Hyperglycemia is the cause of protein glycation, and a previous month long diabetic life style management of glucose can be measured as glycated blood hemoglobin, known as HbA1c. Bambeck cut his milk teeth in diabetic research by developing an electrophoretic isoelectric focusing HbA1c diagnostic test for Isolab Inc. in 1981. The test also detected sickle cell anemia, fetal hemoglobinopathy and 70 other mutational hemoglobinopathies. It gained FDA approval and was widely used on newborns throughout the 80's and 90's. Glucose management is critical, in diabetics.

 

When the hi FCS monomers rapidly enter the blood stream in very high concentrations, the sharp glucose hyperglycemic state initiates a rapid insulin spike, that causes intense cellular uptake of glucose, soon instituting a precipitous glucose drop, manifest as hypoglycemia. Insulin over response, in the first place, results in an unusual circumstance, not common prior to Hi FCS, manifest as hyperinsulinemia co-incident with hypoglycemia. This condition creates a huge craving for sweet tasting ‘stuff', to relieve the conflicting fuel and fuel driver dilemma. This creates a vicious cycle of eating and craving, that fosters the obese condition. This is the pre-MS condition. The second, and more covert sugar, is fructose. Fructose in the blood stream does not induce insulin secretion, and is not readily taken up by most somatic cells. Instead, it is sequestered in the liver, where it is converted to triacyl glycerols, which are then, esterified to fatty acids to form triglycerides, which are stored in the liver. Over time, this causes fatty liver (steatosis). Steatosis up regulates Apo B protein, causing increased VLDL production, and thus, increased triglyceride transport to adipose tissue. Elevated VLDL is also implicated in cardiovascular disease, as discussed, later. Chronic steatosis, if unchecked, institutes early stage liver cirrhosis in about a decade, then relentlessly progresses to advanced liver cirrhosis and death, or to advanced liver cirrhosis, hepatic cancer and death, depending on the luck of the draw. Progressive liver failure causes increasing hepatic ROS, pro-inflammatory molecule production and increasing loss of detoxification functions. Inflammatories and toxins flood the vascular tree, and initiate system wide molecular damage that induces peripheral somatic cell ROS and inflammation throughout the body, and a vicious cycle ensues. At this point, ‘cell city' is burning. This occurs, co-incident, with adipose/muscle involvement.

 

 It is estimated that thirty percent of the American population suffers from liver steatosis, that the disease is appearing in large numbers, in obese teenagers, for the first time in history, is occurring in parallel with diabetes II, and is a harbinger of a need for future liver transplants in the untold thousands, or even millions. (A more thorough review of fatty liver disease can be found in Cohen, J.C. et.al. Science, p.1519, 6/24/11.)  Does this mean that we add a liver transplant epidemic to the already existing obesity, steatosis and diabetes II epidemics? In addition, what do we do about the fact that these traditionally middle and old age onset conditions/diseases are now commonly appearing in young adults?

 

Silibinin, one of our phytonutrient gold medal winners, was originally used to save mushroom poisoning victims from hepatotoxic liver failure. Later, it was put into use for general hepatotoxicity. Medical drug applications, like some actors, get ‘type cast' for their function and more creative research becomes stalled, as it did so, for silibinin. Just recently however, silibinin has also been found to be useful as an adjuvant to conventional cancer therapy across numerous tumor types, thus showing a metabolic commonality between cancer and diabetes. We would note here, that anyone thinking of linking silibinin with the modern ‘sugar junkie' diet would be living in a fool's paradise. 

 

Inactive muscle does not raid adipose tissue for fat energy because it is white fiber muscle, is almost totally anaerobic and burns glucose to lactate, for export to the liver for gluconeogenic reconversion to glucose, the whole process known as the Cori cycle. Highly athletic endurance red muscle fibers are the ones that use fat and oxygen as fuel for the Kreb's cycle. Couch potatoes have virtually no red muscle. It has recently been found that white muscle is almost absent of peroxisome proliferator activated receptor (PPAR gamma), a vital component necessary for the transfer of fat from the adipose compartment to the muscle compartment. Not only is it true that white muscle will not oxidize fat, but it cannot, either. Red muscle makes PPAR gamma, and both, will and can oxidize fat. If there is enough muscle tissue oxygen demand, over several months of intense endurance exercise, white muscle content can decrease and red muscle content can increase, and red muscle mitochondrial content can rise from a lowly 5% of muscle volume to over 30% of muscle volume. However, that is not the case for our sugar sucking and lethargic modern human, we have been using, herein, and by this point in the discussion, the condition has become full blown MS. Lastly, tissues other than muscle respond to MS hyperinsulinemia and hyperglycemia by down regulating their insulin receptors, while muscle up regulates its insulin independent Glut 4 receptors.

 

It becomes obvious why whirlwind exercise programs and crash diets will not work on a slowly developing set of circumstances, like those outlined, above. If not checked, the liver/adipose/muscle triad system simply wears out the pancreas and the organ can no longer provide the demanded insulin: this then is diabetes II, and ‘cell city' is now in conflagration. From a metabolic standpoint, it resembles a kind of CG/CM and CR/LE cellular analogue that has gone awry at the tissue and organ level of integration. The downstream activations are similar, in that ROS, glycation and inflammation cause general tissue damage throughout the body. The disease dramatically accelerates aging, heart disease and cancer incidence. With sugar intake reduction, moderate exercise and the phytonutrient metabolic pathway modifiers, discussed in the phytonutrient candidate section, the preconditions can be halted and reversed. The full blown disease cannot be reversed, but its progress can be slowed.

 

Pharmeceutical metformin, a direct activator of AMPK, and thus CR/LE, has been widely used for decades in ‘beyond MS' low level diabetes II, to control blood sugar and to delay insulin dependence. It decreases insulin resistance, up regulates the CR/LE pathway and down regulates the CG/CM pathway, and with all the appropriate myriad downstream impacts. In a multi-patient survival record analysis, it was shown to dramatically increase the survival time of diabetic brain glioblastoma victims over those patients not taking metformin, regardless of all other therapies used. Our three gold medal winners have a mechanism of action similar to metformin, and they have all shown efficacy in glucose control and across a startlingly broad array of tumor types. To our knowledge, metformin has not yet been tested across a broad array of tumors. Again, and this time with a pharmaceutical and CG/CM and CR/LE rationale, cancer and diabetes show therapeutic linkage via a metabolic commonality. We hardly thought that nature could ‘turn it up any louder', but it did, as we shall soon see.

 

The metabolic syndrome/diabetes sequence can daisy chain into very serious cardiovascular damage, as is both common knowledge, and as we shall see presented in the next section. Of the three aging disease states outlined here, atherogenic cardiovascular disease is the most cryptic and obscure, from the standpoint of our CG/CM and CR/LE metabolic map, as the disease is a mixed bag, of as much of an effect from other conditions, as it is from its own causes.

 

Atherogenic Cardiovascular and Related Disease

 

The rough and tumble environment of the vascular tree is far different than that of the calm extracellular interstitial fluid backwaters bathing most of the body's cells. The vessel walls are directly exposed to mechanical and chemical stresses that arise from distant sites and are delivered or manifest throughout the system. For instance, hypertension accelerates the rate of formation of atheratomous lesions, initiating LDL repair mechanisms. Also, MS, initiated else where, as hyperinsulinemia, hyperglycemia, hyperglycation and hyperinflammatory ROS, TNF, COXII, ILs etc., cause molecular damage within and throughout the lumen exterior and interior walls of the arterial system. The lipid delivery system is somewhat unique to the circulatory system and has its own peculiar ways of going awry, as we shall see, with LDL, HDL, foam cells and arterial intima smooth muscle cells. Atherosclerosis is almost exclusively restricted to the much higher pressured and most thickly walled arterial side of the vascular network, where turbulence inflicted damage is most pronounced, and where the damage resulting from the reaction to the initial damage, is even more pronounced. The response and response to a response sequence, somewhat obscures a direct interpretation of our metabolic map. Rational salvation lies in the fact that the disease causes and therapeutic outcomes share that same, previously mentioned, Occam's razor.

 The classical low density lipoprotein (LDL)(bad cholesterol) and high density lipoprotein (HDL) (good cholesterol) story is the most widely known, medically instructed and publicly disseminated narrative in the history of medicine, and will only be given a cursory brush over, herein. We will, however, give some space to a few very lethal, but less known variations of the theme. The lipoproteins LDL and HDL precursors are synthesized in the liver as a hyper lipid packed very low density lipoprotein (VLDL) and the lipid void form of HDL. VLDL and LDL engage in lipid delivery to the peripheral cells via the vascular network, while HDL acts as a lipid scavenger and transfer agent. Hyperlipidemic disease participates in the cause of atherogenesis by typically manifesting as a genetic or environmentally induced over representation of LDL or as a genetic or environmentally induced under representation of HDL. Thus, the notion of the LDL/HDL ratio, as the famous ‘bad cholesterol to good cholesterol' index of cardiovascular disease risk, has now become a common household phrase. Environmental and genetic factors synergize, so that one born with a genetic proclivity for atherosclerosis requires less of an environmental insult than one born with a more normal genotype. We try to integrate our approach, so as to provide as few examples as possible.

 In the normal process, VLDL in the blood stream slips between the endothelial lining cells of arteries, veins and capillaries, where it is converted sequentially from VLDL to intermediate IDL to LDL and then to mostly lipid depleted LDL by sequentially binding to B, E and B plus E receptors on cells, where lipids are off-loaded. The mostly lipid depleted LDL returns to the blood to be decommissioned by the liver and replaced by nascent LDL. An LDL molecule can be ROS oxidized, or is all too frequently present in the population as a small dense (SDLDL). The SDLDL form is much more readily oxidized and is viciously atherogenic. After being converted to its active form, the lipid void HDL-3 mostly fills up with lipid by binding to E receptors, which further activates a blood born new form, now called HDL-2a to utilize  the cholesterol ester transfer protein (CETP) for LDL interactive transfer. Fully lipid loaded HDL-2b is captured by liver E receptors and is decommissioned. There appears that some people have an unknown defect that interferes with HDL-3 conversion to HDL-2a, possibly interfering with Apo AII removal or Apo E activation. Bambeck created a lipoprotein subractionation assay, over a decade ago, for both SDLDL quantitation and HDL-3 quantitation. The test also revealed two VLDLs, three IDLs, seven LDLs in two diagnostically useful groups and thirteen HDLs in three diagnostically functional groups. This was a bit much for the research and diagnostic communities to digest at that time.

 The quantitation of SDLDL should be a medical priority, because it is very atherogenic, appears in about 27% of the general population, does not appear on any traditional cholesterol screen and does not respond to statin drugs, but does respond to fibroates, such as gemfibrizil. Approximately half of all SDLDL victims show no other risk factors with conventional diagnostics. About six years ago, as contract work, Bambeck proposed that SDLDL ‘disease' is represented by a single co-dominant allele of an unknown gene, the only other allele being the normal form. The disease was proposed to manifest in its homozygous form at about age twenty five and kill by age 45 in about 2% of the population. More disheartening, is that in its hypothesized heterozygous form, it manifests in about 25% of the population at age 45 and kills by age 65. The disease is almost a perfect match for a two allele system in Hardy-Weinberg equilibrium with a 14% general population penetrance. How it gained such penetrance remained a mystery until it was discovered that grossly obese children of parents with SDLDL, who were put on emergency lipid free diets, ‘turned on' the SDLDL response at the unheard of, early age if ten. That, plus the dietary response to intestinally active gemfibrozil, indicated that the mutation had a strong gut lipid extraction survival advantage in a small human race founder population that faced severe nutritional lipid semi-starvation for many generations. We have no idea if this notion ever gained any traction. Regardless, SDLDL is a major league population killer, for which, resolution is readily available, if we would only test for it and treat it.

 The non-functional HDL-3 situation is less severe, but just as ‘silent' as SDLDL, and appears in about one-fourth of the general population. About 90% of individuals with elevated HDL-3 have an elevated LDL, but conventional diagnostic assays report only the total HDL number, which includes HDL-3 in the aggregate, thus under reporting the risk as a lower LDL/HDL than it should be. The risk is even more skewed in the 10% without other known risk factors. The impact of HDL-3 was not clearly defined until recently, and the Cleveland Clinic bemoans the fact that there is no available non-functional HDL test. Unfortunately, the source of the HDL-3 assay filed for dissolution in 2004. All samples used for the lipoprotein subfraction assay came from 4,000 participants in the Framingham Study, and were kindly provided by Judy McNamara of Tufts University.  

 The lipoproteins are only part of the atherogenesis story, although, for most arterial disease, LDL and its variants are most often considered to be the culprits. In response to arterial wall injury due to baromechanical, chemotoxic or inflammotoxic origin, macrophages migrate to the intima layer of the artery and acquire lipids from LDL for use as fuel, repair and maintenance. In the abnormal condition of hyperlipidemic LDL, high numbers of ROS induced OXLDL and/or genetic SDLDL, macrophages become lipid overloaded, taking on a golden lipid droplet engorged state, microscopically referred to as ‘foam cells'. Foam cells hyperactivate an immediate vicinity NF-kB cascade and cause mitosis in the smooth muscle cells lining the intima layer. Necrotic foam cells make up much of the fatty part of the forming atherosclerotic placque, while replicating smooth muscle cells form beneath a fibrous placque capsid that acts as a surface seal to the growing atheratoma, which eventually protrudes into the arterial lumen. Some scientists have speculated that smooth muscle cell proliferation is akin to benign tumor growth and that the macrophage foam cell and smooth muscle cell inflammatory/mitotic cascade form a progressive self-reinforcing vicious cycle that facilitates and exacerbates placque growth and its spread as colonial groups. This makes sense from a molecular damage stand point, and is consistant with the CG/CM pathway dynamic

 Ultimately, placque artery blockage becomes, so severe, as to cause downstream tissue ischemia and hypoxia. Sudden death often occurs when a placque capsid tears and fibrinogenic polymerization blocks the artery with a clot, or a clot breaks off and lodges further downstream, causing anoxic death to vital function tissues such as heart, lung or brain.

 There are a host of other cardiovascular disease states, more particular to the heart, that result from a shift from a CR/LE pathway driven to CG/CM pathway driven status. Inflammation, ROS and glycation are neuropathic and can disrupt the cardiac cycle, leading to arrhythmias, fobrillation and infarction, as well as causing valvular and endocardial lining damage. Mitochondrial inefficiency and low mitochondrial numbers can reduce ATP production and force of contraction, as found in congestive heart failure and ventricular hypertrophy. Shifting the drive state from CG/CM to CR/LE has been shown to be neuroprotective, as well as neuroregenerative in both heart disease and diabetic neuropathy. This metabolic shift has been shown to increase mitochondrial numbers in both cardiac and skeletal muscle, to increase ATP production and to increase muscular force of contraction, thus relieving all the above mentioned conditions. Our three gold medal winners perform all these functions, in addition to their anti-diabetic and anti-cancer functions, as described earlier. The silver medalists synergistically support the gold medalists. Finally, we are ready to discuss our selected dietary supplements.

 The Phytonutrient/Nutriceutical Candidates

 The health food stores and giant pharmacy chains are awash with a bewildering array of hundreds, if not thousands of natural (and otherwise) dietary food supplements and herbal extracts from the four corners of the world. Just walking down the aisles should institute some form of clinical depression. Where to begin? How does one separate the questionable legitimacies of; folk remedies, old wives' tales, heap big mojo shamanism, venerable ancient medical wisdom, mythology, cultural favorites, modern marketing snake oil hucksterism etc. from actual fact and good medicine? As an alternative to taxing our already enfeebled brains, we hit on the best idea we've had in years. Instead of embarking on an interminable grand search, we let the world's best and brightest topic specific professional brains do our thinking for us, and we went in with a strategic plan.

 We embraced a copy Disease Prevention and Treatment, published by The LifeExtension Foundation (LEF). Therein lies the combined efforts of ‘thousands of research studies and the clinical experience of physicians around the world' (to put it in LEF's own words) devoted to the over riding purpose of life extension. After reviewing what LEF had to say, we used scientific publications and the internet to update and modernize our understanding. Having our CG/CM and CR/LE map in hand, and our three principal diseases to both direct our search and institute the strategic plan, we plunged in.

 The plan had a few simple but inviolate and all inclusive rules. Each candidate must have utility against multiple cancers and against diabetes and against atherogenesis; all three. It must both, statistically prevent or delay onset of all three diseases by significantly reducing the probability of age related population incidence and must slow the progression of all three disease states, once disease is instituted. Where the principle target and/or mechanisms of action are known, it must regulate its target, and in turn, their downstream pathway targets in the direction consistent with the CG/CM and CR/LE map. Where principle target or mechanism of action is not yet known, downstream effects must match the regulatory directions of our metabolic map. Although not an absolute requirement, each chemical should have an extremely high LD-50, in the multiple dozens to hundreds of times its functional dynamic range and a history of extreme safety, which all our winners do. The probability of satisfying all of these and requirements is minute and is a powerful set for a true candidate.

 Limiting our search from the world at large to the LEF compendium, instantly whittled the search from thousands of possibilities to a few hundred. Applying the all inclusive rule set to these few hundred, fairly quickly drove the number down to a few dozen and then, much more slowly and agonizingly, chipped its way down to a handful. Incidentally, route of administration was not a consideration as some of these molecules have poor oral bioavailability in a pure form, but much higher bioavailability in a soluble injectable form, or in a conjugated oral form. Winning candidates might be more accurately defined as nutriceuticals rather than as phytonutrients or dietary supplements due to their mechanism of action. We have already provided a general description of the differential therapeutic merits of our gold medal and silver medal winners, and we will diversify those merits and differentials, later.

 Before we begin, we must say a word or two, about antioxidants. For one thing, antioxidants are good for us, plain and simple. Thus, it is not surprising that antioxidants have been all the rage for the last two decades, and for a host of good reasons. They protect us from the major diseases of aging, reduce ROS formation, give us more vitality and with a long list of well worn etceteras, allow the population survival curve to leptokurticly shift toward the maximum life expectancy. However, they simply do not institute LE, albeit being ‘the best game in town'. Driving this point home is that organisms on a CR or CR mimetic protocol manifest LE without any antioxidant supplementation whatsoever! Check and mate. End of game. 

For this and other reasons the ROS damaging hypothesis is now seen more from the avoidance of the life shortening side, as opposed to the life lengthening side of the equation. The antioxidant hypothesis has been found to be limited and in need of modification. We must remember here, that critical elements of the LE pathway were only discovered during the last one to two years, so a theory modification was not even realistically possible prior the very recent present. For instance, the LE pathway institutes mitochondrial regenesis and reduces ROS production, in the first place, obviating the need to mop up ROS ‘after the fact' with antioxidants. Prior to the elucidation of the LE pathway, any LE system activator would have been, and in fact was called an antioxidant, simply because of mitochondrial regenesis; and mitochondrial regenesis was not hypothesized at the time. We believe ourselves to be the first folks to attempt to formulate a primitive global CG/CM and CR/LE map that includes the notions of cancer metabotype, mitochondrial neogenesis/regenesis, CR/LE pathway, CG/CM pathway, CR/LE pathway mimetic and functional antioxidant classification as simple antioxidant, funnel antioxidant and metabolic pathway antioxidant, even though all of these things are well described in the literature, but disjointed, because this age of specialization obscures any ‘big picture' review approach, such as ours. 

The health food supplement world is awash in phytonutrient antioxidants, and our metabolic map has helped us to loosely classify them into three broad categories with considerable overlap. Simple antioxidants are, to put it simply, basically just antioxidants. Vitamin C is a simple antioxidant. In fact, if it doesn't have a partner to defuse it, it becomes a pro-oxidant in its ROS activated state. Funnel antioxidants are antioxidants that both accept ROS from other antioxidants and pass their ROS activated electron(s) to a metabolic system to defuse them and to extract useful energy. For instance, the vitamin C, vitamin E, NAD sequence, sets vitamin E as a funnel antioxidant. Better yet, a little system like coenzyme Q (CoQ) and alpha lipoic acid funnel ROS energy from ROS and many other antioxidants, with CoQ being a requisite functional element in the metabolic pathway itself, for passing ROS electrons to the OX/PHOS system of mitochondria for energy capture as ATP production. In addition, alpha lipoic acid restores vitamin E and vitamin C to full antioxidant status by reducing their oxidized state; a possible recycling alternative to massive simple antioxidant dosing. Best of all, are giant macromolecular machine system antioxidants such as the mitochondrial OX/PHOS efficiency system of mitochondrial regenesis, as turned on by activated CR/LE. This third category is the big antioxidant player in our new understanding of the CR/LE phenomenon. Now, we are in a position to consider the functions of our winning candidates. Lastly, we are not going to list all of the impacts of our gold and silver medal winners, or this narrative would read like a phone book. We will bundle wherever possible and stick to main effects, hopefully, without short changing the reader.

The three big gold medal winners are curcumin, silibinin and resveratrol. (Continued at articlesbase article  Life Extension Metabolic Pathway Map Reveals New Phytonutrient Candidates- Part 2). 

Gregory S. Bambeck Ph.D., e-mail: gregorybambeck@yahoo.com

 

Michael Wolfson  J.D., M.B.A., e-mail: mwolfson@stanfordalumni.com

 

Copyright by Gregory S. Bambeck and Michael Wolfson

About the Author

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380 - Large Print Monthly Wall Calendar In Punched Leatherette Binding, 20 X 26, 2012 $19.07 dated Wall Calendar Offers 12 Months Of Planning From January To December. One-month-per-page Format Includes Ruled Daily Blocks (3-3/4 inch X 25/8 inch ), Julian Dates, Days Remaining And A Full-year Calendar Reference. Calendar Is Three-hole Punched For Hanging And Is Printed In Dark Brown And Beige Ink. The Brown Binding Is Made Of Simulated Leather. Heavy, Noncurling Recycled Paper Is Made From 100 Percent Post-consumer Material. [HOD380] Recycled UPC: 040983302111 UNSPC: 44112002 1 LB

GBC Premium Binding Cover $61.99 0% 1 / Box 40% 8.75" x 11.25" 9742490 Premium Binding Covers offer the look and feel of real leather. Each delivers exceptional durability and quality. Edges feature square corners. Binders are made with 40 percent post-consumer material. ACCO Brands Corporation Binding Cover Black Corner GBC Navy No Premium Premium Binding Cover Presentation www.acco.com

Banana Plug Binding Post for PRC Hardline Cases $5.99 Your PRC Hardline Case is as customized as you want to make it, and these Banana Plug Binding Posts are just one more way to create the charging setup that's right for you. Whether you want to be able to plug your charge cables into the side of your case, or you've put a deck lid over your power supply and want to easily hook up your charger through it, these connectors give you the options you need.SpecificationsDimensions: 35x17x38mm Color: Black

GBC Imprintables Binding Cover $22.99 0% 20% 2001592 25 / Pack 8.50" x 11" Bring your next presentation to life with brilliant color, and print high-resolution images and logos on the cover. Compatible with inkjet and laser printers. Premium covers with plain, square corners are made from 30 percent post-consumer material. ACCO Brands Corporation Binding Cover Corner - Square GBC Imprintables Imprintables Binding Cover Letter Light Gray No Yes www.acco.com

370 - Two-Months-Per-Page Wall Calendar In Punched Leatherette Binding, 20 X 26, 2012 $16.47 dated Two-months-per-page January Through December Wall Calendar Displays Both Current And Upcoming Month And Includes A Recycled Logo On Each Page. Provides Ruled Daily Blocks And A Full Year Calendar Reference Blocks On Each Page. Shows Julian Dates/days Remaining And National And Religious Holidays. Calendar Pages Are Perforated At The Top With A Three-hole Punched Headband For Hanging. Printed On 100% Recycled Paper That Contains 30% Post-consumer Material. [HOD370] Recycled UPC: 040983302012 UNSPC: 44112002 0.54 LB

Steren 251-509-10 10Pk Single Binding Post/Banana Adapter $14.99 Type: Single Binding Post/Banana Adapter Specifications: Color: Gold Number of Connectors: 2 Connector Details: 1 x Female Audio 1 x Banana Jack Female Audio Features: Red Band Gold Plated Packaged Quantity: 10 Parts: 2 years limited Labor: 2 years limited

Audio Enhancers DB3S 2.88 Opening LCup Chromed Binding Post Terminal $18.54 Chromed Binding Post Terminals. Accepts 10Gauge Wire. Spring Loaded Banana Plug. 27/8 Opening. Huge selection to choose from. Using only the highest quality materials. Providing you with great selection and quality. Satisfaction ensured.

Observation Post Alpha $79.66 High Quality Content by WIKIPEDIA articles Observation Post Alpha, OP Alpha or Point Alpha was a Cold War observation post between Rasdorf, Hesse, West Germany and Geisa, Thuringia, East Germany. The post overlooked the Fulda Gap, what would have been a prime invasion route had the Cold War erupted into actual warfare. The Point Alpha memorial commemorates its fortyyear existence, and was dedicated to keep it and a section of East German wall as reminders of German division and the confrontation of NATO and the Warsaw Pact in the Cold War. Author: Surhone, Lambert M./ Timpledon, Miriam T./ Marseken, Susan F. Binding Type: Paperback Number of Pages: 112 Publication Date: 2010/07/25 Language: English Dimensions: 6.00 x 9.02 x 0.27 inches

Weathered Post $199.99 Zhen-Huan Lu Weathered Post - Wall Tapestry

Post Haste $59.99 Lawson Wood Post Haste - Wall Decal

251-509-10 - Steren Single Binding Post/Banana Adapter $18.39 [Y66875] UPC: 884645106538 UNSPC: 43201500 4L x 4W x 1H 0.15 LB