Life Extension Metabolic Pathway Map Reveals New. Phytonutrient Candidates. D and Michael Wolfson J. The 3 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 3 sickness metabolic pathways sprint in direct opposition to life extension pathway. We have generated a metabolic flow chart map that shows most processes like a dynamic singularity. We make sense of these diseases and life extension within the text, in terms regarding the metabolic map. From a compendium of phytonutrients, we discovered a mini handful of them that satisfied a very stringent set of criteria for fighting these diseases and accomplishing genuine life extension. The 3 most successful candidates shape a remarkable fit in terms of our metabolic map, while the 5 runners up are very close fits.
Used singly, or in combination, all eight have located efficacy in treating many dozens of age related diseases beyond the 3 primary killers we describe, herein. Introduction The greatest common and deadly diseases of aging are the two atherosclerotically induced cardiovascular sickness group, 3 middle age onset kind II diabetes and 4 the multitudinous array of cancers. Obesity may be regarded a fourth disease, but since its morbidity usually manifests its outcome like a consequence of one or more regarding first 3 diseases, it shall only be treated in an ancillary fashion, like 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, due to the fact that they operate in different physiological compartments and at different grades of cellular organization.
For instance, in cancer, the metabolic pattern operates at the intracellular level, and in fact, can begin in a lone cell. Extracellular physiological manifestations of cancer grow to evidenced at the multicellular level, many 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 position of integration. Atherosclerotic cardiovascular sickness also involves the participation of gaggles of cells operating at the position regarding the vascular tree. The common denominator includes mal adaptations to carbohydrate metabolism that grow to fixed and self exacerbating, ultimately leading to each sickness possessing characteristic forms of outcomes.
Recent developments release us 3 best proofs that the aforementioned statements are true. First, similar metabolic pathways and or or their downstream destructive outputs are evidenced in all 3 sickness situations. Second, and more importantly, pharmaceutical or phytonutrient metabolic pathway differential rectifiers prevent, delay onset, delay progression, and in some cases, definitely reverse all 3 sickness states with a lone therapeutic regimen. Lastly, pushing the metabolic system within the reverse direction of its multiple sickness manifestations definitely extends life beyond its normal time span limit. This is multi-serendipity enough to induce a lustful look for for an Occam's razor.
We have developed an essential skeletal outline regarding 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 lone cell. Subsequent to describing its functions, we shall probe its perturbations manifest as cancer cell growth, followed by those of diabetes II and atherosclerosis. Throughout the discussion, we shall contrast these sickness pathways with the opposing life extension pathway.
First, the system should be articulated from the perspective regarding the lone cell and sickness perturbation at the lone cell level. Then, we shall branch out to somewhat more obscure and fewer 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 most well and poorly understood phytonutrients that are known to have had a beneficial impact on all 3 sickness states, but have not had the benefit regarding the cell growth and life extension pathways, to be matched to, until the present time. Figure two is available at 1. The cell growth CG Icancer metabotype CM versus caloric restriction CR Ilife extension LE pathway flow system map.
Circled ovals represent the core elements regarding the CR or LE system. Containers are used to contrast the mitochondrial CG neogenic state from its CR driven regenic state, as shown in ovals. represent very recently discovered or described phenomena which created this map likely for 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 display downstream impacts of a special core catabolic interaction.
TSC2 and TOR are the heart regarding the input or output tree. A listing of abbreviations is provided within the text. Arrows represent up regulation and blocking end plates represent below regulation. All components are to be thought of as if within the activated state, when upstream effects are ignored and below stream effects are followed. The map should be kept at the ready when reading the text, due to the fact that they can be inextricably co-dependant.
The CG or CM and CR or 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 fewer inclined, we recommend that you skip forward to 3 sickness kind examples or to phytonutrient candidates section. For those that wish to brush up a bit prior to jumping in, we recommend that you view the metabolism Special Section located on p.
1337 within the 12 or 03 or 10 issue of Science, Z. Feng, Cold Springs Harbor Lab Press, p. 199, 2010, and Seyfried and Shelton, Nutrition and Metabolism, 7 or 7,1 or 27 or 10. This is up to date review fabric 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 regarding the Figure two CG or CM and CR or LE metabolic map on the side, like a reference guide, when reading this paper, as we refer to map throughout the narrative.
Within the mid twentieth century, it was discovered that calorically restricted CR mice lived detailed than their normal maximum life expectancy, which we term as true life extension, just life extension or LE, LE for short. Since then, studies has reported the CR or LE phenomenon throughout all primary branches regarding the proto-animal and pet 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 creating use of the anti-tissue rejection drug rapamycin and the anti-diabetic drug metformin. Knowing their molecular targets provided first inklings of a pharmaceutically induced up regulation regarding similar pathways activated by CR. We call these drugs CR mimetics.
Even more recently, cancer investigators located powerful tumor cell growth CG inhibiting properties within 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 regarding the CG pathway, allowing us to connect the CR or LE and CG processes into a singularity. A new and dawning realization within the cancer studies community, that mutations within the CG proteins controlling core metabolism caused cells to remain stuck' in CG, resurrected an extended 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 fewer obvious, but became an easy fit, when understood from the CG or CM-CR or LE context, as described later. Conclusions published within the March 2010 issue of Science, helped integrate this singularity by knitting an antioxidant sestrin redox containing active website protein SESN to tumor suppressor protein P53 and into the CR or LE pathway. We shall describe, later, how it was compulsory to divide mitochondrial biogenesis into 3 functionally discrete domains sequential to render the pathway unification hypothesis consistent, coherent and realistic. The December 2010 admission, in Science, referred to earlier, that the denial regarding the notion that core catabolic metabolism like a requisite manage element in cancer, had been a thirty year dogmatic blunder of primary 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 within the flow chart is a skeletal outline regarding the regulatory manage pathways monitoring, responding to and governing catabolism, anabolism, nutrient availability, cell life status and cell damage and repair integrity; all being in terms regarding the cell's decision' to grow and divide below CG drivers or to hunker below and wait out a famine. The map is basically shown from an intracellular cytoplasmic perspective, due to the fact that that is where the core system initially evolved, and is still housed, even in technological eukaryotic cells. The chart does not with wholesale nuclear gene system activation and deactivation, as they can be described, as needed, within the narrative. The plasma membrane is provided to relate the core system to extracellular milieu, which evolved from being the earth at huge for lone cell organisms, to being the many integrated tissue trafficking interstitial fluid processes of technological multicellular organisms.
Being the vertrebrate chauvenists' that we are, we shall bias our description from the standpoint of person physiology. Viewed superficially, tuberous sclerosis complex 3 TSC2 and target of rapamycin TOR act like the trunk of a tree with 3 input branches' feeding in from the protein kinase AKT AKT and the adenosine monophosphate kinase AMPK. On the left side, AKT is the primary CG or CM input, and AMPK, on the right side, is the primary CR or LE input. Like a tree, finer branches feed into the 3 primary branches. TOR outputs represent the roots' of our metaphorical tree.
Arrows represent component activation, while blocking plates represent inhibition. All components within 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 for example AMPK etc. For the greatest component except for PGC1 alpha and mitochondrial neogenesis, the right paw side regarding the chart represents the CR or LE pathway, while the left paw side regarding the chart represents the CG or CM pathway. The top 1/2 regarding the chart represents TOR inputs, while the bottom 1/2 represents TOR outputs. The large take home lesson is that the chart shows that the CG or MS and CR or LE processes operate in direct opposition via TSC2 or TOR. What is not shown within the chart is that there is considerable reinforcing regulatory self-talk and counter reinforcing cross-talk between the 3 pathway systems.
For instance, activating regulatory stimulators of one pathway synergistically co-stimulate multiple components within the self-same pathway, while inhibiting manage elements within the opposing pathway. Thus, not only are the pathways in opposition, but they operate in self reinforcing and in oppositional inhibition. By acting like a dual function toggle switching system, TSC2 and TOR help to mitigate self-reinforcing vicious cycles, mostly via outside the pathway external inputs for example mitogenic growth factors or internal life status sensors. This permits the system to invest in massively sweeping gene sets controlling giant pathway circuits, for example anabolism or catabolism, and to sustain them until they done their processes. As we shall look later, mutational flaws within the system, as present in cancer cells, initiate vicious cycles by brief 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 shall also display how diabetes brief circuits the system at the physiological position of a liver, adipose and muscle tissue triad, with the pancreas mostly being enslaved to triad. To articulate the general overview regarding the systems, we shall begin with the CG or CM system, and follow with the CR or 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, due to the fact that it so closely resembles cancer, but in a regulable form. For instance, cell growth and replication, within the fetus, advances at a furious pace, is in a hypoxic environment, wants 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, higher than twenty others, stimulate neither the rat sarcoma virus oncogene protein RAS and or 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 regarding the anabolic system. Lipid catabolism is shut down, in favor of lipid synthesis and is replaced by heightened anaerobic glucose metabolism via transcription regarding the little Km fetal glycolytic enzyme set ordered by HIF. In essence, the cell becomes a sweetener fuel junkie' so as to preserve amino acids, fats and nucleotides as new cell construction material. Glycolytic end products, for example pyruvate, pile up and cannot be assimilated by the OX or PHOS incomplete neogenic mitochondria.
Glycolytic intermediates and feedstocks, like glyceraldehyde 4 phosphate, dihydroxyacetone phosphate and glucose seven phosphate, pile up and are diverted to 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 should 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 help the growth system for impending tissue invasion, PKC and TOR stimulated S6K activates the release of cytoplasmic bound nuclear factor of kappa chain activated Be cells NF-kB to nucleus, where inflammatory cytokines for example cyclo oxygenase 3 COX 2, tumor necrosis factor TNF and interleukins ILs grow to transcribed and exported to initiate extracellular edema, interstitial matrix breakdown and a furthering regarding the inflammatory cascade.
Within 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 subsequent to the CG driver system was shut down. These respiratory proteins render inefficient neogenic mitochondria into efficient regenic mitochondria. Below 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 regarding the glycolytic or PPP system. Mitochondria should possibly 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 look how the core catabolic processes complement the anabolic drive state initiated by the CG or CM pathway.
Mitochondrial participation in CG has always been a bone of contention, particularly within the case of cancer cells. The recent elucidation regarding the CR or LE pathway interaction with the CG or CM pathway, by our selves and others, has helped to resolve this debate. Mitochondrial biogenesis has long been thought of like a singular process, initiated principally, via PGC1-alpha. It was known, for over 3 decades, that mitochondrial biogenesis consists of 3 transcription phases, aptly named, the early phase and the late phase. The early phase begins immediately subsequent to TOR activation of PGC1-alpha, and produces the bulk regarding the thousand, or so, proteins that make up the vast majority regarding the proteins constituting the mitochondrion.
Indeed, from all outside appearances, an entire 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 subsequent to mitosis, and have been traditionally thought to complete' the mitochondrial biogenesis process. This mitochondrial 2nd phase lag' is seen throughout fetal development, and has traditionally been thought of like a mere consequence of rapid proliferation and, therefore, like a component in a singular biogenic process. We look it like a dual process with first phase requiring the absence regarding the 2nd phase if cell growth and proliferation is to be can occur at all. The elucidation regarding the CR or LE system, its ROS activated SESN component, TOR like 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, creates new OX or PHOS inefficient mitochondria and participates in CG metabolically. When CG shuts below and or or CR turns on, regenesis creates late gene mitochondrial OX or PHOS efficiency, and switches to functioning within the between replication cell quiescence, cleaning and maintenance phase. Our CG pathway implied as much, and its oppositional CR pathway, described below, distant illustrates the point. The CR or LE pathway upstream of TOR is greatest described by starting at AMPK. Until a mere year ago, AMPK was primarily viewed like a cell life status sensor, being up regulated by elevated concentrations of life poor AMP and NAD, and being below regulated by their absence, like a result of high concentrations of their alternative life wealthy forms as ATP and NADH.
AMPK is now also known to participate like 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 most like a mitochondrial neogenic or regenic function feedback sensor as well like a nutrient availability, CG drive state and life status sensing and response cluster. When activated by cell life 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 grow to efficient in OX or PHOS and dramatically slice ROS production, which in turn, reduces genotoxic stress, which shuts below p53 induced DNA repair mechanisms. Of course, this deactivates AMPK if and only if the cell is life 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 below 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 component by NF-kB and COX2, in a complex system called the retrograde response RTG. This helps facilitate the switching return and forth between mitochondrial metabolic states associated with regenesis and neogenesis within the context of up and below regulation of glycolysis. In general, the RTG response is utilized within 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 located in fetuses and within the core of neoplastic tumors.
Interestingly, in cancers, mitochondrial telomerase can relocate to nucleus to initiate immortalization. It is intriguing that the central elements of most cell suicide apoptosis-cytochrome c and immortality mitotic index-telomerase were most evolved to be released from mitochondria. Suicide versus immortality, WOW! In teleological terms, that seems like a rather god-like position to be in, for such a lowly organelle. A many deeper treatment of mitochondrial function is provided by Seyfried and Shelton, as referred to previously. It should be so easy if everything just feeds into and out of TOR like a simple toggle switch.
However, nothing in biology is simple. There exists many TOR molecules in a cell, and they should be geographically and microsomally compartmentalized within the cell, with some within the on' position in one compartment, while others are within the off' position, elsewhere, as is revealed within the six or 20 or 11 issue of Science. Most TOR conditions should be operating in a pseudo homeostatic condition, when there is no simple slice 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 simple slice drive states, like starvation or ad libitum fetal growth, the TOR system is caused to respond wholesale to preponderance regarding the inputs. Such is the case within 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 shape a catabolic core system driven by CG and CR. Furthermore, these processes make coherent and consistent requisite changes depending on the cell state in all pet organisms and all of their cell types. No reason what the status of myriad regulatory elements superimposed on the ancient core system, it should respond in a flexibly limited fixed manner, or the global system collapses. Apoptosis and novel cancer therapies display some regarding the bounds of this limited flexibility. In normal cells, the core system can toggle return and forth between the CG and CR states.
It cannot do this, neither easily, or at all, within the cancer cell, like a result of mutations within the core system or within the regulatory elements regarding 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 like a means of chemotherapeutic attack. The sad tale of this 54 year drought should be look for engined below Bambeck cancer: Mainstream Science Dogma Reversal, on the internet. Recent developments display that many variations of cancer cells should be growth arrested, killed or even differentiated by direct attack on the core system, its most intimate regulators or nearest neighbor or 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 simple CG or CM and LE or CR processes and to conduct a look for for phytonutrient regulators which rectify the system in a method that helps to prevent or renormalize the 3 primary diseases of aging, and which promote life extension. Thus, we shall release a cursory overview of cancer in terms of our metabolic flow chart, and some regarding the therapeutic logic that can impact cancer. The cancers are a madhouse of mutagenic realities in terms of most their many cell variations and types, and the myriad ways they can convert CG to CM. For instance, there exists over twenty growth factors, and even more growth factor receptors and downstream cascade components that are critical to different tissue categories and cancers, each of which should need an alternate 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 variations of cancer, for which, Herceptin is useless. of studies time, price and testing to develop such a vast target critical array, is mind boggling. Later mutations within the cascades below stream of growth factors and their receptors can, and do, eventually circumvent such therapy. Even insulin dependence and resistance should be skirted by up regulation of non-insulin dependant glucose transport proteins, for example GLUT 4, to feed CM hyperglycolysis.
We should note that the high ROS index of cancer cells fosters distant mutagenesis to enhance selective survival of lone 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 or LE side, the P53 protein is defective, in two of many likely ways, in about 1/2 of all cancers, being distant and away, the lone 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 cell kind of interest. In addition, too many of a good thing may be an evil thing, as mice with extra copies of P53 genes die prematurely.
Return on the CG or CM side, RAS function shall also be elevated in a plurality of tumors and gives a reasonable therapeutic target, but should be circumvented by P13K. Attacks at this position are more like cancer management than cure strategies, as they basically renormalize metabolic flow into a non-growth dynamic, which may sometimes initiate differentiation into a fewer mitotic form, or delay sickness progression rate by slowing growth, that is a good thing when one has a lethal disease. HIF and the VEGF response family, which lie closer to core metabolic system of glycolysis give many more tempting targets, and are a hotbed of studies today. Blocking HIF should shut below the whole fetal enzyme driven glycolytic pathway while the rest regarding the TOR activated anabolic drive state should still be operating. This should really throw a monkey wrench into the whole CM metabolite flow dynamic.
Like a bonus, this blocks angiogenesis downstream of VEGF, which shuts below the tumor fuel supply, in addition to below regulated HIF already possessing diminished its ability to use a fuel supply. The closer we get to CM core system of metabolism, the more general the impact throughout a broader array of tumor types. Some recent developments in core systerm attack logics have really raised very many 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 should seem wise to broaden our assault distant up the glycolytic chain and its input branches to PPP. These are simple molecules to mimic and there should be thousands of inexpensive candidates. We should have begun all this studies thirty years ago, had we only listened, so for the present, this new' region of studies has only a little weapons. The good news is that we have robotic micro-array tissue race and automated fluorescent cell status and cell apoptosis monitors that let testing thousands of molecules and dozens of cell types, daily. Interesting synergies between glycolysis and mitochondrial therapies should be envisioned.
TOR up regulation of most processes keeps mitochondria spending most of their existence in a neogenic default state. In some cases, this is concomitant with a huge glutamine importation increase, but it always includes a programmed OX or PHOS deficiency or insufficiency. Glutamine deamination inhibitors or Kreb' cycle blockers downstream of oxalosuccinis acid, should inhibit glutamine pathway flow and assist glycolytic disruptors in distant catabolic substrate flow disregulation with TOR activated anabolism. Used judiciously, respiratory chain blockers or OX or PHOS to ATP uncouplers should also disrupt CM flow integrity. These glycolytic or mitochondrial therapy strategies were first presented, in many more detail, within 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: two growth signal self-activation, 3 growth suppressor inhibition, 4 anti-apoptosis, 5 immortalization, six angiogenesis and seven metastatic tissue invasion. Howcome he did not with avoidance of immune surveillance like a seventh hallmark, is mystifying to us. With our new understanding, as discussed throughout our paper, we should list 1, 4 and six below the lone hallmark of CM pathway activation, with 5 like a mitochondrial corollary to our first hallmark. 3 hallmark should stand alone, mostly in terms regarding the CR or LE pathway. seven hallmark should definitely stand alone at our present stage of understanding.
Thus, we should reduce his six hallmarks to 3 and sum immune avoidance like a fourth. Being of a strongly anti-Warburg and anti-metabolic bent, like his predecessor Sydney Weinberg, probably prevented him from being can look what scientists so clearly understand today. From a purely scientific standpoint, the anti-Warburg story is shameful. Everybody admits that preventing cancer, within first place, is the greatest preferable. A correct Spartan diet, plenty of exercise, anti oxidant supplements, not smoking, avoiding glucose or fructose, etc.
can reduce cancer incidence by a whopping, age-indexed 70%, distant in excess regarding 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, will not do it, mostly 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 may be the ticket. The difficulty is that there exists only 3 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.
Kind 3 Diabetes and Metabolic Syndrome By analogy, diabetes II is unnervingly similar to supply and demand conundrum that plagues the present American July 2011 economy. The bank, corporate and wealthy citizen investment or production or supply side is engorged with some $6 trillion in hard cash while the consumer or demand side is unemployed and cashless. Supply fails to invest in domestic but not foreign employment, goods and services due to the fact that its domestic demand side customer base dwindles, while a polarized government remains gridlocked and does nothing to alter the bulk regarding the cash flow dynamic. One side regarding the aisle robs the cash input side regarding the treasury to sip the enfranchised elite, while the other side regarding the aisle spends the treasury, so as to hold the highly weaponized, but job and home dispossessed from starving and rioting. A continued widening regarding the economic gap is unsustainable.
In retrospect, we seriously doubt that even a mentally challenged Marie Antionette should suggest that we repeat the past prior to learning from it. Similarly, diabetes was called a sickness of starvation within the midst of plenty'. It disrupts the carbohydrate balance regarding the whole cell population regarding the body. It does so by coupling massive carbohydrate intake, over an extended 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, within 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 most a hyperglycemic and hyperinsulinemic state, prior to developing into full blown diabetic insulin deficiency due to exhaustive pancreatic collapse in insulin producing capability. Basically put, diabetic end stage glucose is in abundance, and the cells cannot take it up. Many now look that diabetes progresses from a disorder of muscle or adipose origin. These tissues occupy about 1/2 regarding the metabolizing wet' tissue mass regarding the body in normal, non-obese individuals, thus is a sickness process facilitating bulk flow mismanagement regarding the whole carbohydrate or lipid economy.
Within 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 ground, i. We describe the physiochemical process, below. Early within the twentieth century, kind 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 kind II diabetes also responded to insulin replacement, and was most pronounced within the obese.
Thus, initial studies focused around a food intake intestinal, liver and pancreas metabolic triad. Within the late twentieth century, the growing obesity epidemic, the growing fatty liver steatosis epidemic, increased muscular lassitude, a massive upsurge in fructose within the diet and a little key discoveries have shifted our focus toward a muscle, adipose and liver triad, with the pancreas as mostly a response element to triad. The metabolic syndrome MS, in technological developed nations, begins from a combination of over indulgence of prepared convenience and junk' foods, coupled with a physically lethargic life style. These nourishment contain astronomical amounts of rapidly absorbed simple carbohydrates, due to the fact that these carbohydrates are almost dirt cost effective on a $ to mass ratio, creating best filler' and they also foster an eternal tasty tooth' addiction in humans, as described below. There exists 3 primary rapid absorption carbohydrates in these foods, and they are: two high fructose mealie syrup Hi FCS, that is composed regarding the simple sweetener monomers fructose and glucose in a 55 or 45 ratio, 3 sucrose, mostly from sweetener cane, is a sweetener dimer composed of fructose and glucose in a 50 or 50 ratio and 4 simple starch, a mostly linear sweetener polymer composed of nearly 100% glucose.
Hi FCS, being monomeric, enters the blood stream fastest of all, achieving bulk transfer concentrations in about 5 minutes, while sucrose should 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 located in potatoes, rice, simple wheat etc. , is partially cleaved into huge chunks by salivary amylase, then, converted to monomers by distant amylase treatment within the digestive tract. It is bulk transferred to blood over about an hour. Consequently all 3 are rapidly absorbed, Hi FCS is, by far, the worst offender, due to its prodigious and rapid uptake, so we shall 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 should be measured as glycated blood hemoglobin, known as HbA1c. Bambeck slice his milk teeth in diabetic studies by developing an electrophoretic isoelectric focusing HbA1c diagnostic test for Isolab Inc. 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, within first place, conclusions in an unusual circumstance, not common prior to Hi FCS, manifest as hyperinsulinemia co-incident with hypoglycemia. This condition creates a huge craving for tasty tasting stuff', to relieve the conflicting fuel and fuel driver dilemma. This creates a vicious cycle of chewing and craving, that fosters the obese condition. This is the pre-MS condition.
The second, and more covert sugar, is fructose. Fructose within the blood stream does not induce insulin secretion, and is not readily taken up by most somatic cells. Instead, it is sequestered within the liver, where it is converted to triacyl glycerols, which are then, esterified to fatty acids to shape triglycerides, which are stored within the liver. Over time, this causes fatty liver steatosis. Steatosis up regulates Apo Be protein, causing increased VLDL production, and thus, increased triglyceride transport to adipose tissue.
Elevated VLDL shall also be 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 regarding 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 large 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 or muscle involvement. It is estimated that thirty percent regarding the American population suffers from liver steatosis, that the sickness is appearing in huge numbers, in obese teenagers, for first time in history, is occurring in parallel with diabetes II, and is a harbinger of a need for future liver transplants within the untold thousands, or even millions. A more thorough review of fatty liver sickness should be located in Cohen, J. 1519, seven or 24 or 11. Does this mean that we sum a liver transplant epidemic to already existing obesity, steatosis and diabetes II epidemics? In addition, what do we do regarding the fact that these traditionally middle and old age onset conditions or diseases are now commonly appearing in young adults? Silibinin, two of our phytonutrient gold medal winners, was originally used to keep mushroom poisoning victims from hepatotoxic liver failure.
Later, it was place into use for general hepatotoxicity. Health related drug applications, like some actors, get kind cast' for their function and more creative studies becomes stalled, as it did so, for silibinin. Just recently however, silibinin has also been located to be useful as an adjuvant to conventional cancer therapy throughout numerous tumor types, thus showing a metabolic commonality between cancer and diabetes. We should note here, that anyone thinking of linking silibinin with the technological sweetener junkie' diet should be living in a fool's paradise. Inactive muscle does not raid adipose tissue for fat life due to the fact that it is simple fiber muscle, is almost totally anaerobic and burns glucose to lactate, for export to 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 located that simple muscle is almost absent of peroxisome proliferator activated receptor PPAR gamma, a vital component compulsory for the transfer of fat from the adipose compartment to muscle compartment. Not only is it true that simple muscle shall not oxidize fat, but it cannot, either. Red muscle creates PPAR gamma, and both, shall and can oxidize fat.
If there is enough muscle tissue oxygen demand, over multiple months of intense endurance exercise, simple 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 sweetener sucking and lethargic technological human, we have been using, herein, and by this spot within the discussion, the condition has grow to full blown MS. Lastly, tissues other than muscle respond to MS hyperinsulinemia and hyperglycemia by below regulating their insulin receptors, while muscle up regulates its insulin independent Glut 5 receptors. It becomes obvious howcome whirlwind exercise programs and crash diets shall not work on a slowly developing set of circumstances, like those outlined, above. If not checked, the liver or adipose or muscle triad system basically wears out the pancreas and the organ can no detailed give 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 or CM and CR or LE cellular analogue that has gone awry at the tissue and organ position of integration. The downstream activations are similar, in that ROS, glycation and inflammation cause general tissue damage throughout the body. The sickness dramatically accelerates aging, heart sickness and cancer incidence. With sweetener intake reduction, moderate exercise and the phytonutrient metabolic pathway modifiers, discussed within the phytonutrient candidate section, the preconditions should be halted and reversed. The full blown sickness cannot be reversed, but its progress should be slowed.
Pharmeceutical metformin, a direct activator of AMPK, and thus CR or LE, was widely used for decades in beyond MS' little position diabetes II, to manage blood sweetener and to delay insulin dependence. It decreases insulin resistance, up regulates the CR or LE pathway and below regulates the CG or 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 receiving metformin, regardless of all other therapies used. Our 3 gold medal winners hold a mechanism of action similar to metformin, and they have all shown efficacy in glucose manage and throughout a startlingly broad array of tumor types. To our knowledge, metformin has not yet been tested throughout a broad array of tumors.
Again, and this time with a pharmaceutical and CG or CM and CR or LE rationale, cancer and diabetes display therapeutic linkage via a metabolic commonality. We hardly thought that nature should turn it up any louder', but it did, as we shall soon see. The metabolic syndrome or diabetes sequence can daisy chain into very serious cardiovascular damage, as is most common knowledge, and as we shall look presented within the next section. Regarding the 3 aging sickness states outlined here, atherogenic cardiovascular sickness is the greatest cryptic and obscure, from the standpoint of our CG or CM and CR or LE metabolic map, as the sickness is a mixed bag, of as many of an effect from other conditions, as it is from its own causes. Atherogenic Cardiovascular and Related Sickness The rough and tumble environment regarding the vascular tree is distant different than that regarding the calm extracellular interstitial fluid backwaters bathing most regarding the body's cells.
The vessel walls are directly exposed to mechanical and chemical stresses that arise from distant webpages 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 regarding the arterial system. The lipid delivery system is somewhat unique to 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 many higher pressured and most thickly walled arterial side regarding the vascular network, where turbulence inflicted damage is most pronounced, and where the damage resulting from the reaction to 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 within the fact that the sickness causes and therapeutic outcomes share that same, previously mentioned, Occam's razor. The classical little density lipoprotein LDL bad cholesterol and high density lipoprotein HDL good cholesterol story is the greatest widely known, medically instructed and publicly disseminated narrative within the the past of medicine, and shall only be provided a cursory brush over, herein. We will, however, release some space to a little very lethal, but fewer known variations regarding the theme.
The lipoproteins LDL and HDL precursors are synthesized within the liver like a hyper lipid packed very little density lipoprotein VLDL and the lipid void shape of HDL. VLDL and LDL engage in lipid delivery to peripheral cells via the vascular network, while HDL acts like a lipid scavenger and transfer agent. Hyperlipidemic sickness participates within the cause of atherogenesis by typically manifesting like a genetic or environmentally induced over representation of LDL or like a genetic or environmentally induced below representation of HDL. Thus, the notion regarding the LDL or HDL ratio, as the well-known bad cholesterol to good cholesterol' index of cardiovascular sickness risk, has now grow to an usual household phrase. Environmental and genetic factors synergize, such that one born with a genetic proclivity for atherosclerosis requires fewer of an environmental insult than one born with a more normal genotype.
We try to integrate our approach, so as to give as little examples as possible. In the normal process, VLDL within 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 Be plus E receptors on cells, where lipids are off-loaded. The mostly lipid depleted LDL returns to blood to be decommissioned by the liver and replaced by nascent LDL. An LDL molecule should be ROS oxidized, or is all too frequently present within the population like a mini dense SDLDL. The SDLDL shape is many more readily oxidized and is viciously atherogenic.
Subsequent to being converted to its active form, the lipid void HDL-3 mostly fills up with lipid by binding to E receptors, which distant 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 most SDLDL quantitation and HDL-3 quantitation. The test also revealed 3 VLDLs, 3 IDLs, seven LDLs in 3 diagnostically useful groups and thirteen HDLs in 3 diagnostically functional groups.
This was a bit many for the studies and diagnostic communities to digest at that time. The quantitation of SDLDL should be a health related priority, due to the fact that it is very atherogenic, appears in about 27% regarding the general population, does not appear on any general cholesterol screen and does not respond to statin drugs, but does respond to fibroates, for example gemfibrizil. Approximately 1/2 of all SDLDL victims display no other risk factors with conventional diagnostics. About six years ago, as contract work, Bambeck proposed that SDLDL disease' is represented by a lone co-dominant allele of an unknown gene, the only other allele being the normal form. The sickness was proposed to manifest in its homozygous shape at about age twenty 5 and kill by age 45 in about 2% regarding the population.
More disheartening, is that in its hypothesized heterozygous form, it manifests in about 25% regarding the population at age 45 and kills by age 65. The sickness is almost a done match for a 3 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 place 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 tough gut lipid extraction survival advantage in a mini person race founder population that faced severe nutritional lipid semi-starvation for many generations. We have no plan if this notion ever gained any traction.
Regardless, SDLDL is a primary league population killer, for which, resolution is readily available, if we should only test for it and treat it. The non-functional HDL-3 situation is fewer severe, but just as silent' as SDLDL, and appears in about one-fourth regarding 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 within the aggregate, thus below reporting the risk like a decreased LDL or HDL than it should be. The risk is even more skewed within 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 regarding the HDL-3 assay filed for dissolution in 2004. All samples used for the lipoprotein subfraction assay came from 4,000 participants within the Framingham Study, and were kindly provided by Judy McNamara of Tufts University. The lipoproteins are only component regarding the atherogenesis story, although, for most arterial disease, LDL and its variants are most often regarded to be the culprits. In response to arterial wall injury due to baromechanical, chemotoxic or inflammotoxic origin, macrophages migrate to intima layer regarding the artery and acquire lipids from LDL for use as fuel, repair and maintenance. Within the abnormal condition of hyperlipidemic LDL, high numbers of ROS induced OXLDL and or or genetic SDLDL, macrophages grow to lipid overloaded, receiving 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 within the smooth muscle cells lining the intima layer. Necrotic foam cells make up many regarding the fatty component regarding the forming atherosclerotic placque, while replicating smooth muscle cells shape beneath a fibrous placque capsid that acts like a surface seal to 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 or mitotic cascade shape a progressive self-reinforcing vicious cycle that facilitates and exacerbates placque growth and its spread as colonial groups. This creates sense from a molecular damage stand point, and is consistant with the CG or 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 distant downstream, causing anoxic death to vital function tissues for example heart, lung or brain. There are a host of other cardiovascular sickness states, more critical to heart, that result from a shift from a CR or LE pathway driven to CG or 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 little mitochondrial numbers can reduce ATP production and force of contraction, as located in congestive heart failure and ventricular hypertrophy. Shifting the drive state from CG or CM to CR or LE was shown to be neuroprotective, as well as neuroregenerative in most heart sickness and diabetic neuropathy.
This metabolic shift was shown to increase mitochondrial numbers in most cardiac and skeletal muscle, to increase ATP production and to increase muscular force of contraction, thus relieving all the above mentioned conditions. Our 3 gold medal winners perform all these functions, in addition to their anti-diabetic and anti-cancer functions, as described earlier. The silver medalists synergistically help the gold medalists. Finally, we are ready to discuss our selected dietary supplements. The Phytonutrient or Nutriceutical Candidates.
The well-being 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 4 corners regarding the world. Just walking below the aisles should institute some shape of clinical depression. Where to begin? How does one separate the questionable legitimacies of; folk remedies, old wives' tales, heap large mojo shamanism, venerable ancient health related wisdom, mythology, cultural favorites, technological marketing snake oil hucksterism etc. from actual fact and good medicine? As an alternative to taxing our already enfeebled brains, we hit on the greatest plan we have had in years. Instead of embarking on an interminable grand search, we let the world's greatest and brightest topic critical professional brains do our thinking for us, and we went in with a strategic plan.
We embraced a copy Sickness Prevention and Treatment, published by The LifeExtension Foundation LEF. Therein lies the combined efforts of thousands of studies studies and the clinical skills development of physicians around the world' to place it in LEF's own words devoted to over riding purpose of life extension. Subsequent to reviewing what LEF had to say, we used scientific publications and the net to update and modernize our understanding. Possessing our CG or CM and CR or LE map in hand, and our 3 principal diseases to most direct our look for and institute the strategic plan, we plunged in. The system had a little simple but inviolate and all inclusive rules.
Each candidate should have utility against multiple cancers and against diabetes and against atherogenesis; all three. It should both, statistically prevent or delay onset of all 3 diseases by significantly reducing the probability of age related population incidence and should slow the progression of all 3 sickness states, once sickness is instituted. Where the principle target and or or mechanisms of action are known, it should regulate its target, and in turn, their downstream pathway targets within the direction consistent with the CG or CM and CR or LE map. Where principle target or mechanism of action is not yet known, downstream effects should match the regulatory directions of our metabolic map. Consequently not an absolute requirement, each chemical should have an extremely high LD-50, within the multiple dozens to hundreds of times its functional dynamic section and a the past 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 look for from the earth at huge to LEF compendium, instantly whittled the look for from thousands of possibilities to a little hundred. Applying the all inclusive rule set to these little hundred, fairly quickly drove the no. below to a little dozen and then, many more slowly and agonizingly, chipped its method below to a handful. Incidentally, route of administration was not a consideration as little of these molecules have poor oral bioavailability in a pure form, but many higher bioavailability in a soluble injectable form, or in a conjugated oral form.
Winning candidates may 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 regarding the differential therapeutic merits of our gold medal and silver medal winners, and we shall diversify those merits and differentials, later. Before we begin, we should speak a phrase 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 final 3 decades, and for a host of good reasons.
They protect us from the primary diseases of aging, reduce ROS formation, release us more vitality and with an extended list of well worn etceteras, let the population survival curve to leptokurticly shift toward the maximum life expectancy. However, they basically don't ever institute LE, albeit being the greatest play in town'. Driving this spot home is that organisms on a CR or CR mimetic protocol manifest LE without any antioxidant supplementation whatsoever! Confirm and mate. For this and other reasons the ROS damaging hypothesis is now seen more from the avoidance regarding the life shortening side, as opposed to life lengthening side regarding the equation. The antioxidant hypothesis was located to be limited and in need of modification.
We should do not forget here, that critical elements regarding the LE pathway were only discovered during the final one to 3 years, so a theory modification was not even realistically likely prior the very recent present. For instance, the LE pathway institutes mitochondrial regenesis and reduces ROS production, within first place, obviating the need to mop up ROS subsequent to the fact' with antioxidants. Prior to elucidation regarding the LE pathway, any LE system activator should have been, and in fact was called an antioxidant, basically due to the fact that of mitochondrial regenesis; and mitochondrial regenesis was not hypothesized at the time. We know ourselves to be first folks to attempt to formulate a primitive global CG or CM and CR or LE map that includes the notions of cancer metabotype, mitochondrial neogenesis or regenesis, CR or LE pathway, CG or CM pathway, CR or 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 within the literature, but disjointed, due to the fact that this age of specialization obscures any large picture' review approach, for example ours. The well-being food supplement world is awash in phytonutrient antioxidants, and our metabolic map has helped us to loosely classify them into 3 broad categories with considerable overlap.
Simple antioxidants are, to place it simply, basically just antioxidants. Vitamin C is a simple antioxidant. In fact, if it does not hold a partner to defuse it, it becomes a pro-oxidant in its ROS activated state. Funnel antioxidants are antioxidants that most 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 like a funnel antioxidant.
Better yet, little system like coenzyme Q CoQ and alpha lipoic acid funnel ROS life from ROS and many other antioxidants, with CoQ being a requisite functional element within the metabolic pathway itself, for passing ROS electrons to OX or PHOS system of mitochondria for life 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 likely recycling alternative to massive simple antioxidant dosing. Greatest of all, are giant macromolecular mechanical system system antioxidants for example the mitochondrial OX or PHOS efficiency system of mitochondrial regenesis, as turned on by activated CR or LE. This third category is the large antioxidant player in our new understanding regarding the CR or LE phenomenon. Now, we are in a position to think about the functions of our winning candidates.
Lastly, we are not going to list all regarding the impacts of our gold and silver medal winners, or this narrative should view like a phone book. We shall bundle wherever likely and stick to primary effects, hopefully, without brief changing the reader. The 3 large gold medal winners are curcumin, silibinin and resveratrol. Continued at articlesbase story Life Extension Metabolic Pathway Map Reveals New Phytonutrient Candidates- Component 2. Bambeck and Michael Wolfson.
