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Cervical Cancer Prevention Training Program to Launch in Port-au-Prince, Haiti

Cervical Cancer Prevention Training Program to Launch in Port-au-Prince, Haiti

Dr. Rachel Masch trains a Haitian physician in visual inspection with acetic acid (VIA) screening, a low-cost method used to detect cervical pre-cancers.

New York, NY (PRWEB) January 31, 2013

Basic Health International (BHI) is excited to announce that Direct Relief International will support a cervical cancer prevention training program in Port-au-Prince, Haiti for health care educators and providers at St. Damien’s Hospital. Dr. Rachel Masch, BHI board member and long-time volunteer will lead the initiative.

Direct Relief will work with BHI to increase the capacity of medical professionals at St. Luc to prevent the disease using low-cost screening and treatment techniques. The Direct Relief sponsored program will support delegations of skilled BHI physicians who will train local doctors at St. Luc to identify pre-cancerous cells, using Visual Inspection with Acetic Acid (VIA), and to treat pre-cancerous cells with a freezing technique called cryotherapy.

This program will train 30-40 local physicians, through a combination of classroom instruction and hands-on experience, to screen and treat women for cervical cancer. BHI will use its proven method developed in El Salvador to train community health workers to work directly with the community to increase awareness of cervical cancer and to inform women that free screenings and treatment will be available.

It is anticipated that 300-500 women will receive services during each of the training delegations. Once the training sessions are completed, the equipment used by the medical delegations will be donated to the local physicians, enabling them to incorporate VIA screening into their overall standard of care.

This project will launch in January, in recognition of cervical cancer awareness month, with scheduled training workshops to begin in March of 2013. BHI and St. Damien’s Hospital collaboration will occur over a 3-year period.

Basic Health International believes that no woman should die from cervical cancer. Founded in 2005, BHI is a non-profit organization dedicated to preventing cervical cancer in Latin America and the Caribbean through innovative, low-cost, low technology screening and treatment methods. BHI also provides medical training, policy guidance, and research on cervical cancer issues in the developing world. BHI’s efforts have now been focused on the Caribbean country Haiti.

Haiti suffers from one of the highest cervical cancer rates in the world. In 2000, the International Agency on Research for Cancer estimated that Haiti has the highest incidence of cervical cancer in the Western Hemisphere at 93.9 per 100,000 women. Cervical cancer as the leading cause of female deaths in Haiti and that the mortality rate is more than 30 times higher than in the United States (Partners in Health, 2010).

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World’s First Gay Men with Erectile Dysfunction Support Program Developed by Malecare Cancer Support

World’s First Gay Men with Erectile Dysfunction Support Program Developed by Malecare Cancer Support

Malecare Gay Men’s Health Support

NewYork, NY (PRWEB) July 09, 2012

A new support group program for gay and bisexual men presenting with erectile dysfunction and impotence has been developed by the national nonprofit gay men’s health organization, Malecare. GayED.org includes in-person and on-line support groups, on-line lecture series and teleconferences and will also promote research into the unique issues gay men with erectile dysfunction face.

“GayEd.org responds to a problem facing gay men throughout the world,” said Darryl Mitteldorf, LCSW, the social worker who is Malecare’s Executive Director.

“GayED provides peer to peer support and great advice and information on treatments and techniques for having love filled and intimate relationships between men who enjoy sex with other men. It doesn’t matter if your impotence is caused by prostate cancer treatment or emotional issues…GayED.org will be there to help you” Mr. Mitteldorf reported.

Malecare facilitated the first gay men with erectile dysfunction support groups as an outgrowth of it’s work in prostate cancer, in 2002 and started to develop them into a comprehensive national program starting in 2011. The online support group at http://www.gayed.org launched Monday, July 9, 2012. The groups are supervised by Malecare’s volunteer social workers and psychologists.

“Gay men deal with impotence differently than straight men. The GayED.org support group is a lifesaver for me,” said Fred S., a 59 year old out gay man who is suffering impotence from diabetes.

About Malecare Gay Men’s Health Support

Founded in 1998, Malecare is America’s first and still only gay focused men’s health support and advocacy national nonprofit organization. Focused mainly on cancer survivorship, Malecare is known as the founding organization for gay men with prostate cancer support groups and is a leader in promoting research in LGBT cancer survivorship. More information can be found at malecare.org.

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Find More Developing Nations Press Releases

Less Cancer Founder, Bill Couzens Takes a Look at Cancer Prevention

Less Cancer Founder, Bill Couzens Takes a Look at Cancer Prevention

Less Cancer Founder Bill Couzens

Rye, New Hampshire (PRWEB) December 22, 2011

Beginning with Nixon’s War on Cancer in 1971, cancer cure fundraisers have proliferated, Couzens writes. While Couzens appreciates those efforts, he argues in his post that more attention must go to how people live their lives and to striking down the causes of cancer. This reduction of risk focus means that people will have to live their lives differently.

That change includes radically altering our priorities: “As a culture, we have looked the other way as profit rose above human health and the environment,” Couzens writes.

Cancer has essentially become an expected stage of life and, in his post, Couzens cites startling statistics: between 1975 and 2004, of increased incidences of primary brain cancer that have increased nearly 40 percent, while leukemia has increased over 60 percent among children 14 years and younger. (Children’s Environmental Health Center-Mount Sinai) The work to reduce cancer risks also provides an opportunity to address other public health issues that may include diseases such as Obesity or even Asthma according to Couzens.

Other than the human toll, cancer’s economic pressure is astounding. Couzens cites worldwide cancer cost burden was $ 895 billion in 2008. (Lancet Oncology)

The time to begin a new fight against cancer, before it starts, is long past, Couzens argues. Now, we all must make up for lost time.

Couzens regularly speaks on human health and environment issues. The U.S. Congress has recognized Couzens’ work to reduce cancer risks. Couzens’ work includes Less Cancer launching the National Cancer Prevention Day, which Michigan and Virginia recognize on Feb. 4.

Please find Couzens’ blog here: http://lesscancer.blogspot.com/2011/12/look-at-cancer-prevention.html

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Why is the incidence of Colon Cancer higher in wealthy nations than in developing nations?

Question by Ghfgh G: Why is the incidence of Colon Cancer higher in wealthy nations than in developing nations?
I need some help answering the following question. Any help would be greatly appreciated:

1. What conclusion might you draw from the fact that in wealthy nations the incidence of colon cancer is higher than in developing nations? Justify your answer.


Best answer:

Answer by Lakewood C
Individuals in wealthy nations tend to consume richer food and more processed food — and less fibre.

Add your own answer in the comments!

Mainstream Science’s Dogma Reversal: Aerobic Glycolysis/ Metabolic Alterations are finally seen as Necessary for Cancer Cell Initiation/ Maintena

Mainstream Science’s Dogma Reversal: Aerobic Glycolysis/ Metabolic Alterations are finally seen as Necessary for Cancer Cell Initiation/ Maintenance.

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


          After a half of a century, mainstream big science has completely reversed its dogma on how it is necessary that cancer cells partition their nutrient resources, in a specific way, between material for cell growth and energy production. A thirty years ago modified version of the originally rejected Warburg theory, now has powerful support from newly integrated metabolic pathway studies and core system therapies. This theory was worse than ignored, as it was actively squelched by a small, but elite group, controlling the publication and funding philosophy of cancer during this whole time span. Only the future will tell how much human suffering, could have been prevented, if just honest inquiry and scrutiny had also been allowed to flower, instead of the exclusionary and prejudicial pursuit of personal influence over pet investigative paradigms. Much precious time, knowledge and human life were lost enforcing such preconception, assumption, and opinion upon the course of scientific investigation. Fortunately, but belatedly, data and fact finally triumphed over politics and elevated position. Newly discovered metabolic control systems may benefit us all, not only in the medical area of cancer, but in therapeutic arenas of some other major diseases of aging, as well. A brief human, scientific, data and fact history is contained, herein.


          In a watershed reversal of an entrenched fifty four year old dogma, Science magazine published a Special Section issue on 12/03/10 devoted to metabolic energetics; and more so to the diseases of aging, such as heart disease, diabetes II and especially, cancer. Most important, from a historical (and this document’s) standpoint, is the article on p.1340 by Levine and Puzio-Kuter, which concludes that key elements of the Warburg aerobic glycolysis hypothesis are critical to and necessary for the initiation and maintenance of the transition from the normal cell to cancer cell metabolic pattern. In most of our previous (and this) papers, we refer to this conversion as the cancer ‘metabotype.’ This publication did not surprise us, as our prediction that such a ‘revelation’ would happen soon, has its basis not just in new, but in firm, and very old, evidence. From 1956 to near present times, such a pronouncement would have been considered heretical, and so taboo as to be refused publication in any major scientific journal or to have received any research funding by any respectable granting agency. This sorry story goes back to the mid twentieth century. Although science itself may be impartial, scientists, being all too human, are not. Their organizations and institutions consist of hierarchies of power, influence and opinion no different from that of any other political system. Sometimes, even the ‘show me’, ‘replicate to prove’, and peer review crosscheck and verification safeguards of scientific inquiry can be swept away in the emotional heat of the moment. As such, was the fury and wholesale rejection surrounding the towering influence of the Nobel laureate, Otto Warburg and his aerobic glycolysis hypothesis. Fortunately, for science and the rest of us, blunders of this magnitude are rare.

     Science, for all its outward appearances of rational intelligence and progresses that have arisen from its aggregate achievements, can obscure the view from inside individual laboratories or in narrow areas of specialization, where it can be actually shown that science moves forward more so in fits and starts, lurches and bounds and often in haphazard random walks. Scientific disagreements usually take place without much beyond a few political ripples, as friendly (or otherwise) combatants ruffle each other’s feathers on a one to one, or small group basis. In short, things do not normally get out of hand.

     Such is not the case with the Warburg  hypothesis, or the refinements of its one and only significant shortcoming. For over a half of a century, the subject of aerobic glycolysis has been verboten; sealed with skull and crossbones. In 1956, Warburg’s two valid hypotheses went down the same drain used to flush down his third imperfect hypothesis. More significantly, even the study of general intermediary metabolism, itself, has moved into similar backwaters for the last 30 years. How and why did this happen? What has caused such a profound reversal in our thinking? How have we, (science and medicine) been hurt by this?  Can we, or do we resolve the inequities of the past and/or give credit where credit is due? What are the medical implications of our newly found logical reversal? Where do we go from here?

          Answers to some of these questions, in part or more fully, are available in the Science article referenced in the second sentence of this paper. We highly recommend that the reader look into this article, because it (ever so quietly) represents probably the biggest biomedical upheaval, reversal and revolution in more than a half century. This is no small potatoes. We are looking at a genuine historical paradigm shift of momentous dimensions, the historical importance, of which, aerobic glycolysis naysayers would wish to remain hidden in the attic, like a senile grandparent, because the ‘unquiet’ story version is simply just too embarrassing. We know this is true, because one of us was there; lived it. We take a little different tack than Science, when answering such questions and while remembering the fifty-four year aformentioned history. We are going to talk a little science, but the real heavy stuff we will leave to the reader to find in our short, but highly informative reference list. Regardless, it helps to have a basic background in metabolics, nutrition and bioenergetics or biochemistry 101. For the less technically initiated, scan over the science stuff, paying deeper attention to the human narrative woven throughout this document, as it is instructive in its own way.

 Ancient history: Warburg and Aerobic Respiration   

     About 70 years ago, Otto Warburg, a highly prestigious paragon of theoretical metabolics, hypothesized that aerobic glycolysis, lactic acid production and mitochondrial respiratory deficiency were a triple requirement for the conversion from a normal to a cancer cell. This cellular state completely changed the way a cell made the vital energy carrier molecule, ATP, which is required to power most cellular functions. In a normal cell, glucose is the primary fuel burned to make ATP. This occurs in two stages. The first stage, called glycolysis, burns without oxygen, produces two ATP and feeds its product, pyruvate, into the second stage, called the Kreb’s-OX/PHOS system, which burns with oxygen and produces 32 ATP. The second system also makes two ATP without oxygen. Thus, in total, four ATP (12%) result from burning without oxygen (substrate phosphorylation) and 32 ATP (88%) are made by burning to carbon dioxide, with oxygen (oxidative phosphorylation-OX/PHOS). Glycolysis occurs in the cell cytoplasm, while Kreb’s-OX/PHOS occurs in the cellular organelles called the mitochondria. When oxygen concentrations are limiting (hypoxia), mitochondria cannot burn all the pyruvate that glycolysis produces. So instead, the pyruvate, is converted to lactate and exported from the cell. Rather than dying an energy death due to lack of ATP, the cell elevates glucose importation and the rate of glycolysis increases dramatically (often exceeding 1000%) to make up for the ATP energy production shortfall. When oxygen levels rise, the normal cell system returns back to its efficient 12/88% ATP production ratio. This we call the Pasteur affect. This return to normal does not occur in cancer cells when adequate oxygen supply returns to normal, once again. Thus, Warburg used the term aerobic glycolysis, when ascribing this phenomenon to cancer cells. Warburg stated that cancer cells were different from normal cells in that they were ‘stuck’ in a state of 1) elevated glycolysis, 2) elevated lactate production and 3) mitochondrial oxygen consumption deficiency.  

          It was postulate number three that became the fly in the ointment. Scientists successfully attacked his mitochondrial respiratory defect concept because many cancer cell mitochondria had normal respiration. Warburg countered that low mitochondrial numbers, on a per cell basis, could yield the results seen, as it is the cell, which is the unit of life. This whole debate came to a head in 1956-1959, in a duel between Warburg  and Weinhouse, Chance and others. Warburg’s third hypothesis was upended, when it was demonstrated that more than just a few types of cancer cell mitochondria have normal respiratory chains and that a small number of cancers even show elevated respiration on a ‘per cell’ basis (Warburg, Science 123, 309-314, 1956. Weinhouse, 124, 267-269, 1956. Chance, 128, 700-708, 1959). When Warburg shifted his emphasis toward mitochondrial ATP production deficiency, Weinhouse countered by assuming that normal carbon dioxide production and oxygen consumption were a proof of adequate ATP production. Weinhouse was wrong on this one, but it was before the days of the chemiosmotic hypothesis of Mitchell, and the concept of respiration being uncoupled from ATP was unknown and not readily measurable with the technology of the times, so his knowledge error can be overlooked, but his assumption cannot, because it was no more proven than its antithesis. Even though Weinhouse was very wrong, he won the day. In fact, he won the next four decades, and even in 1999, metabolism was still not considered in Hanahan and Weinberg’s highly touted ‘six hallmarks of cancer’, even though by this time, convincing data to the contrary had been available for more than 25 years. By this time, not only was such thinking wrong, but it was ‘wrong on steroids, wrong’ as they say, these days, and as we shall show, later. Suffice it to say, that Warburg was dethroned, and like fallen rock stars, giants of science rarely arise again to any degree of former glory. Moving his target from oxygen to the cell to ATP undid him.

          From that time forward, cancer cell metabolism, and bioenergetic metabolism became the handmaidens of regulatory molecular biology. By the 1970’s, genomic instability, mutability, oncoviruses, signaling systems, immortalization, growth factors, growth factor suppressors, angiogenesis, metastatic cell recognition etc. became the research paradigm focus of cancer causation, while aerobic glycolysis was perceived as a mere effect of these ‘greater’ factors. By the time the 1980’s rolled around, genomics, followed by massive DNA sequencing and mining in the 1990’s, completely dominated the cancer research agenda, to the point that their was no one left who could even remember thinking of cancer in metabolic terms. Below, we tell a brief story about someone who did think about it, and deeply.

Intermediate History: A Single Case Study

     About 20 years after the 1956 Warburg debacle, a young and very politically naïve Kent State University graduate student thought that he saw something that caused him to revisit the Warburg hypothesis. In short, he agreed that respiratory deficiency, on a per cell basis, was not a feature of all cancer cells, but was common to many tumor types, but also, that something was ‘funky’ about cancer cell mitochondrial ATP production.

     A new semi-micro-technique had arrived in the early 1960’s that allowed us to measure the actual number of ATP produced per oxygen consumed in isolated mitochondria, which could measure to what degree ATP production was actually linked (coupled) to oxygen consumption. In general, and without getting into details, mitochondria produce three ATP per oxygen consumed when 100% coupled. Anything less is considered ‘uncoupled,’ and is expressed as a ratio of full coupling in terms of the ADP/O ratio; i.e. an ADP/O of two tells us that mitochondria are 67% coupled, or 33% uncoupled, as one might prefer it. Thus, uncoupled mitochondria are measurably ATP production deficient. Since our grad student only had a single mouse lymphoblastic lymphoma model in his own lab, he decided to review and compile, and conduct a broader experiment as an armchair exercise, by reviewing the literature, which was subject impoverished, but adequate. We call this gedanken, or mind science, often employed by pure theoreticians.

          What he did find was that per cancer cell mitochondrial ATP production, was severely diminished in all cancer types in which there were mitochondrial population, respiration and/or ADP/O data. He concluded that virtually all cancer cells might have lower than normal Kreb’s-OX/PHOS produced ATP as a result of 1) lower than normal numbers of mitochondria per cell, 2) deficient respiration per mitochondria, 3) decreased Kreb’s cycle/NADH production, 4) lowered coupling to OX/PHOS or 5) a combination of any two or more of the above. Whether the per cell mitochondrial ATP production shortfall was due to an intrinsic internal central system defect(s) in the actual mitochondrion itself or whether it was due to some external regulatory control element(s) defect(s) did not matter, as long as the net output ATP deficiency was the same end result. “By whatever means,” “must be present” and “on a per cell basis” was the central mantra of his dissertation: Mitochondrial Alterations in a Lymphoblastic Lymphoma Transplanted into DBA/1J Mice. He also showed how this necessary aerobic glycolytic change would switch the whole of the panoply of intermediary metabolism into state of relentless cell growth, as a cause of cancer, and not an effect. As we shall see, thirty years later, we finally know all of these propositions to be true.

          This kid was not only naïve he was a glutton for punishment. Among other things, he was an intermediary metabolism junkie. He memorized every chemical structure and reaction of the thousand plus biochemical components of the intermediary metabolic system and stared for endless hours, (for over three years) at the accumulated metabolic pathway charts that covered the entire expanse of his bedroom walls. In time, the charts began to morph from a gigantic hairball of nouns into the dynamic singularity of a verb. It became clear to him that mitochondrial Kreb’s-OX/PHOS ATP production deficiency, in the presence of glycolytic enhancement and pyruvate diversion to lactate, would shift the whole schematic toward anabolism in exactly the way necessary to enforce irreversible cell growth, and to satisfy ATP requirements.

          As a for instance, in the presence of dramatically enhanced glucose importation, elevated glycolytic fetal enzymes, pyruvate diversion and Kreb’s-OX/PHOS deficiency, a number of things must, and do, happen. Glucose becomes partitioned between glycolysis and the pentose phosphate shunt (PPP), an anabolic drive system, which can be assisted by a pyruvate log jam that piles up glycolytic intermediates, principal, of which, is glyceraldehyde-3phosphate (G3P). Glucose and G3P are feedstocks for PPP. The PPP canon taught is that the PPP principally provides NADPH for anabolic reduction, and ribose for nucleotide synthesis. A lesser emphasized hat trick of PPP is that it generates its own feed stocks, glucose phosphate and G3P, as its outputs, thus reinforcing its own pathway inputs to deplete glucose to carbon dioxide, via anaerobic hydrolysis. Also little regarded, but worthy of honorable mention, is that the phosphorylated PPP feed stocks, do not burn up all the ATP energy in their formation, but conserve some of it as high energy intermediates. This is also true of NADPH, which defuses highly mutagenic reactive oxygen species (ROS) from systems like uncoupled OX/PHOS.

          Our grad student also envisioned Kreb’s-OX/PHOS ATP production inefficient mitochondria as participating in the anabolic process via its amino acid transaminases and amino acid exchange shuttle systems, in concert with the urea cycle ornithine decarboxylase (ODC) off ramp to help provide a balanced nitrogen substrate mix for protein and nucleotide synthesis. The ODC pathway participated in tumor metabolism, as ODC blockers can inhibit cell growth and induce differentiation in some cancers. He did not view the mitochondrial glutamine pathway as a glycolytic substrate phosphorylation and ATP generation synergizer or partial glycolytic alternative in cancers that were not rampantly glycolytic. He saw it as included in the nitrogen balance amino acid system. Yes, it is also true that alternative glutamine pathway upregulation can make an aerobic glycolysis contribution in some tumors, but it does not seem to be a ‘metabotype’ necessity, as it appears to be, most often, an adjunct that assists aerobic glycolytic substrate phosphorylation in exacerbating the cancer metabolic phenotype, and is not significantly present in many cases. Regardless, its substrate phosphoryation ATP contribution is substantial and supports glycolytic up regulation in some cancers. Not surprisingly, he presented his case with condensed metabolic flow diagrams.

          Although there was virtually no research on the topic at that time, our grad student was heartened to find that Kim and Song, in 1976 and 1978, had seen incredible cancer cell kill rates with 5-thio-D-glucose (5TG), a glycolytic inhibitor. This indicated that their tumor model cancer cell mitochondria could not recover for the lost glycolytic cellular ATP production from such an insult, while normal cells were unaffected. In fact, in vitro, 99.9999% of their cancer cells died, in four hours, with 5TG and radiation while normal cells lived, and were actually radiation protected! This shows the potential of a direct aerobic glycolytic pathway attack synergy with conventional therapy. Imagine how far we could have run with a ‘concept’ ball like this by now, if we had only taken advantage of the 32 years ago head start, instead of having to ‘rediscover’ other glycolytic blocking agents in just the last few years.

          With his ‘unassailable’ armaments in hand, our intrepid graduate student went to cell biology and physiology meetings for several years, only being allowed lowly poster sessions because their were no symposia on the subject and no podium presentation space available for such topics. One would think that such a global hypothesis, with ancient debate resolving data and such stupendous differential cancer cell death rates, at least, would inspire debate. Among the young scientists, there was no debate because they had no idea what the H he was talking about, most of them, never even having heard of the Warburg effect. Among the old guard, there was no debate because they dismissed him out of hand, derided him or flat out abused him. It was worse than humiliating that there was not even enough consideration for rational discussion. The chronic “We don’t believe that crap anymore.” type of response, was more like a religious rejoinder than a scientific argument. His vague hopes of publication, at least as an ‘off the wall’ and ‘crazy’, but a somewhat creative and forward thinker, evaporated, when rejected, even by the ‘liberal’ Journal of Theoretical Biology. Having been (un?)duly castigated by the reigning Olympic gods of science, he assumed the appropriate ‘insignificant insect’ posture and opted to publish his dissertation under the aformentioned more humble title, as opposed to the more strident version appearing after the colon in the title of this present article. Oh! Incidentally, his lymphoblastic lymphoma mitochondria were completely uncoupled, in direct opposition to the full coupling of all normal tissues tested.

     So, here we sit, thirty much too many years later, ‘rediscovering’ a brand new discovery! killing cancer through taking advantage of its ‘sweet tooth’. Not only had they thrown out the baby with the bathwater, and then the tub and the plumbing fixtures; now, they have even ‘discovered’ this whole, new thing! called a bathroom. Meanwhile, all this happens while a special edition of Science decries the paucity of existing intermediary metabolic specialists because the field is now so unbelievably fallow. Go figure.

          So, what has become of our ‘insignificant insect’? He remains as unknown today as he was thirty years ago, in spite of the fact that his postulates outlined a simple and direct, but adequately detailed description of the central metabolic and energetic framework (sans glutamine, partial oops!) that we now know to be true. However, he finally has a sense of belated relief, now that a critical area of cancer research is receiving its due scrutiny. Scrutiny was no more than what he was asking for, in 1980, in the first place.

          Following 1980, molecular biology entered the age of genomics, with DNA fingerprinting, DNA sequencing, gene splicing and cloning, leading the pack. By 1990, this had taken on all the trappings of a genuine gold rush. The DNA molecule became the new belle of the ball of life science, while protein function, now called proteomics, became a wallflower. That is, by no means, a bad thing (except for the proteomics part). A new and bountiful harvest of knowledge, unlike anything ever seen in the life sciences, was being born. The DNA light of new understanding was burning so brightly as to ‘blind, shock and awe’. Although hidden in the data storm, eventual salvation for aerobic glycolysis was grinding slowly, but relentlessly, through the back door.

          However, this would still take time. For the next two decades of the 80’s and 90’s, cancer cell metabolism investigation, now reduced to a sub-handmaiden to genomics, and already reeling from its first two decades of insult, was now in line for 20 more years of the same. Even as late as 1999, Hanahan and Weinberg did not even mention metabolism in their famous six hallmarks of cancer, those being: 1) growth signal self activation, 2) growth suppressor  inhibition, 3) programmed cell suicide evasion (anti-apoptosis), 4) immortalization, 5) sustained vascularization (angiogenesis) and 6) metastatic tissue invasion. These may have sounded complete at the time, but it had been a long cold winter for cancer metabolism, and things were about to change.

      After the human genome project finished at the turn of the century, the scientific community woke up to an obvious next question. We have over 22,000 genes here, coding for proteins, the functions of the majority of which, we are clueless. What do the proteins that all these genes code for, actually do? After the turn of the millennium, this question would lead us back, full circle, to a real serious and sober rethink of a modified Warburg hypothesis. As unsympathetic as it may sound, it helps that the old school knee jerk anti-Warburgians are now  mostly gone, and aren’t around to manipulate, ‘bulldog’ and run roughshod over contrary thought. In addition, a dearth of metabotypic data has permitted a new crop of open-minded scientists to arrive with unencumbered metabolic preconceptions onto a fresh playing field. What a new playing field it is! There now exists a profusion of data around cancer cell intermediary metabolic regulatory control systems that would have had any graduate student from thirty years ago brimming in anticipation of understanding their significance. Some of this meaning is just coming into the light, like a fresh marriage between then and now, reminding us of the phrase; “Something old, something new, something borrowed, something blue.” 

Present History: The New Millennium

     During the last decade, since the turn of the millennium, the golden age of biology went from a promise to a reality. Not only has there been a zillion fold increase in the speed of molecular, genomic and proteomic data collection, but there has also been a similar concomitant decrease in the price per data point collected. For example, in the last ten years, DNA sequencing has decreased its time/price ratio from 5 years and billion per genome to 3days and ,000 per genome. This represents a 99.6% improvement in time and a 99.996% reduction in price that yields a 99.9999%+ overall improvement in efficiency. This comes with a promise of a 100 times more efficiency increase over the next couple of years. Similarly, computational speed, memory and topic specific software have kept abreast with the barrage of genoproteomic and metabogenoproteomic information, and most noticeably, on a gene conservation evolutionary scale. In the case in point, that being, our cancer metabolism discussion, a much deeper understanding of the huge and growing array of metabolic control elements has led us to a more mechanistic understanding that a modified Warburg hypothesis is correct, and may provide us with, paradoxically, a smaller, but more powerful suite of  differential cancer cell killing strategies and molecules. There is also evidence (from now and thirty years ago, as the reader may recall 5TG) that these central pathway target molecules could synergize with lower dose forms of existing chemotherapies that could confer fewer and milder side affects, and that they could dovetail with simple dietary and life-style changes.   

          In this brief review, we will be providing a kind of ‘Cliff Notes’ rendition of the regulatory control metabotype system, as we now understand it, because its interaction set is huge. Otherwise, this article would become a more burdensome tome than it already is. Instead, we will later provide about a handful of Wow! Gee-Whiz!  BIG SCIENCE review articles, so that you do not have to wade through a lot of the professional ‘muck’ to get to the real juice. Besides, their bibliographies provide all the ‘muck’ that you would ever need. However, we believe that it is very beautiful muck, so, have at it.

           Shortly after the year 2000, the nutrient and energy sensing regulatory metabolism control papers began to grow, and then expand profoundly around 2005. Almost immediately thereafter, some of the regulatory pathways came into focus, and soon, the dam burst wide open. By the latter part of the decade, we understood that an interwoven and layered regulatory hierarchy, was integrating the primary glycolytic and mitochondrial intermediary metabolic pathways in all dividing cells, be they embryonic, wound healing, adult replacement or cancer cells. The only caveat was that cancer cells were mutationally ‘stuck’ in this metabolic trench while normal cells were not. This was a genuine new discovery in that it demonstrated a new level of aerobic glycolysis creation, control and dynamics. This is a higher level of manipulation of the same core system described in 1980. This rendered the cancer ‘metabotype’ to be true. Thus, central aerobic glycolysis blockers, and blockers of their regulatory pathways should inhibit or kill cancer, which is also true. The new notion is; that if we could identify the specifics of the system more rationally, and with a more diversified weapon set, we could do some serious damage to this disease we call cancer. The system is so anciently conserved in evolution that system modifiers should be strewn (like resveratrol, anti-oxidants etc.) throughout the world’s ecological biota. Some new weapons are already emerging and the beneficial results tell us that there is a lot of work yet to do, but with a plan. The good news is that we finally know where we are going. If there was ever a time for the pharmaceutical companies to stand tall, this is that time. If there was ever a time to throw a buck at cancer research, this is that time. Using cancer’s own growth system against itself would be preferable to the historical strategy of beating it to death with primitive chemical and radiation clubs that also kill normal cells and render the patients ‘sicker than dogs.’ Thus, this article also registers a vote for the importance of the preservation of the world’s ecosystems.

      New core pathway blockers are already showing some promise. For instance, 3-bromopyruvate (3BP) blocks Hexokinase II, a mitochondrial ATP highjacker, that dramatically enhances the glycolytic and PPP systems. This resulted in total eradication of 100% of metastatic tumors in rats, in a hepatocarcinoma model system. Similarly, dichloroacetic acid (DCA) inhibits pyruvate kinase-2 (PKM2), a fetal pyruvate to mitochondria blocker found in a broad range of tumors. Purportedly, both 3BP and DCA kill cancers that cannot up regulate mitochondrial OX/PHOS due to critical central or regulatory pathway mutation, while shrinking or halting growth in benign and metastatic cancers that can still maintain enough OX/PHOS for quiescent survival. Although both are preferable to the full blown disease, cancer kill is preferable to growth stoppage, because it eradicates the tumor, while growth arrest is more akin to resetting the clock on a time bomb, as an already mutated system simply awaits not much further mutation, which may or may not happen. But, hey folks! At this point, we will take any port in a storm. DCA is yielding results in a broad array of animal cancers, and clinical trials are underway in human brain glioblastomas. Preliminary results are not short of thrilling. We already discussed 5TG, as something old. Other aerobic glycolysis and mitochondrial blockers are in the works, as something new.

     In addition to the core, or central metabolic pathways of aerobic glycolysis, an interwoven and layered set of regulatory pathways control the central pathways. Genetic errors in the regulatory pathways can force the central pathways to get ‘stuck’ in the cancer metabotype. Blockers, rectifiers and mutations in these pathways institute the same or similar effects as seen by blockers, rectifiers and mutations in the central pathways. For example, when driven by mutated nutrient sensing growth signals or repressed by activated mutant energy sensing growth suppressor signals, aerobic glycolysis is instituted, and multiple benign tumors result, in animal models. Eventually, these new highly ROS enhanced, and therefore, mutagenic tumors, go metastatic. Throwing a monkey wrench into this aerobic glycolysis activated system can kill the cancer, but spares normal cells, because they are adaptable.

     If there is anything approaching a metabolic main control element in the nutrient fuel and energy sensing metabolic regulatory system, it is target of rapamycin (TOR). An actvated TOR switches the system toward nutrient importation, OX/PHOS inefficient anabolism and cell growth, while an inhibited TOR switches the system toward internal metabolite recycling, OX/PHOS efficient catabolism and cell quiescence. Like a spider in the center of a web, with all legs tuned to a host of quivering silk strands, TOR performs a balancing act between the parts of a huge array of individual inputs from an integrated ‘cross-talking’ set of metabolic status sensors. Then, it activates and represses, in turn, gene activators and repressors of several thousand genes that change metabolism, which in turn, changes the inputs from its metabolic status sensors. This regulatory feedback system allows the cell to settle into several principle types of homeostatic drive states such as cell growth and division, quiescence, response to starvation, ROS load and cell component stress damage. The elucidation of the regulatory TOR affected and effected systems are what finally cemented the modified Warburg concepts into stone.

     Briefly, the cell growth factor nutrient sensing IGF/P13K/AkT/TOR pathway upregulates HIF to stimulate anaerobic glycolysis and PGC-1alpha to institute mitochondrial neogenesis, which makes new, but OX/PHOS inefficient mitochondria. This activated TOR pathway inhibits the 4B-EP mitochondria regenesis pathway, which when stimulated, up regulates respiratory gene activation, in turn, rendering mitochondria OX/PHOS efficient. These are pro-cancer and anti-cancer systems, respectively, as well as being pro and anti-metabotype. We use the terms neogenesis and regenesis to distinguish between the two separate phases of mitochondrial biogenesis. When operating normally, the cell growth system institutes a temporary and reversible pseudo-aerobic glycolysis, and when mutated, this process gets irreversibly ‘stuck,’ and institutes the cancer metabotype. In addition to up regulation of glycolysis, HIF activates vascular endothelial growth factor (VEGF), which institutes angiogenesis. Thus, we now know that three of Hanahan and Weinberg’s six hallmarks of cancer form a singular direct TOR systems link to aerobic glycolysis. The fact that the immortalizing ribonucleoprotein, telomerase, relocates from the mitochondria to the nucleus under this metabolic condition, as it does in rapidly dividing embryonic cells, implicates a fourth hallmark. The fact that the activated TOR system also turns off autophagy and down regulates the apoptotic cell suicide program, in addition to the notion that growth rate progression and metastatic invasion typically correlate with a progressively more ruthless aerobic glycolysis drive state, as adjuncts to the last two hallmarks, cannot be overlooked. In spite of the thousands of mutated oncophenotypes that plague our present cancer cell miasma, the modified Warburg effect remains the most central, consistent, and universal ‘hallmark’ of pre-cancerous hyperplasia, cancer cell initiation, cancer cell maintenance and cancer cell progression that we know of. Maybe, we need fewer hallmarks and less assumption. Now, Weinhouse and Weinberg are both wrong. The ‘Wein’ philosophy followers should, by now, be retreating from their dogma.

     Even with a virtual absence of knowledge of the external regulatory interactions between Kreb’s-OX/PHOS and glycolysis, in 1980, the system, at that time, was conceivable from its central elements alone. This was possible for our grad student, because it is the central system that is changed, regardless of whether it is driven by core internal defects or external regulatory pathway defects. The bifurcation of mitochondrial biogenesis into growth driven Kreb’s-OX/PHOS inefficient neogenesis and Kreb’s-OX/PHOS efficient regenesis is real illuminating, particularly in helping to understand more esoteric regulatory features than those provided in the 1980 hypothesis.   

     For those who wish to delve ‘knee deep’ into this system, a general overview, with simple life style practical applications, is available in our article: Cardiovascular Disease, Cancer cell Metabolism, Diabetes II, Muscular Wasting and Life Extension are all Linked as a Single Controllable Molecular Pathway, by Bambeck and Wolfson, which can be search engined on the internet. For those who wish to plunge ‘eyeball deep’ into these systems, they can look up the following articles: (Z. Feng, Cold Springs Harbor Laboratory Press, 2010 p.199; I. Topisirovic and N. Sonenberg, Science, 327, 3/5/10 p.321; L. Fontana et.al., Science, 328, 4/16/10, p.1223; T. Seyfried and L.Sheldon, Nutrition and Metabolism, 7,7, 1/27/10; and for multiple papers and articles, Science, Special Section, 3/12/10, p.1337). Search engine word sets like AMPK-TOR-cancer; mitochondrial regenesis or neogenesis; Bambeck-cancer and/or life extension; caloric restriction pathway; aerobic glycolysis-Warburg and other obvious search engine words in this article will get you to anywhere you want to go.

     The main reason that there is such a recent explosion of work on the nutrient sensing IGF/P13K/AkT/TORc1/HIF and its converse energy and stress sensing p53/AMPK/TORc2/ROS/FOXO/SESN loop pathways has to do with the fact that they cast such a broad net. First, they are highly conserved in the evolutionary tree, from yeast to humans. Second, they integrate across a wide array of disease vs. health, conditions. The cancer metabotype is just the tip of this iceberg, albeit being one damn big tip; big enough for it to be a mega-topic all its own. The relative ease and simplicity of controlled manipulation of the core and regulatory elements of this system promise to deliver a powerful anti-cancer armamentarium, in addition to providing  weapons and life style tools for fighting heart disease, muscular wasting, obesity and diabetes II. Including cancer, these diseases/conditions are often referred to as ‘the diseases of aging,’ and account for a whopping 85% of all death in the developing and developed world. Probably the most surprising discovery of all is that up regulation of the AMPK/TOR/SESN loop initiates genuine life extension beyond the normal maximum via caloric restriction (CR). Even more astounding is that CR mimetics such as metformin (an AMPK activator and anti-diabetes II drug), rapamycin (a TOR inhibitor and anti-tissue rejection factor) and perhaps, ‘high bioavailability’ resveratrol (a common dietary supplement, AMPK activator and anti-oxidant), fight all of these major diseases. They reduce diabetes severity via increased insulin sensitivity, inhibit cancer cell metabotype formation as previously described, promote weight loss via lipid catabolism up regulation, decrease muscular wasting and cardiac insufficiency via mitochondrial regenesis and extend life beyond its normal maximum length via increased cell cleaning autophagy, ROS reduction and all of the above items described. We talk in more detail about the life extension pathway in our aforementioned publication.

     These diseases already strain our national budget to the breaking point, and threaten to undermine and overwhelm our economy in the next decade or two. With our present economy spending almost a fifth of its GDP on medicine, we have never been in more need of the proverbial white knight in shining armor. Well folks, this just might be that white knight, albeit a rather historically beaten, bruised, tarnished, but finally renewed and reinvigorated white knight. If we are lucky and if we are right, all we need to do is roll up our sleeves, get to work, and send cancer back to the same hellhole where it came from. Maybe we can take the other common diseases of aging along with it, while we are at it.


     The saddest, and sickest, part of this whole, pathetic dirge is that we had a correct outline of a coherent cancer metabolism theory; and a few central pathway assault systems, over thirty years ago. These are just being ‘rediscovered’ today.  Only the future will tell us how much unnecessary time and life have been lost.Let us just hope that we will never suffer from the likes of such a ‘theory-bigotry’ ever again.


Copyright: January 23, 2011 by


Gregory S. Bambeck Ph.D.                     

E mail: gregorybambeck at yahoo dot com

Michael Wolfson J.D., M.B.A.

E mail: mwolfson at stanfordalumni dot com 


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In the early to mid twentieth century Otto Warburg hypothesized that cancer cells could be characterized by dramatically elevated glycolysis and mitochondrial respiratory deficiency locked in a relationship he called ‘aerobic glycolysis’. The respiratory deficiency claim was proven false and cancer cell biochemistry shifted its studies toward oncogenes, cell growth factors and their cascades, cancer cell growth suppressor systems, apoptosis, telomeric immortalization, cell recognition and adhesion mechanisms etc. Any global hypothesis devoted to mitochondrial inefficiency or dysfunction related to the anabolic and catabolic control requirements to cancer cell function, such as those proposed by G. Bambeck were refused funding or publication, and in fact, were quietly chaperoned out of the halls of science. Now, some 30 and some 50 years later, the pariahs may have been proven to be visionaries. Glycolytic blocking and retrafficking agents, such as dichloroacetate etc. can either kill or ‘renormalize cancer cells. Caloric restriction, the only known mechanism for extending life well beyond its normal span, in everything from roundworms to primates, is now known to rejuvenate aging cells and down regulate cancer cell initiation and growth by turning on a suite of 745, or more,   genes that renormalize glycolysis and initiate phagocytosis of inefficient mitochondria concomitant with biogenesis of efficient, new mitochondria. Resveratrol turns on the exact same suite(s) of genes, and by every measure, has the same cytological impact. The ‘metabotype’ continuum from juvenile cell, to aging cell, to cancer cell, make even more sense in an evolutionary context. 


This is a general review article which is presented as a narrative. It is not intended for peer review, in part, for reasons contained in the abstract and the body of the text. That does not mean that this work is unimportant. In fact, it might be very important, because it connects together lines of research that converge on medical implications of great magnitude. It is written by a PhD scientist with over thirty fruitful years of scientific research under his belt, who hopes that he may have the time, later, to write a more formal article. This information should be gotten out there informally and quickly, rather than not to be gotten out at all.

There is no bibliography or references in this work, but at the end of this text, a short list of search engine words and suggested readings are provided, so that more than enough bibliography is provided to see ‘the big picture’ presented by the hypothesis contained, herein. This article is restricted to the basic catabolic and anabolic changes in intermediary metabolism and how they relate to juvenile, adult and cancer cells, because this area of cancer research has been left fallow. Other very important areas of research, such as the aforementioned cell growth factors etc., have tens of thousands of articles that may be referred to.

This article is devoted to an area of research that has been relegated to a backwater, in particular, in regards to cancer cell intermediary metabolics. If it had not been for anti-aging and life extension research results, stumbling through the metabolic ‘back door’, so to speak, some thirty years after a modified Warburg hypothesis, coupled with some new cancer metabolism blockers, the important connections could not have been made. Throughout history, serendipities and/or convergences have come together to form holistic emergent systems with more than just notable impact. Hopefully, this one of those times.

Lastly, this article is written a la Scientific American in that it is, hopefully designed to be understood by the educated lay person, while not short changing the serious scientist, too much. Professional jargon will be held to a minimum. It is my hope that a more in depth review won’t be necessary, if enough interest ensues. It would certainly be far more gratifying if interested parties would take up the discussion, or even initiate lines of investigation that might knit the outlines of these semi-integrated patches into a more complete fabric of either enhanced, or wholly new understanding. So, here we go, more or less ‘off the cuff’. 

Earlier Times                                                                                                                         

Approximately 96% of a cell’s organic biomass consists of carbohydrates, fats, nucleotides and proteins. All four of these components can be either burned as fuel to power the cell, or as construction materials to replace defective parts in a quiescent cell or to build a new cell, as in the case of a dividing cell. In a normal, healthy quiescent cell, there is a balance between energy production and repair rates, so that the cell is said to be in homeostasis, or balance. In a normal, healthy dividing cell, growth factors set up a cascade of directives that order the cell to both increase its energy output and to import raw materials and build those raw materials into the components of a new cell. In short, nucleotides become RNA and DNA, amino acids become proteins, sugars become complex carbohydrates and fatty acids become lipids in a process called anabolism, while these same four starting materials can, alternatively, be burned as fuel to create energy, in a process called catabolism. The anabolic intermediate products can further assemble, by anabolism, into molecular assemblies, such as ribosomes, enzyme complexes etc., and, even further, into organelles such as mitochondria, lysosomes, a cell nucleus etc. Eventually, a whole new cell is formed. Cancer cells do this to, but as we shall see later, they don’t do it the same metabolic way as normally dividing cells. Instead, they do it more like in an extended metabolic version of aged cells.                                                                                                                                                                                                                     

Although, what has been presented so far, is a gross oversimplification, suffice it to say, that by the middle of the twentieth century, a pretty sophisticated outline of many hundreds of the molecular trafficking pathways of the catabolic and anabolic interplay of organic molecular transitions, were mapped out. Wall posters in classrooms demonstrated these processes in a fashion analogous to watching automotive freeway traffic flow from an aerial view over a large city. Many discoveries have been made by observing disruptions in the flow, just as auto accidents cause clogs on off-ramps, on-ramps and thru-ways on the freeway system.                                                                                                                                                                                            

Otto Warburg, in charge of a large research organization, and a highly respected molecular researcher of his day, being the early to mid twentieth century, thought he saw an intermediary metabolic perturbation both unique  and specific to all cancer cells. More precisely, he hypothesized that this perturbation was critically confined to the catabolic, or fuel burning side of metabolism, but also set in motion an anabolic shift as a consequence. Even more specifically, he targeted the anomaly to the burning of a single fuel, glucose, to the relative exclusion of other fuels.                                                                                                                                                                                             

Glucose is the primary, but, by no means, only fuel that is burned by cells of the body, and it is burned in two complex systems, called glycolysis and the Krebs cycle. Glycolysis obtains energy from glucose and other sugars by an anaerobic (non-oxygen utilizing) mechanism to produce ATP, an energy carrying molecule. The Krebs cycle, contained in an organelle called the mitochondrion, burns the glycolytic end product, pyruvate, utilizing an aerobic (oxygen consuming) mechanism to produce ATP. The burning with oxygen process sequentially strips hydrogens from the glycolytic end product, converting NAD to NADH2 and then couples the NAD hydrogens to oxygen to form water, while releasing the sugar carbons to form carbon dioxide. The formation of water is a stepwise process in which the energy of the hydrogens and their electrons are rejoined in a stepwise process called electron transport, while the energy of the process is captured by converting ADP to ATP, while H and O form water, in a process called oxidative phosphorylation. Anabolism is the opposite process in that NAD hydrogens and ATP energy are utilized to build cell components. Thus the two swing molecules in the process are ATP and NAD as they switch back and forth between their low and high energy forms and their oxidation and reduction forms, respectively.                                                                                                                                       

In a healthy homeostatic cell, many fuels are used, and about 5% of the ATP is produced by glycolysis, while about 95% of the ATP is produced by the mitochondria. Anabolism and catabolism are in a steady state balance with mitochondria producing this ATP energy at about 99% efficiency. In a healthy dividing cell, the entire energy production system is upregulated to make ATP energy and NADH reducing power for the anabolic requirements to make a new cell. Otto Warburg notice an uniqueness in the catabolism of cancer cells, in that glycolysis was considerably elevated, that respiration was depressed and that mitochondria in cancer cells appeared small, malformed or disorganized. Furthermore, he proposed that, unlike fetal or other normally dividing cells, the cancer cell was irreversibly ‘stuck’ in this metabolic phenotype. Although the glycolytic part of his hypothesis was never refuted, the respiratory defect notion was struck down in a furious debate in 1955-1956. Mitochondrial respiratory deficiency, although found in many tumor types, was not found in all tumor types, and was not considered required as a fundamental requisite of the cancer cell condition.                                                                                                                                                                               

As mentioned before, Warburg was a big name during his time. He made and broke many scientific careers, and was known for having a bit of an irascible nature. Well, the bigger they are, the harder they fall. Many of Warburg’s detractors became journal editors, reviewers and laboratory directors. Woe be it to anyone positing any form of mitochondrial defect/cancer hypothesis, even twenty five years later.                                                                                                                                                                               

After the Warburg hypothesis rejection, cancer research shifted away from metabolic studies toward oncoviruses, oncogenes, cell growth factors and their cascades, cell growth suppressor systems, apoptosis mechanisms, telomeric immortalization, cell recognition  and adhesion systems etc. These studies have had a huge impact upon our understanding of the normal, to cancer cell, transformation process. It has become obvious that evolution has provided numerous impediments to lethal carcinogenesis in its attempts to keep cell division under control. There is also no doubt that these new areas of research would have opened up regardless of the outcome of the Warburg hypothesis. However, it is also true that investigations of mitochondrial interactions in the intermediary metabolic interplay in the cancer cell, would not have all but dried up, as it most certainly did.                                                                                                                                                                                            

In 1975, some twenty years after the Warburg hoopla, a very politically naïve graduate student, named G. Bambeck became fascinated with mitochondria, in a Kent State University laboratory, that happened to have a mouse lymphoblastic lymphoma model. He isolated mitochondria from many mouse tissues and noted that the lymphoma mitochondria had uniquely low ADP:O ratios. This means that these mitochondria were producing abnormally low amounts of ATP energy per oxygen consumed. This could mean that either ATP was being uncoupled from oxygen consumption via the respiratory chain, that reduced NAD was either being decoupled from oxygen or being exported from mitochondria in abnormally high rates, via some kind of chemiosmotic shuttle, for anabolic purposes, or in some combination, thereof, by some unknown mechanism(s).                                                                                                                                                                                                                   

Thus, he began a literature search and, among other things, he ran into the Warburg debacle. But, being socially unsophisticated, he pressed on, and he pressed on because he found something very interesting, so interesting, in fact, that he virtually abandoned his wet lab (hands on) research for a mental form of research. In mental research, one reviews the work of other researchers in the hopes of ‘an unique synthesis of thought’, or, in other words an overlooked ‘big picture’, that, in this case, might also be suitable for a  PhD dissertation.                                                                                                                                                                                                                                                                 

First, G. Bambeck found that there were a lot of cancer cell mitochondria vs. normal cell mitochondria papers out there, a number of them showing that Warburg’s respiratory defect was not there, in more than just a few cases. What he did find, in every cases where the data was taken, that net mitochondrial ATP production on a per mitochondrion and/or, more importantly, per cell basis, was significantly lowered compared to normal dividing cells. He further noted that mitochondrial net ATP synthesis shortfall could be due to low mitochondrial numbers per cell, inefficient electron  transport, increased NAD/NADH  shuttle export  of reducing power, inefficient coupling of ATP formation to hydrogen chemiosmotic potential, a shift in the ATP synthetase to ATPase equilibrium dynamics or some fundamental metabolic Km shift in the chemical pathway linking glycolytic end products to the Krebs cycle. Anything that would block the connection between the NAD/NADH redox coupling to ATP formation, could tip the balance of carbon flow to anabolism. Most importantly, these mitochondrial shortfalls of ATP production could change the glycolytically produced to mitochondrially produced ATP production ratio by over 1000%. He proposed that this ratio differential forced fuel dependency upon glucose while simultaneously forcing other metabolites, reducing power and ATP energy flux toward anabolism. In the light of modern discoveries, to be discussed later, one could say that such a system pre-adapts the cell, metabolically, for a more uncontrolled growth format when not necessarily signaled by a growth factor: a precancerous state or hyperplasic non-dividing growth condition, as one might have it. If carcinogenesis is a multi-step process, why not have a metabolic process, or a progression toward a metabolic state that predicates the terminal process when suitable mutations and their associated stimuli arrive?                                                                                                                                                                                                                                                              

G. Bambeck optimistically presented his conclusions to the scientific community with the expected dismissive results. Even though his dissertation was of a somewhat heretical nature, he received his PhD because the logic was essentially sound. But with nowhere to publish and nowhere to work on his findings, he evaporated from obscurity to nothingness in the annals of cancer research. Instead, he plied his trade in medical diagnostics and research tool technologies. The tools of 1975-1980 were not available to address a rationale for the collapse of mitochondrial efficiency in cells. For one, there seemed to be too many ways for it to happen. Gene switches and gene switching systems were just in their early days of initial elucidation. There were simply too many unknowns and alternatives. G. Bambeck took a stab at the problem, and notioned that reactive oxygen species (ROS), called free radicals at the time, might be peppering the mitochondrial  and nuclear genome, causing a sequential randomizing of the mitochondrion and manifesting itself as a progressive decline in fuel burning efficiency. Paraphrasing, he said that, ‘by whatever means, the per cell mitochondrial ATP production deficiency is there’. We now know this to be true, and not just in cancer cells, but in aging cells as well. Its most severe manifestation appears to occur in the cancer cell. The anaerobic to aerobic ratio of ATP production appears to increasingly exacerbate as cells age and become transformed. Cell heat production and adaptation to hypoxic conditions are hallmarks of glycolytically adapted cells with poorly coupled ATP formation, as is witnessed by the limited success with hyperthermic, hypobaric and lactic acid export blocking cancer therapies. G. Bambeck hypothesized that more specific blocking agents to glycolytic and mitochondrial systems, might have greater efficacy, either for instituting differential kill or cancer cell renormalization. The now known facts that glycolytic blocking agents can kill or that fetal pyruvate kinase blocking agents can renormalize cancer cells to a non-anabolic and non growing state, and that conditions and agents that create efficient aerobic catabolism via mitochondrial biogenesis, reduce cancer incidence and increase cell rejuvenation, show a more mechanistic support for the concept. However, much of these data come from research areas originally perceived as only tangentially related, or not at all related, to cancer.                                                                                                                                                                

Toward Present Times 

From the 1980’s to the present, there has been a lot of work with ROS and their mutagenic and aging effects on cells. Basically, ROS are highly reactive oxygen species containing an unshared electron which allows the ROS to react with just about any available organic molecule, including DNA, RNA, proteins etc. Naturally, ROS are mutagenic and, therefore, carcinogenic, akin to ionizing radiation, causing the highly specific and organized genome and its protein products to become more randomized, or nonsensical. Because they are immersed in an oxygen atmosphere, either directly or by blood delivery, body cells produce ROS and utilize free radical scavenger molecules to mop up these nemeses. Anti-oxidants, such as vitamin C, vitamin E, bioflavinoids etc. are such free radical scavengers, and experiments with elevated doses of anti-oxidants and their effects upon cancer induction and aging rates are rife. In general, the results are positive, helping organisms to more closely achieve their well nourished natural life expectancy potential, but not beyond that potential.                                                                                                                                                                                                  

The mitochondrion produces more ROS than any other part of the cell because it is the seat of oxidative fuel burning, where the electron cascade of the respiratory chain is used couple the energy of the Krebs cycle intermediate hydrogen electrons to ATP formation, then, ultimately to oxygen, to yield water. To protect itself from its own internally produced ROS, the mitochondrion utilizes endemic anti-oxidants and a special enzyme called SOD to mop up ROS.                                                                                                                                                                                                                                       

Each mitochondrion has several copies of its own DNA, and when ordered to do so, mitochondria can multiply, similar to cells. But unlike cells, mitochondria can do something amazing. Via a mostly unresolved process, mitochondrial biogenesis (to be distinguished from simple division), results in new efficient mitochondria arising from old inefficient mitochondria. Cell nuclear genomes pass on the mistakes that their DNA repair systems fail to detect or faultily repair, as do mitochondria, when simply dividing, but not when undergoing biogenesis. Perhaps it is because a single cell has only one nuclear genome (or at most, two half genomes), but as many as over a thousand mitochondrial genomes that might be coupled to some selection process, maybe based upon some kind of selection for fidelity of consensus sequence. It seems obvious that there must be some kind selective renewal system, because mitochondria pass from generation to generation via oogenesis, on average, without a single point mutation. Without such a process, it would not take many generations for eggs to contain a gibberish of mitochondrial sequences, rendering the following of the matrilineal line to a virtual impossibility. The fact that we can follow the matrilineal line through thousands of generations, supports this notion. I envision something like a polytene chromosomal sequence comparator mechanism of some kind, or perhaps, a highly protected and sequestered mitochondrial ‘mother genome’ somewhere in the cell.                                                                                                                                                                                                                                

Evidence for real biogenesis mounts. In adult body cells, mitochondria progressively degenerate into inefficient couplers of hydrogen, electrons and oxygen to ATP and water production. And not just one thing, but a host of things go wrong with mitochondria as adult cells age, with one of the hottest causal suspects being ROS mediated mutagenesis. Concomitant with reduced mitochondrial efficiency over time, is an increase in glycolytic ATP production. Thus, as cells age, the anaerobic to aerobic ATP production ratio rises, and begins to appear more like the pattern seen in cancer cells. Since most adult cells are terminally differentiated, and can no longer divide, such a ratio shift does not pose a cancer risk, as would adult stem cells, which still have functional telomeres, and could possibly become telomerase immortalized. Telomere shortening to terminal differentiation is a well established mechanism, putatively, for avoiding cancerous progression in adult cells.                                                                                                                                                                                                                                                    

However, non-terminally differentiated adult cells and adult stem cells can divide, and they generally divide to replace dead or missing adult tissue, under the directive of growth factors. Under such conditions, tissues are replaced but they are not rejuvenated. Instead of young dividing new cells replacing old dead cells, old dividing cells are replacing them, in part because mitochondrial biogenesis is not occurring. Cells are being replaced, but the tissue is not being rejuvenated. It appears that as we age, the metabolic phenotype (metabotype) of the aging cell operates more and more like a cancer cell metabotype. Somehow, it seems that that there is no great evolutionary pressure to put additional roadblocks to such a metabotype progression, especially with the, aforementioned, long list of non-metabolic quality assurance mechanisms already in the toolkit. In fact, such a progressive metabolic transition probably assists the evolutionary process. From an evolutionary perspective, it is preferred at a certain point to dispose of the old bodies, which represent yesterday’s genetic experiment, with the next generational gene mix experiment. After all, it is the genome that has a shot at perpetuity, and not the vehicles it employs to get there. In summary, it appears that adult tissues are aged metabotypes of juvenile tissues and adult stem cells are aged metabotypes of fetal stem cells, and that their metabotypes progress toward the cancer cell metabotype, irrespective of other components of the cancer cell transformational process. There appears to be a blended metabolic continuity between these basic temporal cell types, and recent science on cancer and aging are yielding insights that show metabolic crossover applications between these once disparate fields of research. It appears that we are beginning to achieve a degree of control over both aging and cancer, at least from a metabotype perspective.                                                                                                                                                                                 

To a rather remarkable degree, the aging cell and cancer cell metabotype have recently been reverted to normal with dramatic increases in life extension and incidence reduction in cancer, from groups of apparently unrelated experiments that only share their fortunate results by viewing them from a shared metabolic perspective. By life extension, it is meant to mean ‘age beyond its normal well nourished maximum’ This not to be confused with achieving the natural maximum by delaying premature death, but instead, by going beyond its natural healthy maximum by a considerable extent. Also, it is far too early to talk of cancer ‘cure’, but the early data point to a significant cancer renormalization or kill. But first, there is a need for a bit of a preamble.                                                                                                                                                                                                                                                              

Until recently, the only technique known to cause genuine life extension is to initiate a condition known as caloric restriction. Caloric restriction and its life extension affects hails back seven decades, but its many manifold mechanisms of action are just now coming to light, due to new technologies grown out of the genomics revolution. Studies had shown that caloric restriction rejuvenated cells, by virtually every measure, and in virtually every tissue and organ of the body, from neuroregeneration, to delayed and reversed muscular wasting, visual impairment, skin wrinkling  etc. These rejuvenation-like phenomena occurred in organisms, as lowly as yeast, upward through the multicellular organism evolutionary chain ranging from roundworms to mice. Just this past year, a 25 year caloric restriction study on rhesus monkeys extended these findings to the primate order, of which humans are a member. Preliminary results on humans are yielding parallel results. By hindsight, such findings make evolutionary sense, because feast and famine cycles go back to the dawn of time. There is a distinct survival advantage in being able to sweat out the lean times until nutrient availability of fat times allows energy availability to support cell division in single cell organisms or procreation in multicellular organisms. Hibernation or estivation may work for periodic circumstances such as winter snow or summer drought, as it does for northern bears or desert toads, but variable and unforeseen conditions have led to a much more ancient and flexible metabolic solution, as observed by caloric restriction. It seems apparent that untold millions of generations have been honed by caloric restriction to utilize it as a generic life extender as a means of avoiding extinction.                                                                                                                                                                                                                                       

In just the last couple years, the genetic mechanisms behind the caloric restriction phenomenon have become much more elucidated. First, caloric restriction turns on a gene called SIRT1 that activates a suite of, at least, 745 genes that is normally turned on in juveniles, but is turned off in adults. At the very least, SIRT1 is turning on a hugely complex gene system in adult cells that is normally only operational in juveniles, tempting the notion of ‘rejuvenation’, especially since life extension is the result of their activation. It appears obvious that this must be an ancient system for it to be composed of such a high number of orchestrated components, and in such a pan specific manifestation, with a particular bent toward extending organism life length by mimicking, or attempting to mimic the juvenile period and imposing it on adult cells. The impact seems to be most pronounced on metabolic efficiency.                                                                                                                                                     

For one thing, the entire metabotype of the aging cell shifts over to a juvenile metabotype when SIRT1 turns on. Surprisingly, homeostatic non-dividing adult cells undergo mitochondrial biogenesis, in which, old inefficient mitochondria become replaced by new efficient mitochondria. This is not just inefficient mitochondria dividing to produce more inefficient mitochondria, as is the case in aging adult replicating cells and cancer cells, but an actual biogenesis of young behaving mitochondria yielding cells of a juvenile metabotype. This probably, helps account for the reduction in insulin resistance, by dramatically reducing the cell’s glucose dependency, and for a host of rejuvenating effects caused by rebalancing catabolic energy production, and, probably ROS reduction, or ROS scavenging. There is support for the notion that mitochondrial biogenesis alone can have very substantial impact upon cell rejuvenation, as direct elicitors of mitochondrial biogenesis (PGC1 alpha) in mice, reduces muscular wasting and visual impairment. We can expect to see an explosion of research in this area, now that mitochondria are known to be so vital to cellular health, far more so, than was thought, in the traditional sense.                                                                                                                                                                                                 

However, the amount of caloric restriction needed to institute these alterations, is draconian; tantamount to humans trying to live for 110 years in hell-like semi-starvation vs. living in relative comfort for only 80 years. But, stay tuned. There are indications that caloric restriction gene systems might be, in good part, chemically inducible.                                                                                                                                                                                                                 

There is a new kid on the block, called resveratrol. Over the last decade, or so, resveratrol has become hailed as an anti-aging super anti-oxidant. Originally touted as a component of the lycopene/tomato, omega 3/olive oil and resveratrol/ red wine Mediteranian diet, resveratrol has emerged as a heavy weight contender in its own right, and for some good reason. Shotgun gene affinity experiments, which measure up and down regulation of over 20,000 genes at a time by measuring mRNA gene transcript annealing to DNA sequence leaders, demonstrate that more than` 745 genes are regulated by resveratrol in the same fashion as done by caloric restriction, in mouse tissues. In fact, the number and direction of regulation shows a remarkable 99.7% concordance with caloric restriction, the remaining 0.3%, which somehow bypasses SIRT1. Similar results were obtained with other tissues. The effect even occurs in fat mice, even though the jury is still out on its impact on longevity in these animals. Importantly, resveratrol initiates mitochondrial biogenesis and a laundry list of cytological and tissue regenerative affects similar, if not identical to caloric restriction. The probability of such a high gene activation concordance is so minute as to border on the incalculable. The fact that it does so via some kind of bypassing of the putative cascade initiation control genes SIRT1 and Insulin-like Growth Factor (IGF), is initiating some rather heated discussion between pharmaceutical companies with vested interests on both sides of the resveratrol gene control issue, and whether it is a true caloric restriction mimetic. Based upon the impacts seen from mitochondrial biogenesis, I would guess that a very sizeable percentage of the genes induced by SIRT1 or resveratrol, are devoted to mitochondrial biogenesis and its consequences on aging and cancer cell metabotype.                                                                                                                                                                                                 

There can no longer be a doubt that many, if not most cancer cells have some entrenched metabotype that is fundamentally more fixated than in normal cells. Briefly put, in-vitro studies of glucose mimicking glycolytic blocking agents such as 2-deoxy glucose and 5-thio D glucose, can kill up to 99.999% of cancer cells in a few hours while leaving normal dividing cells alive, with the cancer cells being radiation sensitive and the normal cells being radiation insensitive. These agents slam glycolytic ATP production to a halt leaving only pyruvate starved mitochondrial ATP production to remain. Being glycolysis end product dependant, much more so than most normal cells, cancer cells die, while normal cells can utilize, or switch off to alternate fuels, more readily. Unfortunately, these results don’t translate to in-vivo use because the therapeutic dose is to close to the contraindicating dose, probably because they are glucose analogues. Brain cells are highly dependant upon glucose, for instance.                                                                                                                                                                                                                                                    

 In cancer cells, glycolysis often produces many times more pyruvate than the inefficient mitochondria can assimilate, so the excess pyruvate is converted to lactate for cell export to the liver, where it is converted to glucose for re-export to the tumor, in a closed loop system called the cori cycle. Other cells, such as hypoxic cells and low oxidative fast twitch muscle cells, can reversibly utilize the cori cycle, while cancer cells are much more entrenched in the cori loop. Hyperacidification by lactic acid export blockers has instituted differential cancer cell kill, in many cases, but usually fails to finally eradicate tumors that adapt to hypoxic conditions. Also, it is necessary, as with glucose feedstock blocking, to thread a narrow path between efficacy and contraindication.                                                                                                                                                                                                                                   

Bypassing cell glucose importation and lactate export systems may efficaciously demonstrate an alternative outcome. A recent strategy, applied across a broad spectrum of tumors in mice, utilizes dichloroacetate (DCA) to block a fetal puruvate kinase (FPK) enzyme in these tumors, thus renormalizing metabolic flow away from anabolism, and stopping cell growth. Apparently the switchout from adult PK to FPK is very common in such mouse tumors. Unfortunately, the results are so promising, and dichloroacetate, being a common unpatentable reagent, have led to a growing illegal market for dichloroacetate, among desperate cancer victims.                                                                                                                                                              

Caloric restriction and antioxidants both have impact on cancer incidence and severity. Carcinogenesis is both delayed, and once initiated, growth rates are slowed. It would be very interesting to see the results of resveratrol and dichloroacetate together. One could postulate a synergistic effect, in which dichloroacetate renormalizes glycolytic flow, and resveratrol reinforces the effect via anti-oxidation and/or mitochondrial biogenesis. Then again, things may not be so simple. The FPK system might not work the same way in humans as it does in mice, because people using DCA are reporting huge cell kill rates in their tumors and the associated dead cell load problems, indicating that DCA is acting more as a blocking agent than a pathway switching agent. If true, it could all be for the better, as kill is far more preferred than renormalization, as it allows the therapy to be stopped, at some point, instead of having to remain interminable. Besides, long term use of DCA is hepatotoxic.                                                                                                                                                                                                                                               

The DCA effect has resurrected the name of Otto Warburg, and rightly so. For the first time in 50 years, metabolism is again, moving into the forefront of cancer research. Please note that the metabotype referred to herein is only one of a number of required steps in cellular transformation to a full blown metastatic cancer. However the metabotype now assumes a required status, uniquely different from other dividing cells, such as fetal cells and adult stem cells. Cancer, it seems, is not just related to aging, but might be a mutated stepwise progression form of it. These integrated set of results give rise to an interesting evolutionary perspective.

A Short  Evolutionary Perspective                                                                                                                                                                                                                            

Now that we have whole genomes, from bacteria to human beings sequenced, many obvious first questions arise. One of the most tempting is: How did something as complex as a mammal, with well over 200 different cell types, operating in a highly integrated symphony, evolve to have a few times more genes than a eukaryotic single cell life form, such as yeast. What makes this even more puzzling, is that our 25,000, or so, genes seem mostly to have arisen from a couple of duplicating of, perhaps a 5,000-7,000, or fewer, gene containing archaic genome. One notion is that duplicating whole genomes creates a regulatory opportunity for multicellularity, as it allows for differential expression of each genome in each of two cells that fail to separate after division, allowing each cell to perform unique tasks that enhance the survival of each, together. Over time, this leads to multicellularity, and simple repeating body plans, such as segmented worms, developing segments into complex body parts and plans, such as insect mandibulata or mammalian inner ear etc. Over time, gene remnants fail to transcribe, sister chromatids cross over millions of times, viral transposons shuffle DNA around, evolutionary pressures select for gene gains, losses and mutations, gene regulatory systems advance, more and more cell types and there regulatory systems evolve, and create an ever diversifying array of body plans etc, until, at present times, the archaic genome, although readily statistically apparent, is barely still visible in the mish-mash. This is not quite like doing more with less, as it is like doing a helluva lot more with more of the same. Not to take anything away from Darwin, but nature does seem to ‘learn’ from, or pseudo-repeat, her successes. The genome duplication demonstrates how a gigantic array of regulatory elements in multicellular organisms can take an existing array of genes to new heights of diverse expression and function without actually having to create real ‘new’ genes.                                                                                                                                                                                                                                     

The new field of epigenetics is a case in point, because it pulls an apparent Lamarckian  ‘acquired characteristics’, end around, the more temporally linear notion of Darwinian survival selected fitness traits resulting from serially generational genomic mutagenesis. Briefly, the epigenome responds to environmental conditions, such as famine in the sex cells of the parents, by selectively methylating genes to up and down regulate them so that these regulatory systems are passed on to the offspring, purportedly to pre-adapt the offspring to the existing environmental conditions experienced by the parent. The number of possible variations of epigenetics dwarfs the size of the genome itself. This area of research is in its infancy, but one of its discoveries is serendipitous with this narrative. One epigenomics experiment shows that feast and famine leave a differential impact on sons and daughters that significantly affects their life expectancy. More so, the epigenetic signature passes through several generations before it fades out. From a Darwinian perspective, the only way to have the appearance of a Lamarckian outcome, is for pre-adaptation to have arisen from numerous, widely spaced, earlier or many, highly selective, recent exposures to a phenomenon. The more gene systems affected in a more orchestrated fashion, the more ancient and more protracted the system must be. Open ended circular arguments apply to life, because life has ‘been there’ before, especially in the case of famine, and because, successful gene systems replicate and fan out over time. In regards to the subject focus of this document, there appears to be a much more ancient and a much larger and much more controlled famine gene manipulation system than epigenetics at work.                                                                                                                                                                                               

I broached these topics to put forth the notion that ancient systems, such as intermediary metabolism, mitochondrial function and anciently occurring phenomena, such as feast and famine, grew along with the growth of the metabolic pathways themselves. Whole suites of genes are involved with their control, but over time the system evolves to arrive at a relatively few fixed sets of ‘tried and true’ tactics that have become, more or less, successful fixed response systems. Other, more flexible life components, such as length of time as a juvenile, or length of life as an adult, may be operating in an intermediate time spectrum, as they are responding to phenomena much longer than epigenetics, but much shorter than raw metabotype, although all three systems outlined, here, from a feast and famine standpoint, can leave their mark upon metabotype expression.                                                                                                                                                                                                                            

My point is this: even though there are hundreds of cell growth factors, the unique mixes, of which, tell each cell type when and how fast to grow and divide, there seems to be a veritable paucity of system(s) setting mitochondrial biogenesis in motion, with its apparent requisite reestablishment of the 5/95 glycolytic/Krebs ATP production ratios, and the resultant catabolic/anabolic rate shift. This rejuvenating biogenic system appears to paint with a broad brush, saying essentially ‘on’ in juvenile cells, ‘off’ in adult cells, and when in the ‘off’ position, mitochondria slowly age (as in humans), or rapidly age (as in mice), toward the inefficient cancer-like metabotype. This becomes a precancerous, or hyperplasic condition awaiting growth signal and signal related mutations, to transform it into the cancerous state. Amazingly, the juvenile system can be turned back on in adult cells, but only when the organism is in dire straights of a type recurrent from the dawn of metabolic evolution. Interestingly, most mammals fail to ovulate if they are not carrying enough fat supply, so caloric restriction carries extended life in exchange for the loss procreative capacity, thus allowing species replacement numbers to be deferred to a more nutrient plush future. Conversely, when feast times return, fat storage ensues, high ATP production efficiency is no longer a life sustaining requirement, and after a few procreative cycles, the now shorter lived adults, are disposed of. It is rather interesting that nature has also found a mechanism for failing mitochondria to act in a metabolic default toward cell growth, the caveat of it, being linked to life saving energy supply availability, on the one hand, and the potential to assist in the death dealing carcinogenic process, on the other.                                                                                                                                                                                                                                         

There does not seem to be any real overt need to modify this ancient system, save to change the length of the juvenile and adult stages to suit the environmental conditions demanding such. These life stage length differences between mice, dogs, horses, humans etc. are independent of metabolic rate, body size, the brain to body ratio, just as is the time from birth to the elevated cancer risk incidence curve. Instead, they seem more tied to the mitochondrial decay rate as per life expectancy. It is as if the vast array of environmental constraints set the necessary life length of the organism and that cellular metabolism doesn’t have a very difficult time complying by setting juvenile and adult stage length as needed. Of mice and men; old at age three or old at age 100; several thousand percent difference in life expectancy and 99% identical metabolic pathways. This gives argument to the notion of not what, or how you do something, but when you do it. It probably works the same in mice as it does in men, with the switches being turned off and on at different times and at different strengths. The central metabolic system, and its core regulatory elements haven’t changed much since the most advanced animal was a sponge.                                                                                                                                                                                                                                                    

In retrospect, glycolysis and aerobic respiration are systems entrenched in times so ancient, that it was before earth even had an oxygen atmosphere. When early oxygen producing photosynthesis first evolved in the ocean, anaerobic glycolytic bacteria, in one or more branches of life, began oxidatively extracting energy from glycolytic end products by removing hydrogen and adding oxygen in a stepwise process. Eventually this oxidative process evolved to extract the maximum obtainable energy by extending the oxidative chain all the way to the natural carbon dioxide and water, as waste product, endpoint. A symbiosis was formed when a nucleus containing archaeobacterial species housed an aerobic bacterial life form within itself, probably providing predatory protection in exchange for abundant energy. This is a relationship similar to that which exists today when coral polyps house algae within themselves. Before the first sponge-like simple multicellular life forms evolved, a nearly billion year relationship between the host and its symbiont had been maturing. Eventually, this relationship became so inextricable that, by the time that the first eukaryotic fungal/animal precursor cell arrived, the aerobic symbiont had been mostly reduced to the status of slave to its host, giving up most of its genome in exchange for providing critical energy producing advantages to its host (except for the notable, and rather disturbing distinction of retaining a host cell killing command center, called apoptosis). We call this relic, the mitochondrion. Today, the animal cell mitochondrion contains only the genes for its respiratory chain and some of its protein synthesis and replication machinery, cell suicide mechanism, included. All other ancient pre-mitochondrial functions are now sequestered in the DNA of the cell nucleus, and their gene products are imported into the mitochondrion from the cytoplasm. This is true in even though most primitive animal life forms, and in even earlier life forms, such as single celled yeast. Thus, aerobic and anaerobic systems were intricately enmeshed, in terms of each others operation and control mechanisms for a period of time longer than the existence of the Kingdom Animalia. It is no small wonder that we see the birthings of a SIRT1 control system in organisms that predate the animal kingdom.                                                                                                                                                                              

It seems incredible how both deeply entrenched and unchanged the caloric restriction response system has remained over time. We find it throughout the entire animal kingdom, from worms, through insecta, up the vertebrate tree, from ancient to modern life forms. The system is also remarkable in its versatility, and in its short term, intermediate term and its long term applications to organismic, species and Kingdom survival. When we look at mammals, in our attempts to utilize models more akin to our human selves, we see the sweeping SIRT1 system applies to every tissue and organ tested. Although the SIRT1 cascade ‘rejuvenation’ is nowhere near to being confused with the word ‘immortalization’, it is an apt nomer, nonetheless. Among other things, the system institutes production, via mitochondrial biogenesis, of efficient catabolism, which yields survival advantages during nutrient energy shortages, and yields energy efficient rapid growth during the growth factor directed  juvenile period of rapid body expansion. It reverts adult cells to a juvenile state, inasmuch as it can within mutagenic constraints, causing a true 30% to 80% increase in life span, depending upon which model is used.                                                                                                                                                                                                                   

After puberty, under ad libitum conditions, it becomes pretty clear that the SIRT1 system is, not only, not needed, but is not utilized, probably because it becomes disadvantageous in the statistical evolutionary survival sense. In the adult phase it, appears that cell senescence is an obligatory rule that can only be violated if survival of the next generation is at risk, due to the risk to the survival of the present generation, via starvation. Thus it does not matter if, under feast conditions, with procreation accomplished, that cancer becomes a natural outcome of declining metabolic efficiency, combined with the other required changes in cell growth control systems. In the adult system, inefficient catabolism diverts anabolic processes toward fat storage and pushes cells to become more dependant upon the cori cycle as they become more fuel dependant upon glucose by diverting excess pyruvate to lactic acid for export to the liver for gluconeogenesis. Such cells are metabotype ‘pre-adapted’ for cancer, as well as for organism aging or death, due to disrepair, because it really doesn’t matter how the organism is disposed of, as long as it is disposed of, usually by predation or disease, of course, due to its aged and weakened condition, Only under nutrient fuel paucity conditions does this natural decay process seem to be interrupted. The fact that SIRT gene knockout mice age rapidly and die very early, only underscores these conclusions.                                                                                                                                                                                                                                             

SIRT1 up regulation has just the opposite effect. Mitochondrial biogenesis occurs, the metabotype reverts to a juvenile metabotype , adult life span lengthens, cancer incidence declines, regain of tissue function, such as that of muscle, liver, neurological etc. takes place and total organismal energy output efficiency and general vitality ensues. The fact that resveratrol mimics this general condition, is a most fortunate discovery. The fact that the pharmaceutical giants are at war over resveratrol and its caloric restriction mimetic capacities, shows just how far human folly can escalate when so many billions of dollars are at stake, especially if the leading candidate drug is unpatentable. Although the affinity chip data indicate that resveratrol bypasses SIRT one and IGF, the fact that it activates 99+% of its downstream cascade, in at least three tissue types, speaks volumes. The physiological and cytological studies, which support the rejuvenative effects, arise from too many sources for it to be a collusion, accident or folly.  

Regardless, continued research on actual SIRT1 activators, resveratrol, its analogues or SIRT1 downstream cascade activators, these recent breakthroughs should spur a huge amount of basic research in both aging and cancer, and should, especially, reinvigorate a long overdue reinvestigation of the therapeutic efficacy of cancer cell intermediary metabolic interventions. This is particularly true, in light of the preliminary results from the employment of  DCA, and the pivotal position between glycolysis and the mitochondrion occupied by pyruvic acid.                                                                                                                                                                                                        

At the present time, the list of anti-aging supplements that need to be taken to ward off the plethora of cell systems in decline in aging organisms, is mammoth, to put it lightly. Many of these supplements (but, by no means all, such as, vitamins, anti-oxidants, phytonutrients etc.) are provided abundantly by juvenile cells, but are produced in progressively lessening quantities by aging organs, tissues and cells. However, by turning on a SIRT1 rejuvenation gene cascade, it appears that life extension occurs in the absence of such supplementation. This fact alone has incredible implications, because it proves that the vast majority of youthful cell vigor information, remains intact, and is recoverable with the right inducement(s). The implications are gargantuan, because it declares with a delightful certainty, that normal aging is not, so much so, a process of irreversible decay, as it is a form of highly controlled preplanned obsolescence. The investigation of modified supplementation, in tandem with rejuvenation gene cascade initiation and mitochondrial biogenesis control systems, could offer a fertile field for the cultivation of a broad area of applications. It is becoming progressively more clear that glycolytic and mitochondrial catabolic control systems, in and of themselves, have deep impacts upon cellular function, outside the governance of cell growth control signaling pathways. The notion that such a system has, at its roots, control over such sweeping concepts, as aging, biogenesis, rejuvenation and cancer, is almost stupefying. After all, these systems, and their core control elements, predate multicellularity and the need for differential cell 

help on Biology essays. stem cell, cancer, genetically engineered foods, human ecology?

I have to write 4-1000 word essays for my biology class, and I am running out of time and words. They’re very repetitive. I need someone else’s thoughts on the subjects to give good counter arguments.

1. What is stem cell research, and what is the hype/hypo?
2. Are genetically engineered foods safe to eat?
3. Is cancer a problem of genetics or environment?
4. What is human ecology?

any thoughts/opinions help. i’ll throw some extra points your way.