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Life Extension Metabolic Pathway Map Reveals New Phytonutrient Candidates

The three most typical and lethal illnesses of getting older are atherogenic heart problems, the cancers and diabetes II. The metabolic pathway conferring life extension has only recently been outlined. The three illness metabolic pathways run in direct opposition to the life extension pathway. We have generated a metabolic circulation chart (map) that reveals each methods as a dynamic singularity. We make sense of those illnesses and life extension within the textual content, when it comes to the metabolic map. From a compendium of phytonutrients, we found a small handful of them that glad a really stringent set of standards for preventing these illnesses and engaging in real life extension. The three most profitable candidates kind a exceptional match when it comes to our metabolic map, whereas the 5 runners up are very shut suits. Used singly, or together, all eight have discovered efficacy in treating many dozens of age associated illnesses past the three fundamental killers we describe, herein. Introduction

The most typical and lethal illnesses of getting older are the 1) atherosclerotically induced heart problems group, 2) center age onset kind II diabetes and three) the multitudinous array of cancers. Obesity could be thought-about a fourth illness, however since its morbidity often manifests its end result as a consequence of a number of of the primary three illnesses, it should solely be handled in an ancillary vogue, as a situation. All these illnesses share, at their causative core, a metabolic sample of imbalances which might be remarkably related. Viewed superficially, this doesn’t look like the case, as a result of they function in several physiological compartments and at completely different ranges of mobile group. For occasion, in most cancers, the metabolic sample operates on the intracellular degree, and in reality, can start in a single cell. Extracellular physiological manifestations of most cancers develop into evidenced on the multicellular degree, a lot later, as mesenchymal and metastatic 3D tumor invasion and dispersal. Diabetes requires the mobilization of trillions of cells working in live performance on the tissue and organ degree of integration. Atherosclerotic heart problems additionally entails the participation of gaggles of cells working on the degree of the vascular tree. The widespread denominator consists of mal diversifications to carbohydrate metabolism that develop into mounted and self exacerbating, finally main to every illness having attribute types of outcomes.

Recent developments give us three nice proofs that the aforementioned statements are true. First, the identical metabolic pathways and/or their downstream harmful outputs are evidenced in all three illness conditions. Second, and extra importantly, pharmaceutical or phytonutrient metabolic pathway differential rectifiers forestall, delay onset, delay development, and in some instances, truly reverse all three illness states with a single therapeutic routine. Lastly, pushing the metabolic system within the reverse route of its a number of illness manifestations truly extends life past its regular time span restrict. This is multi-serendipity sufficient to induce a lustful seek for an Occam’s razor.

The Phytonutrient/Nutriceutical Candidates

The well being meals shops and big pharmacy chains are awash with a bewildering array of lots of, if not hundreds of pure (and in any other case) dietary meals dietary supplements and natural extracts from the 4 corners of the world. Just strolling down the aisles ought to institute some type of medical despair. Where to start? How does one separate the questionable legitimacies of; folks treatments, previous wives’ tales, heap large mojo shamanism, venerable historic medical knowledge, mythology, cultural favorites, trendy advertising and marketing snake oil hucksterism and so forth. from precise truth and good medication? As an alternative choice to taxing our already enfeebled brains, we hit on one of the best concept we have had in years. Instead of embarking on an interminable grand search, we let the world’s finest and brightest subject particular skilled brains do our considering for us, and we went in with a strategic plan.

We embraced a duplicate Disease Prevention and Treatment, revealed by The LifeExtension Foundation (LEF). Therein lies the mixed efforts of ‘hundreds of analysis research and the medical expertise of physicians around the globe’ (to place it in LEF’s personal phrases) dedicated to the over using goal of life extension. After reviewing what LEF needed to say, we used scientific publications and the web to replace and modernize our understanding. Having our CG/CM and CR/LE map in hand, and our three principal illnesses to each direct our search and institute the strategic plan, we plunged in.

The plan had a couple of easy however inviolate and all inclusive guidelines. Each candidate should have utility towards a number of cancers and towards diabetes and towards atherogenesis; all three. It should each, statistically forestall or delay onset of all three illnesses by considerably lowering the likelihood of age associated inhabitants incidence and should sluggish the development of all three illness states, as soon as illness is instituted. Where the precept goal and/or mechanisms of motion are identified, it should regulate its goal, and in flip, their downstream pathway targets within the route according to the CG/CM and CR/LE map. Where precept goal or mechanism of motion isn’t but identified, downstream results should match the regulatory instructions of our metabolic map. Although not an absolute requirement, every chemical ought to have an especially excessive LD-50, within the a number of dozens to lots of of occasions its useful dynamic vary and a historical past of maximum security, which all our winners do. The likelihood of satisfying all of those and necessities is minute and is a strong set for a real candidate.

Limiting our search from the world at massive to the LEF compendium, immediately whittled the search from hundreds of potentialities to a couple hundred. Applying the all inclusive rule set to those few hundred, pretty shortly drove the quantity down to a couple dozen after which, far more slowly and agonizingly, chipped its means right down to a handful. Incidentally, route of administration was not a consideration as a few of these molecules have poor oral bioavailability in a pure kind, however a lot increased bioavailability in a soluble injectable kind, or in a conjugated oral kind. Winning candidates could be extra precisely outlined as nutriceuticals relatively than as phytonutrients or dietary dietary supplements attributable to their mechanism of motion. We have already supplied a common description of the differential therapeutic deserves of our gold medal and silver medal winners, and we are going to diversify these deserves and differentials, later.

Before we start, we should say a phrase or two, about antioxidants. For one factor, antioxidants are good for us, plain and easy. Thus, it isn’t stunning that antioxidants have been all the trend for the final twenty years, and for a number of excellent causes. They shield us from the main illnesses of getting older, cut back ROS formation, give us extra vitality and with an extended listing of properly worn etceteras, enable the inhabitants survival curve to leptokurticly shift towards the utmost life expectancy. However, they merely do not institute LE, albeit being ‘one of the best recreation on the town’. Driving this level house is that organisms on a CR or CR mimetic protocol manifest LE with out any antioxidant supplementation by any means! Check and mate. End of recreation.

For this and different causes the ROS damaging speculation is now seen extra from the avoidance of the life shortening aspect, versus the life lengthening aspect of the equation. The antioxidant speculation has been discovered to be restricted and in want of modification. We should bear in mind right here, that crucial components of the LE pathway have been solely found over the last one to 2 years, so a concept modification was not even realistically potential prior the very latest current. For occasion, the LE pathway institutes mitochondrial regenesis and reduces ROS manufacturing, within the first place, obviating the necessity to mop up ROS ‘after the very fact’ with antioxidants. Prior to the elucidation of the LE pathway, any LE system activator would have been, and in reality was referred to as an antioxidant, merely due to mitochondrial regenesis; and mitochondrial regenesis was not hypothesized on the time. We imagine ourselves to be the primary of us to try to formulate a primitive world CG/CM and CR/LE map that features the notions of most cancers metabotype, mitochondrial neogenesis/regenesis, CR/LE pathway, CG/CM pathway, CR/LE pathway mimetic and useful antioxidant classification as easy antioxidant, funnel antioxidant and metabolic pathway antioxidant, regardless that all of this stuff are properly described within the literature, however disjointed, as a result of this age of specialization obscures any ‘large image’ evaluate method, comparable to ours.

The well being meals complement world is awash in phytonutrient antioxidants, and our metabolic map has helped us to loosely classify them into three broad classes with appreciable overlap. Simple antioxidants are, to place it merely, mainly simply antioxidants. Vitamin C is an easy antioxidant. In truth, if it does not have a associate to defuse it, it turns into a pro-oxidant in its ROS activated state. Funnel antioxidants are antioxidants that each settle for ROS from different antioxidants and move their ROS activated electron(s) to a metabolic system to defuse them and to extract helpful power. For occasion, the vitamin C, vitamin E, NAD sequence, units vitamin E as a funnel antioxidant. Better but, slightly system like coenzyme Q (CoQ) and alpha lipoic acid funnel ROS power from ROS and plenty of different antioxidants, with CoQ being a requisite useful aspect within the metabolic pathway itself, for passing ROS electrons to the OX/PHOS system of mitochondria for power seize as ATP manufacturing. In addition, alpha lipoic acid restores vitamin E and vitamin C to full antioxidant standing by lowering their oxidized state; a potential recycling various to huge easy antioxidant dosing. Best of all, are big macromolecular machine system antioxidants such because the mitochondrial OX/PHOS effectivity system of mitochondrial regenesis, as turned on by activated CR/LE. This third class is the large antioxidant participant in our new understanding of the CR/LE phenomenon. Now, we’re ready to contemplate the features of our successful candidates. Lastly, we aren’t going to listing all the impacts of our gold and silver medal winners, or this narrative would learn like a cellphone guide. We will bundle wherever potential and follow fundamental results, hopefully, with out brief altering the reader.

The three large gold medal winners are curcumin, silibinin andresveratrol. Cumin root will be partially purified to turmeric, taken as is, or additional purified to its most energetic ingredient, curcumin. Milk thistle extract, referred to as silymarin, may also be taken as is, or will be purified to its most energetic part, silibinin. Resveratrol is most frequently alcohol extracted from waste grape skins or Japanese knot weed roots, and supplied as an impure combination of about 80/20 to 60/40 ratio of phytosterols to resveratrol and consumed as is. It can be obtainable in its most energetic kind, trans-resveratrol. All three are low-cost, available, have an extended historic custom, personal a just about immaculate security file, are unpatentable and are inflicting pharmaceutical corporations to tear their hair out by the roots, in exasperation. On the pharmaceutical upside, is that the businesses are assiduously pursuing higher, extra biochemically centered, patentable and dearer pharmaceutical various mechanism of motion variants. But, till then, we’re caught with the pure stuff. Because their total impacts and principal energetic websites are so related, as described beneath, we bundle all three collectively. Of course, as downstream mitochondrial regenesis activators, all have been traditionally listed as highly effective antioxidants, however now we all know higher.

As succinctly as potential, all three gold medalists down regulate AKT, COX II, inflammatory IL cytokines, NF-kB, HIF, VEGF, angiogenesis, fasting insulin, insulin resistance, LDL, blood glucose, HbA1c, ROS, all incidence and price phases of most cancers cell initiation, development, proliferation and invasion, in addition to all of the phases within the liver steatosis/cirrhosis/MS/diabetes sequence and the atherogenic cardiovascular and associated illness processes and teams, to call a couple of. In addition, all of them up regulate apoptosis, autophagy, insulin sensitivity, AMPK, P53, insulin dependent receptors, coronary heart and skeletal muscle oxygen consumption, ATP output, mitochondrial numbers, pressure of contraction, hepatogenesis, neurogenesis, mitochondrial regenesis, antioxidant response and a number of kind most cancers cell differentiation and illness sufferer survival time, additionally, to call a couple of. These knowledge indicate that that they have to be working upstream of TOR, near a fundamental enter department of TOR, maybe on the CR aspect not removed from AMPK, attributable to robust AMPK and p53 system up regulation within the absence of proof supporting a really robust AKT, P13K, or RAS down regulation. Slightly over a 12 months in the past, Affymetrix gene chip shotgun evaluation confirmed that resveratrol activated precisely the identical close to 1,000 gene set activated by CR downstream of AMPK in all tissues examined. While scripting this paper, we realized, after our map had predicted it, that curcumin activated the identical gene set. We suspect the same end result for silibinin, because it has been just lately discovered to straight, or near straight, up regulate P53 and its down stream most cancers suppressor protein P21. These interactions with AMPK could also be advanced, as a result of P53 is up regulated in all three instances, which seemingly, mustn’t happen with easy or direct AMPK activation. The relatively smooth down activation of the CG/CM pathway reveals itself to be attributable to cross regulatory pathway inhibition by such components as activated P53, partial TOR block and halting of the mitochondrial RTG response, relatively than attributable to direct pathway inhibitors.

Oral bioavailability of curcumin, silibinin and resveratrol is poor, in all instances. Oral bioavailability of curcumin will increase 2,000% when blended with piperine from black pepper. Silibinin is obtainable as bioavailable conjugates of a number of varieties. Resveratrol is out there as lozenges to assist buccal absorption, or is supplied in pure kind, in mega-doses. Resveratrol conjugation wouldn’t work orally, as a result of it’s transformed to kidney eliminable glucoronides and sulfonates within the gut and liver on the primary blood move by these organs, which happens previous to the primary move to the somatic tissues.

The remaining candidates did not make our rigorous gold medal reduce for one cause or one other, however they aren’t slouches by any means, and that’s the reason we give them the excessive standing of the phrase ‘silver medal’. The silver medalists are all glorious dietary supplements and kind highly effective synergies with one another and the opposite three large gold medal winners. Unfortunately, all three gold medalists solely exert their fundamental impact on the CR/LE pathway, relying fully on regulatory CR/LE components to inhibit CG/CM. Some of our silver medal winners are direct CG/CM down regulators, whereas others are CR/LE reinforcers, and one is even a ‘shotgun’ multi-system synergizer.

The shotgun synergizer is an actual powerhouse, a complete system showing to have been advanced to function it. It is the omega 3/6 important oil combine obtainable from flax seed oil, fish oil or krill oil, with flax being by far, the least costly. The most necessary are the 18 carbon omega 6 linoleic acid, the 18 carbon omega 3 linolenic acid, the 20 carbon omega 3 eicosopentanoic acid (EPA) and the 20 carbon omega 3 docohexanoic acid (DHA). These fatty acids incorporate into cell membranes and provides them sturdy integrity, lowering brittleness and thus, growing all membrane dependent cell perform effectivity. They are metabolized to develop into numerous cell system activators and inhibitors. For occasion, the DHA and EPA pathway merchandise cut back arachidonic acid, IL1, COX II and TNF induced irritation. Other impacts embrace growing apoptosis and immune surveillance, and lowering most cancers cell proliferation, cachexic losing and angiogenesis. They act as anti-metastatic, anti-HIF, anti-VEGF and are important for mitochondrial cardiolipin manufacturing, which is crucial within the perform of the mitochondrial complexes III and IV within the respiratory chain. The American weight loss program is critically poor in omega 3/6; some say suicidally poor, containing much less that 10% of the wholesome minimal wanted.

Another synergistic magnificence is alpha lipoic acid. The Linus Pauling institute considers it to be one of the vital highly effective antioxidants identified. Of all the winners listed, it might be labeled as a zoonutrient, however is simply truly obtainable as an artificial, as pure supply isolation is ridiculously costly. Fortunately, its construction is so ‘dust’ easy that its synthesis can be ‘dust’ low-cost. It will be regenerated from its oxidized kind by glutathione. It can be a funnel anti-oxidant, regenerating vitamin C, vitamin E, the ubiquinone type of CoQ and all of the whereas, destroying a wide selection of ROS. It reduces NF-kB and foam cell manufacturing and renders regenic mitochondria extra environment friendly. In truth, alpha lipoic acid preferentially locates to mitochondria, the place it has probably the most ROS discount influence. This strongly helps the CR/LE aspect of the equation.

Coenzyme Q (CoQ) runs alongside related traces as alpha lipoic acid however its major perform is extra particular. It is a strong antioxidant in its personal proper, however preferentially locates to mitochondrial respiratory advanced I, the place it will increase internet mitochondrial ATP manufacturing. This prompts glutathione manufacturing within the liver. Glutathione is probably the most highly effective antioxidant produced by the physique and is a key alpha lipoic acid regenerator. Glutathione has a number of impacts throughout the LE system. CoQ has lengthy been utilized in Japan to battle congestive coronary heart failure and left ventricular hypertrophy by growing cardiac ATP manufacturing and pressure of contraction. CoQ assists the CR/LE pathway to realize its totally supposed mitochondrial regenic effectivity.

The most energetic ingredient in inexperienced and white tea is epigallo catechin gallate (EGCG) whereas probably the most energetic part in soy extract is genestein. They each inhibit the CG/CM pathway someplace downstream of the expansion components and upstream of AKT. There is a few proof that EGCG operates someplace between progress components and RAS. They each have broad spectrum tumor anti-proliferative exercise, and the place measured, down regulate the CG/CM to TOR upstream activators. Finally, we now have CG/CM down regulators to enrich our three gold medal CR/LE activators! With additional analysis, perhaps EGCG and genestein may sometime be elevated to large winner standing.

Vitamin Ok, or extra considerably vitamin K2, may sometime be included as a participant on the CG/CM aspect of the equation, as it’s a tyrosine phosphatase inhibitor of significant components within the cell progress cascade. Inositol hexaphosphate additionally has CG/CM potentialities. A brand new child on the block and creating fairly a stir is moringa oleifera extract. According to the promotional claims, it has all the appropriate biochemical pathway bells and whistles, and like many of the winner and honorable point out extracts, of their crude kind, is loaded with polyphenols. Maybe there’s a magical one within the combine, or it is simply the entire combine. We stay up for a scientific paper battery to substantiate or refute the claims. There additionally could be a couple of extra winners among the many dietary supplements already in widespread use that merely haven’t but been examined inside the framework of the CG/CM or CR/LE system.


We all know that there isn’t any perfection on this actual world, and we’re removed from projecting perfection herein. Animal research present that CR and CR mimetics induce LE, even when began through the pre-adult progress section. They don’t inhibit regular mitosis or cell differentiation, however the resultant animals have barely smaller cells and physique measurement. Until we’re certain, it might appear to be prudent to not apply CR mimetics or CG inhibitors when pregnant, nonetheless rising, taking intentional ROS producing most cancers chemotherapy or affected by GH poor dwarfism. Not surprisingly, there have been a couple of web weblog inklings of the unsubstantiated chance of accelerating the likelihood of such usually widespread situations as kidney casts and gall bladder/bile duct involvement. These would necessitate multi-ten thousand folks inhabitants research to weed out a single trigger from the land fill of identified entities, as 50 million Americans contract these situations throughout their lifetimes, anyway. Besides, no human research have been carried out, nor have been deemed worthy of being carried out, on these matters. Considering the vested pursuits (i.e. no patents, no medical pipeline) of among the sources of those rumors, and there being no actual past arms size knowledge, we chalk this as much as purposeful misdirection or typical web scare tactic mythology.

Although CR/LE mimetics enhance LE, they accomplish that lower than half as a lot as true CR. There is an actual distinction between real CR and CR mimetics. In actual CR, the intracellular surroundings and extracellular surroundings are gas depleted, whereas below CR mimetic situations gas and power are advert libitum. The CG pathway should shut down throughout actual CR, however does it must shut down if solely the CR/LE half of the system is strongly and straight affected? We have already seen (5/20/11 Science) that TOR will be compartmentalized within the cell and behave differentially. All identified CR mimetics function on the CR/LE aspect. Maybe down regulating CG with one among our silver medalists together with a CR mimetic may pressure TOR to function in all compartments prefer it should do in precise CR. Then, we’d have a extra real looking CR mimicry, and a outcome extra carefully approximating ‘the true McCoy’.

Our first primitive try and map out the CG/CM and CR/LE system is only a starting, and we hope that it’s a appropriate starting, as a result of the medical implications are simply altogether stupefying. If this actually is that good starting, then it may perform as a template for future pharmaceutical blockbusters, idea pathway growth and quite a lot of, but unsuspected or wholly unknown fruitful functions. From our perspective, the system is coherent and constant, and appears to clarify lots, in phrases if our current information, particularly in the best way that so many items appears to suit collectively, and so properly. Only the longer term will inform if our concept holds collectively as a worldwide unifying speculation for the getting older illnesses and life extension phenomena.


We can not thank the Life Extension Foundation (LEF) sufficient, as a result of it might have been extra than simply tough to reach the place we did, in an inexpensive time-frame, with out their focus. Even with that in thoughts, the three illness states we needed to examine, included an enormous chunk of chemical armamentarium, consisting of many lots of of potential candidates and over a thousand references. Even although it was left to us to place the puzzle collectively, having LEF put a variety of the items in a single field helped fairly a bit. Then, there was the conclusion that our successful candidates had favorable impacts on about half of the opposite age associated illnesses within the LEF compendium, and a brand new merry chase started. This paper is only a concept presentation narrative, and accommodates no bibliography exterior of its inner references to vitally necessary evaluate or work articles. However, with these referencing capabilities, we imagine that each one we are saying proves true and is well verifiable. Lastly, these are relatively belated discoveries for us, after having lived a close to six many years as a blended bag of widespread social decency blended with questionable dietary habits, and spiced with generic sin, vice and occasional debauchery. Hopefully this information might yield extra advantage for these to comply with.

Source by Michael Wolfson

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