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.
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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.
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 andresveratrol. Cumin root can be partially purified to turmeric, taken as is, or further purified to its most active ingredient, curcumin. Milk thistle extract, called silymarin, can also be taken as is, or can be purified to its most active component, silibinin. Resveratrol is most often alcohol extracted from waste grape skins or Japanese knot weed roots, and provided as an impure mixture of about 80/20 to 60/40 ratio of phytosterols to resveratrol and consumed as is. It is also available in its most active form, trans-resveratrol. All three are cheap, readily available, have a long historical tradition, own a virtually immaculate safety record, are unpatentable and are causing pharmaceutical companies to rip their hair out by the roots, in exasperation. On the pharmaceutical upside, is that the companies are assiduously pursuing better, more biochemically focused, patentable and more expensive pharmaceutical alternative mechanism of action variants. But, until then, we are stuck with the natural stuff. Because their overall impacts and principal active sites are so similar, as described below, we bundle all three together. Of course, as downstream mitochondrial regenesis activators, all have been historically listed as powerful antioxidants, but now we know better.
As succinctly as possible, 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 rate phases of cancer cell initiation, progression, proliferation and invasion, as well as all the phases in the liver steatosis/cirrhosis/MS/diabetes sequence and the atherogenic cardiovascular and related disease processes and groups, to name a few. In addition, they all up regulate apoptosis, autophagy, insulin sensitivity, AMPK, P53, insulin dependant receptors, heart and skeletal muscle oxygen consumption, ATP output, mitochondrial numbers, force of contraction, hepatogenesis, neurogenesis, mitochondrial regenesis, antioxidant response and multiple type cancer cell differentiation and disease victim survival time, also, to name a few. These data imply that that they must be operating upstream of TOR, close to a main input branch of TOR, perhaps on the CR side not far from AMPK, due to strong AMPK and p53 system up regulation in the absence of evidence supporting a very strong AKT, P13K, or RAS down regulation. A little over a year ago, Affymetrix gene chip shotgun analysis showed that resveratrol activated exactly the same near 1,000 gene set activated by CR downstream of AMPK in all tissues tested. While writing this paper, we learned, after our map had predicted it, that curcumin activated the same gene set. We suspect a similar outcome for silibinin, as it has been recently found to directly, or close to directly, up regulate P53 and its down stream cancer suppressor protein P21. These interactions with AMPK may be complex, because P53 is up regulated in all three cases, which seemingly, should not occur with simple or direct AMPK activation. The rather soft down activation of the CG/CM pathway shows itself to be due to cross regulatory pathway inhibition by such factors as activated P53, partial TOR block and halting of the mitochondrial RTG response, rather than due to direct pathway inhibitors.
Oral bioavailability of curcumin, silibinin and resveratrol is poor, in all cases. Oral bioavailability of curcumin increases 2,000% when mixed with piperine from black pepper. Silibinin is obtainable as bioavailable conjugates of several kinds. Resveratrol is available as lozenges to support buccal absorption, or is provided in pure form, in mega-doses. Resveratrol conjugation would not work orally, because it is converted to kidney eliminable glucoronides and sulfonates in the intestine and liver on the first blood pass through these organs, which occurs prior to the first pass to the somatic tissues.
The remaining candidates failed to make our rigorous gold medal cut for one reason or another, but they are not slouches by any means, and that is why we give them the high status of the word 'silver medal'. The silver medalists are all excellent supplements and form powerful synergies with each other and the other three big gold medal winners. Unfortunately, all three gold medalists only exert their main effect on the CR/LE pathway, depending entirely on regulatory CR/LE elements to inhibit CG/CM. Some of our silver medal winners are direct CG/CM down regulators, while others are CR/LE reinforcers, and one is even a 'shotgun' multi-system synergizer.
The shotgun synergizer is a real powerhouse, a whole system appearing to have been evolved to operate it. It is the omega 3/6 essential oil mix available from flax seed oil, fish oil or krill oil, with flax being by far, the least expensive. The most important 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 give them durable integrity, reducing brittleness and thus, increasing all membrane dependant cell function efficiency. They are metabolized to become a number of cell system activators and inhibitors. For instance, the DHA and EPA pathway products reduce arachidonic acid, IL1, COX II and TNF induced inflammation. Other impacts include increasing apoptosis and immune surveillance, and reducing cancer cell proliferation, cachexic wasting and angiogenesis. They act as anti-metastatic, anti-HIF, anti-VEGF and are essential for mitochondrial cardiolipin production, which is critical in the function of the mitochondrial complexes III and IV in the respiratory chain. The American diet is seriously deficient in omega 3/6; some say suicidally deficient, containing less that 10% of the healthy minimum needed.
Another synergistic beauty is alpha lipoic acid. The Linus Pauling institute considers it to be one of the most powerful antioxidants known. Of all of the winners listed, it would be classified as a zoonutrient, but is only actually available as a synthetic, as natural source isolation is ridiculously expensive. Fortunately, its structure is so 'dirt' simple that its synthesis is also 'dirt' cheap. It can be regenerated from its oxidized form by glutathione. It is also a funnel anti-oxidant, regenerating vitamin C, vitamin E, the ubiquinone form of CoQ and all the while, destroying a wide array of ROS. It reduces NF-kB and foam cell production and renders regenic mitochondria more efficient. In fact, alpha lipoic acid preferentially locates to mitochondria, where it has the most ROS reduction impact. This strongly supports the CR/LE side of the equation.
Coenzyme Q (CoQ) runs along similar lines as alpha lipoic acid but its primary function is more specific. It is a powerful antioxidant in its own right, but preferentially locates to mitochondrial respiratory complex I, where it increases net mitochondrial ATP production. This activates glutathione production in the liver. Glutathione is the most powerful antioxidant produced by the body and is a key alpha lipoic acid regenerator. Glutathione has multiple impacts all over the LE system. CoQ has long been used in Japan to fight congestive heart failure and left ventricular hypertrophy by increasing cardiac ATP production and force of contraction. CoQ assists the CR/LE pathway to achieve its fully intended mitochondrial regenic efficiency.
The most active ingredient in green and white tea is epigallo catechin gallate (EGCG) while the most active component in soy extract is genestein. They both inhibit the CG/CM pathway somewhere downstream of the growth factors and upstream of AKT. There is some evidence that EGCG operates somewhere between growth factors and RAS. They both have broad spectrum tumor anti-proliferative activity, and where measured, down regulate the CG/CM to TOR upstream activators. Finally, we have CG/CM down regulators to complement our three gold medal CR/LE activators! With further research, maybe EGCG and genestein might someday be elevated to big winner status.
Vitamin K, or more significantly vitamin K2, might someday be included as a player on the CG/CM side of the equation, as it is a tyrosine phosphatase inhibitor of vital elements in the cell growth cascade. Inositol hexaphosphate also has CG/CM possibilities. A new kid on the block and creating quite a stir is moringa oleifera extract. According to the promotional claims, it has all the right biochemical pathway bells and whistles, and like most of the winner and honorable mention extracts, in their crude form, is loaded with polyphenols. Maybe there is a magical one in the mix, or it's just the whole mix. We look forward to a scientific paper battery to substantiate or refute the claims. There also might be a few more winners among the supplements already in common use that simply have not yet been tested within the framework of the CG/CM or CR/LE system.
Conclusion
We all know that there is no perfection in this real world, and we are far from projecting perfection herein. Animal studies show that CR and CR mimetics induce LE, even when started during the pre-adult growth phase. They do not inhibit normal mitosis or cell differentiation, but the resultant animals have slightly smaller cells and body size. Until we are sure, it would seem to be prudent not to apply CR mimetics or CG inhibitors when pregnant, still growing, taking intentional ROS generating cancer chemotherapy or suffering from GH deficient dwarfism. Not surprisingly, there have been a few internet blog inklings of the unsubstantiated possibility of increasing the probability of such normally common conditions as kidney casts and gall bladder/bile duct involvement. These would necessitate multi-ten thousand people population studies to weed out a single cause from the land fill of known entities, as 50 million Americans contract these conditions during their lifetimes, anyway. Besides, no human studies have been conducted, nor have been deemed worthy of being conducted, on these topics. Considering the vested interests (i.e. no patents, no clinical pipeline) of some of the sources of these rumors, and there being no real beyond arms length data, we chalk this up to purposeful misdirection or typical internet scare tactic mythology.
Although CR/LE mimetics increase LE, they do so less than half as much as true CR. There is a real difference between genuine CR and CR mimetics. In real CR, the intracellular environment and extracellular environment are fuel depleted, while under CR mimetic conditions fuel and energy are ad libitum. The CG pathway must shut down during real CR, but does it have to shut down if only the CR/LE half of the system is strongly and directly affected? We have already seen (5/20/11 Science) that TOR can be compartmentalized in the cell and behave differentially. All known CR mimetics operate on the CR/LE side. Maybe down regulating CG with one of our silver medalists along with a CR mimetic might force TOR to operate in all compartments like it must do in actual CR. Then, we might have a more realistic CR mimicry, and a result more closely approximating 'the real McCoy'.
Our first primitive attempt to map out the CG/CM and CR/LE system is just a beginning, and we hope that it is a correct beginning, because the medical implications are just altogether stupefying. If this really is that good beginning, then it could function as a template for future pharmaceutical blockbusters, concept pathway expansion and a variety of, yet unsuspected or wholly unknown fruitful applications. From our perspective, the system is coherent and consistent, and seems to explain a lot, in terms if our present knowledge, especially in the way that so many pieces seems to fit together, and so well. Only the future will tell if our idea holds together as a global unifying hypothesis for the aging diseases and life extension phenomena.
Afterword
We cannot thank the Life Extension Foundation (LEF) enough, because it would have been more than just difficult to arrive where we did, in a reasonable time frame, without their focus. Even with that in mind, the three disease states we had to investigate, included a huge chunk of chemical armamentarium, consisting of many hundreds of potential candidates and over a thousand references. Even though it was left to us to put the puzzle together, having LEF put a lot of the pieces in one box helped quite a bit. Then, there was the realization that our winning candidates had favorable impacts on about half of the other age related diseases in the LEF compendium, and a new merry chase began. This paper is just a theory presentation narrative, and contains no bibliography outside of its internal references to vitally important review or work articles. However, with these referencing capabilities, we believe that all we say proves true and is easily verifiable. Lastly, these are rather belated discoveries for us, after having lived a near six decades as a mixed bag of common social decency blended with questionable dietary habits, and spiced with generic sin, vice and occasional debauchery. Hopefully this knowledge may yield more merit for those to follow.
Life Extension Metabolic Pathway Map Reveals New Phytonutrient Candidates
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