Major Diseases of Aging Unified by a Global Theory: Easy, Simple Practices Let You Live Longer and Better.
Gregory S. Bambeck Ph.D. and Michael Wolfson J.D., M.B.A. Kent, Ohio U.S.A. 44240
INTRODUCTION
Even before The Human Genome Project, scientists have predicted a ‘new age' of biomedicine. Myriad small improvements continued to accumulate, but no great fulfilling promises have arrived. For nearly thirty very exciting years we have anxiously awaited some "Great Breakthrough". Now, the waiting is over. This century, with good reason, has been labeled the "Century of Bio-Technology" and early fruits are finally ripening on the vine.
One major genetic control system has been found that manipulates several thousand genes which regulate metabolism from the fetus all the way through the aging process, and even in the cancer cell, albeit with a special caveat. From this regulatory control system, we have gained a much better understanding of the aging process, its natural consequences and the things that go wrong, and even more importantly, how to correct many of them.
For the past several decades, most of what we knew about the diseases of aging was disjointed, disconnected ‘pieces-parts' full of potentials and enticements, but lacking a "glue," a central unifying singularity. We now have that glue--a global hypothesis that knits these unconnected cuttings into a whole cloth that is mechanically definable. We have moved from correlation to causation; from best guesses to workable applications. As incredible as it may seem, our greatest killers, such as heart disease, cancer, type II diabetes, neuromuscular/vascular wasting and even aging itself is a single entity with many negative facets, each with its unique features. This even includes the extension of human life length beyond the normal
maximum. Of course, we don't know everything yet, just as we will never know everything about anything, but we finally know enough about this to call it a system. Once you have a system, you can lay intelligent plans. Prior to that, we are stuck with "best guesstimates."
We will provide a brief outline of the theory here, but this document is primarily devoted to the practical applications of that theory—"What YOU can do". These are the things you deploy to avoid these diseases while maximizing the potential to live longer than nature's plan originally built into you. You will be pleasantly surprised by how simple it really can be. A lot of the complexities of the past go away because much of the "voodoo" and confusion go away.
A central theory of the diseases of aging does for biomedicine what E=mc squared did for physics. It allows the scales to fall from our eyes, and it permits us to peer through the halls of mirrors to the window overlooking the garden of understanding. These two authors have studied thousands of scientific papers from the last couple of decades, paying particular scrutiny to those of the last half dozen years, and again and again we find the global metabolic theory making sense of our perplexities. It is a most refreshing epiphany, because a dark and tortuous path has become straight and true in the dappled sunshine. That which was obfuscated is now perfectly clear.
Scientific papers written within the last few years are much more interpretable within this unifying framework. Very soon, these understandings will be known by legions of scientists and soon thereafter, by the world. This document and other documents we have recently published herald the coming of this new age of extended youth and vitality.
Before we launch into practical applications, let's take a brief perusal of the theory. Aside from water and minerals, 95% of the flesh of all animal organisms, from single cell organisms, to sponges, to worms, to insects, to mice, and even to humans, is composed of four basic bio-chemicals: carbohydrates, fats, amino acids and nucleotides, all of which can be used
either as fuel or as cell building materials. They can either be burned as fuel to obtain energy or knitted together in combination to make huge molecules that form the structures and functions of a new cell. The universal regulatory pathway manipulates the flow of these four main constituents and the energy balance of the cell to control the maintenance of the housekeeping functions in non-dividing cells and to provide energy and material flow into the building processes to make new cells. In the past, we knew much about the flow patterns but we didn't know how the component systems were managed. Now we do know, and we are discovering how the regulatory pathway works to control the length of our lives through its rejuvenative, regenerative and degenerative processes.
The core of the regulatory pathway sequence is called the AMPK to TOR to PGC-1alpha to ROS to SESN and back to AMPK, feedback loop. Don't be afraid of the science jargon, it's a simple five item list. Just think of them as the names of five people you haven't met yet, and are just about to begin to know. Write this five-item loop down on a notepad and refer to it as you read this paper, so as to remain grounded in the discussion. A much more in depth description is provided in "The Life Extension Pathway, Resveratrol, etc. and Cancer Control: Mitochondrial Biogenesis Duality, the Metabolic Mechanism and Practical Applications," which can be found via search engine under ‘Bambeck Wolfson Life Extension.
Caloric restriction (CR) is the ‘gold standard' of life extension. CR activates AMPK to inhibit TOR and the rest of the control elements in this pathway, all the way back to AMPK. Put simply, an upward arrow next to AMPK results in a downward arrow next to everything else. Got that notepad? Install arrows, now. Conversely, inhibition of AMPK shortens life, and all the arrows point in the opposite direction. Quite simple, isn't it? Well, yes and no, because the devil is in the details, and each component can be activated individually or in combination. So keep that notepad at the ready. For instance, there are pharmaceuticals, such as metformin and rapamycin, nutriceuticals such as resveratrol, and hormones like growth hormone and thyroxine, which can act singly or in combination
on different parts of the pathway to either mimic or contradict CR. Among other things, this pathway controls the building (neogenesis) and efficiency (regenesis) of the mitochondrion, the major oxygen using fuel burning unit in all animal cells. The mitochondrion sits between PGC-1alpha and ROS. Cancer cells suffer from mutational derangements that alter non-oxygen fuel burning in a process we call forced hyper-glycolysis. New medicines are being found which disrupt these derangements, and yield beneficial outcomes. So, as you can see, on the one hand it is quite simple, but on the other hand it can get a little hairy.
This should be enough for the reader to basically understand the practical applications section, below. If you need more information to supplement your understanding, please feel free to consult the aforementioned publication. And so, folks, let's go take a look at some practical applications. Now, don't forget to drag that notepad along with you. We don't want anybody getting lost.
PRACTICAL APPLICATIONS: EASY THINGS YOU CAN DO
One might consider this to be the wild hypothesis part of the document, but based upon the aforementioned findings, the proposals might actually be more sound than a lot of the health stuff that peppers the grocery store checkout stands. However we remind everyone that we are not medical doctors, and therefore, not licensed to practice medicine. Nor is it our intention to do so. Any use of the information contained in same is at the reader's discretion. We specifically disclaim any and all liability arising directly or indirectly from the use or application of any information contained in any of these articles. What we write herein is more a free speculation of ideas engaging over the counter phytonutrients and life style choices.
Recent longitudinal studies show us that dietary sugar is killing us more resolutely than either saturated fat or high protein content, as found in animal products. The diseases of aging, such as diabetes, heart disease and
cancer, kill the vast majority of us and excess dietary (extracellular) sugar is a main and growing culprit. However, the previously outlined AMPK, TOR, PGC-1alpha, ROS, SESN cycle shows that the system yields to the relentless decay-diseases of aging, in spite of dietary sugar, due to intracellular metabolic shifts over time. In other words, even though sugar powered the creation of our lives from inception to birth, it will eventually kill us even if we don't eat it. This is ‘natural' aging, and the data clearly shows that unnatural or supra-natural efforts must be made to obtain the unnatural or supra-natural state called life extension beyond the natural or normally expected limit. Face it, caloric restriction (CR) is draconian and is only natural in the sense that, in nature, food sometimes runs out. No organism exists that will ‘naturally' CR itself in the presence of adequate food. Mega doses of anti-oxidants or a hundred bottles of wine worth of resveratrol a day is, decidedly, unnatural. In a related vein, amino acid restriction, in the form of a dietary reduction of methionine, seems to act in synergy as a CR mimetic. However, such a dietary regimen seems far too complex, restricted and unnatural to be practical in a preliminary review such as this one. We will leave such things for future consideration in an expanded applications document, later.
That being said, such things have been found to stand the test of time. For instance, the Chinese have been drinking a high resveratrol Japanese knotweed root extract, called itadoli tea, for millennia with claimed beneficial results and no known ill effects save for some occasional intestinal discomfort, found to be mostly due to emodin, a co extract, which incidentally, is not found in modern concoctions. The remainder of this brief discussion is mostly devoted to some unnaturally ‘natural' stuff that folks might do without having to live a supplement menagerie supported life in near anorexia with its attendant impediments to muscularity, wound healing, immune function, fecundity and others. The focus, here will be on forcing a default state to mitochondrial regenesis, which is the heart and soul of life extension and the inhibition of cancer cell induction and maintenance. Thus, the discussion will completely avoid the well worn schoolmarm admonitions such as ‘eat your vegetables,' ‘take your
vitamins,' ‘exercise regularly,' ‘drink plenty of water,' ‘keep your weight down,' ‘don't eat between meals,' ‘brush your teeth after every meal,' ‘don't eat anything that you can't fit into your mouth,' ‘don't ingest it if you can't pronounce i,' ‘holy cow, that sure is a big fish' and other common sense standard fare that we won't even mention, here.
It is difficult to tell how much of dietary resveratrol is neogenic and how much is regenic. It cannot be heavily neogenic due to its TOR bypass, catabolic and anti-oxidant functions plus its average life expectancy increasing and rejuvenative outcomes in the absence of increased cancer induction or any true life length reduction. Standard dietary resveratrol also cannot be very strongly regenic because there is no appreciable up regulation in AMPK, no real reduction in cancer incidence, no increase in cancer cell apoptosis and no true life extension. However, much mitochondrial biogenesis is observed, but how much of this is neogenesis converted to regenesis is unknown because most investigators were unaware of the difference.
Progressive nutriceutical supply companies recognize this and are actively pursuing remedies. The essential problem is simple. When resveratrol is eaten, well over 90% of it is sulfonated and glucuronidated in the intestines and in the liver via the hepatic portal system, rendering it water soluble while targeting it for kidney removal to the urinary tract. Free, unmodified dietary resveratrol is typically less than 2 uM during its one and a half hour elevated blood plasma phase following ingestion. Glucuronate and sulfate derivatized resveratrol do not cross interstitial cell membranes and the low free resveratrol in cell microsomal fractions indicate that the interstitial cell extracellular sulfatases and glucuronidases have no general impact. This may not be true at sites of inflammation, but the desired whole body effect appears not to be there. Although we have no retention or turnover numbers on free intracellular resveratrol, it does not appear to accumulate over time. Experiments have shown that serum soluble free resveratrol concentration in the 20 uM range definitely impact the CR/AMPK pathway. For instance,
DMSO solubilized resveratrol, when injected into mice, causes all the desired AMPK and downstream effects in brain tissue.
As mentioned earlier, nutraceutical suppliers are being very ingenious in their attempts to get serum resveratrol concentrations up to the CR mimetic range. One supplier shows, graphically, how micronization of resveratrol dramatically increases free resveratrol up to and well beyond the minimal required AMPK activating range. Other suppliers are creating encapsulated, solubilized and time released formats. One supplier provides lozenges for sublingual delivery. Resveratrol mixed with synergizers such as quercetin and co enzyme Q, are also offered. We eagerly await their time based serum data, and even more so, their intracellular AMPK up regulation data.
Here's a quick and dirty home remedy. You can dissolve up to about 500 mg of resveratrol in a shot of 86 proof booze, or flavored schnaaps, for the more faint of heart. Solubility is mostly dependant upon alcohol content, so the same should hold for a glass of wine, but it may take a while to dissolve. Besides, the smaller the volume, the better it is for non-intestinal absorption. Take a slug, swirl it around in your mouth for a full minute before swallowing, kick back, and enjoy. Dissolving is what you might call the nanonization technique. It has been shown to enhance buccal and aerodigestive absorption by as much as 800% above dietary methods, and it does not increase the kidney metabolite load one whit. Anyway, many of the medical gurus out there tell us that 10-20 grams of ethanol a day, is good for us.
Then, there's the stretch (or even strain) of your imagination beyond the orbit of Pluto, plan. Human beings have daily circadian and monthly lunar cycles for a reason. Anyone who has read about the circadian melatonin cycle knows what we're talking about. The fact that human females have a lunar cycle length receptivity cycle, and that in small, tight knit groups, cycle together, is no accident. The seasonal based cycle was replaced by
the lunar cycle because conditions made it happen. What made it happen, you query? We thought you would never ask.
The mutational force is the primary evolutionary driver, but it is accidental, generational and is usually a losing proposition, with rare selective advantage. But, the winners support population survival in the form of multi-generational adaptation. The selection advantage of a switch from a seasonal to lunar cycle must have been powerful, simply because it was forced into existence. Consider the following. Over 99% of the last two million years, or so, of human evolution, has been devoted to the slow steady conversion from gathering, to scavenger gathering, to hunter gathering, while the remaining less than 1% is called civilization. Having excellent 3-D color vision, but poor night vision, the night light of the full moon became a great advantage as it advanced geographical food acquiring range and easier pickings. Being bipedal and having prehensile dexterity in a shrinking dryas ecosystem were great evolutionary pre-adaptations and opportunity vs. death drivers for proto-humans.
This dynamic food energy switch created full moon super-nutrition for several days to a week, followed by a remaining month of being trapped in standard fare. This tuned up a monthly cycle of high, then haphazard nutrition, which caused elevated body fat that could conveniently support endometrial growth and fecundity, two weeks after the full moon, during the pitch black nights of the new moon. Since nobody looks ugly in the dark, alcohol not yet being invented, and besides, there being nothing else to do but stumble around like blind idiots, a nutritional match was made in heaven. In addition, sexual glue is social glue. This was already operating in the context of a proto-hominid large brained noisy critter, with its ecological niche pushing a movement toward even more brain growth, symbolic representation as language and a pre-civilization social tool kit simply awaiting large enough population numbers to invent neat stuff like cities, war and jacuzzies. Thus, the African stage was set, and fortunately for us, all four acts played out before we, as the genetic evidence shows, almost became extinct.
This pattern would also be reflected as a natural nutrient driven monthly cycle of low and high AMPK activity and a regular neogenesis and regenesis cycle, which may have assisted us in becoming the longest living primate. The long parturition period, the interminable time stretch from birth to sexual maturity and the creation of history, in the need for elders to pass all that big brained accumulation to the next generational batch of incomprehensibles that seem to arise for the first time in memory with each succeeding generation, could have helped to assist this life lengthening admixture. In the context of this paper, that is, if there still is any context, this kind of long-winded speculative wannabe has just got to be followed with a circadian/lunar cycle recipe format.
The advent of commercially available high concentration bioavilable resveratrol would open the door to possibilities that will really bring the troops home. At full dose, it would bias the system toward true CR mimicry of AMPK driven mitochondrial regenesis, while at one tenth full dose, it would bias the system toward the neogenic meta-mimicry we described in detail, before. Since neogenesis takes several days to complete, while regenesis is much quicker, a circadian/lunar cycle plan that forces the system into lengthy defaults to life extending regenesis, might look something like this: Low dose neogenic resveratrol could be coordinated with anti-oxidants, dietary nutrient loading and/or power based exercise for five to seven days, or so, then followed by high dose resveratrol coordinated with daily food avoidance between dinner and breakfast and/or high oxygen utilizing endurance exercise prior to breakfast in a more extended time frame, say about three weeks, to entrench mitochondrial efficiency, cellular house cleaning and a shift away from glucose toward fat burning. Here we have something for everybody. Lounge lizards could reap the benefits of the phytonutrient pattern only effect, while the more restless spirits among us could enhance those effects by dietary and exercise regimens. Either way, organs and tissues other than cardiovascular and skeletal muscle could become larger recipients of resveratrol's benefits. Numerous daily, weekly and monthly variations of the theme could be envisioned. One plan might be to include one meal a
day to cause chronic fasting default to regenesis and/or with exercise to assist regenesis with glucose nutrient debt and/or a CR mimetic to activate the AMPK life extension loop.
A very interesting rat study of intermittent CR has put the world of CR afficionados on its ear. Using alternate days of ad libitum food supply and total fasting, in rats, results in no long term CR, as the rats make up for fasting by feasting between fast days, while ending up with life extension comparable to CR. This more or less jives with the down regulation of PGC-1alpha to regenesis turn on time frame. In fact, this study is the actual proof of principle, since life extension by CR can't happen without it. This also jives with our notion that, at least partial neogenesis followed by regenesis, won't hurt life extension, and you can avoid the misery and downside risks of genuine CR.
An interesting question emerges here. Since regenesis is a CR long term life extension holding pattern, how long is it good for? By this, we mean: Once mitochondria become efficient, how long do they stay efficient before they need restimulated to become efficient again? In other words, how many days of feast can one ‘get away with' before each day of fasting? If regenesis is good for a week, then a one day a week fast is a small price to pay. Not only that, if 18 hours of fasting works as well as 24, then all one would needs do is miss breakfast once a week. Can this be supplemented with a low or high dose resveratrol regimen that would accentuate the effect?
We need experiments and we need them earlier rather than later. But rats live five or more years, and rats are not people, (as opposed, oft-times, to the other way around). Over the counter metformin is over a decade away, if ever, and rapamycin is too dangerous to become street legal in any time, dimension or reality. Metformin, when used with growth hormone to mechanistically force the system to toggle back and forth between neogenesis and regenesis could ultimately turn out to be the greatest anti-aging plus rejuvenation achievement of all time. This could truly cause
cells to behave more like they do in the juvenile stage. The timing, dosage and testing required in such a scenario would be critical. This is playing with some real big mojo, here, and it would be illegal without a prescription under a doctor's care. Only people, at least in their early middle years, say past thirty, could participate in such a program, safely.
Fortunately, at present, we have resveratrol, which is freely obtainable and we know enough about CR and mitochondrial neogenesis and regenesis, to get answers, fast, and in humans instead of rats. Human volunteers and tissue biopsies that measure CR via AMPK activity and mitochondrial biogenic state from krebs cycle enzymes vs. cytochrome content, can allow us to follow the system status through time. The system is well enough defined, by now that the meanings of these assays point to causation rather than correlation. A wide array of experiments could be rapidly conducted, and could pinpoint which timings, conditions and regimens are optimal, whether there are any down sides and what other items might be included. Ideally, we may find a CR mimetic dose schedule of resveratrol, a better mimetic or a mixture of synergistic components that require no life style changes outside of normal prudent health practices … except for that magic pill, of course.
AFTERWORD
About a week after we completed our first draft of the practical applications section, we read in the newspaper that exercise physiologists had discovered that ‘carbohydrate loading,' health-wise, was far inferior to fasting prior to and during a work-out. The ‘carb loading' thing may work if you're training for the Tour de France, but it isn't for the average Joe. Fasting caused non-oxygen sugar burning to shift over to oxygen fat burning and inefficient white muscle to shift into efficient red muscle, simultaneous with advantageous cardiovascular effects, weight loss and
reduction in diabetes-causing insulin resistance. Quizzically, they hypothesized that hunger induced adrenaline was instituting the changes. Perhaps there is a better hypothesis, and you can probably guess what we think it is. Several months after we published our first paper on cancer metabolism, which describes a thirty year old hypothesis, researchers announced a ‘newly discovered' cancer growth stopping hyperglycolysis blocking concept therapy that ‘reawakened' (their words) mitochondrial regenesis (our words). Then they fumble around for the concept of a mechanism. We are pretty firm on what we think the mechanism is. Diabetic lung cancer victims live longer with metformin, but the researchers do not make the CR connection. Dietary resveratrol with exercise increases mitochondrial muscle volume more than exercise alone or resveratrol alone and slows ventricular hypertrophy. What is the connection? Mitochondrial biogenesis measurements sometimes show one thing and sometimes show another, and scientists are befuddled because they don't know the difference between neogenesis and regenesis. Arguments erupt in kingpin pharmaceutical companies over whether resveratrol is a CR mimetic, or not, because researchers haven't separated CR meta-mimicry from CR mimicry. Everywhere we look, we see examples like this, where specialists understand one or two trees so well and the forest so poorly that the conclusions become almost strange, contradictory and surreal. Many scientists, in the fields we have visited, wouldn't be so surprised or perplexed, if they only had a single unifying global hypothesis to make their results coherent. We have such a theory, and all these conundrums make sense to us. Prudent applications of such a theory can have breathtaking impacts upon the nation's medical bill and the aggregate number of years added to human life; in the first case, measured in the trillions of dollars, and in the second case, measured in the billions of years. This is big stuff … really big stuff.
Gregory S. Bambeck Ph.D. e-mail: mailto:gregorybambeck@yahoo.com" gregorybambeck@yahoo.com
Michael Wolfson J.D., M.B.A. e-mail: mailto:mwolfson@stanfordalumni.org" mwolfson@stanfordalumni.org
Copyright © by Gregory Bambeck and Michael Wolfson June 19, 2010.
