Studies Of Caloric Restriction, Resveratrol And Sirt1 Demonstrate A ?Metabotype’ Continuum From Cellular Rejuvenation To Aging To Cancer
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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
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