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