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Studies of caloric restriction, resveratrol and Sirt1 Demonstrate continuous' Metabotype "Since the cellular rejuvenation of aging to cancer
Studies of caloric restriction, resveratrol and SIRT1 Gene regulation of intermediary metabolism and mitochondrial biogenesis Demonstrate requirement 'Metabotype' transition from the aging cell rejuvenation to cancer, regardless of the factors in cancer cell growth, or suppressive Immortalizers. by Gregory S. Bambeck Ph.D.
Summary
In the early to mid-twentieth century, Otto Warburg hypothesis that cancer cells may be characterized by dramatically elevated glycolysis and mitochondrial respiratory failure locked in a relationship he called aerobic glycolysis. The statement showed respiratory failure false and biochemical cell cancer has changed his studies the oncogenes, growth factors and waterfalls cell, cancer cell growth suppressor systems, apoptosis, immortalization telomeric cell recognition and adhesion mechanisms etc. Any global scenario dedicated to inefficiency or mitochondrial dysfunction associated with anabolic control requirements and catabolic to operate on cancer cells, as proposed by G. Bambeck were denied funding or publication, and in fact, were escorted silently from the halls of science. Now, some 30 and 50 years later, the outcasts may have been proven to be visionaries. Glycolytic blockade and retrafficking agents, dichloroacetate etc as you can either kill or 'renormalized cells cancerous. Caloric restriction, the only mechanism known to extend life beyond of its normal length, on everything from worms to primates, is now known to rejuvenate old cells and down regulate cancer initiation and growth cell by activating a set of 745 or more genes that renormalized glycolysis and phagocytosis launch concurrently with inefficient mitochondrial biogenesis of mitochondria and new efficiency. The resveratrol becomes the exact same suite (s) of genes, and by all measures, the impact has cytological same. Continued "Metabotype" of a smaller cell, the cell aging, cancer cell, make more sense in an evolutionary context.
Forward
This is a general review article is presented as a narrative. It is not meant for peer review, in part, for reasons listed in summary and main text. That does not mean that this work is not important. Indeed, it could be very important, because it links together converging lines of research of the medical consequences of great magnitude. It is written by a Ph.D. scientist with over thirty years of successful scientific research instead of being managed at all.
There is no bibliography or references in this work, but at the end of this text, a short list of search words and readings suggested are provided, so that most of the literature provides enough to see the "big picture" presented by the assumptions contained in the same. This article is limited to base changes in anabolic and catabolic intermediary metabolism and how they relate to children, adults and cancer cells, since this area of cancer research has been left fallow. Other important research areas, such as cell growth factors before mentioned, etc, have tens of thousands of items that can be contemplated.
This article is dedicated to a research area that has been relegated a haven, particularly in regard to cancer cell metabolic intermediate. If it were not for anti-aging and life extension results research, metabolic stumbling through the 'back door', so to speak, about thirty years after a change in Warburg hypothesis, together with the metabolism of some new cancer blockers, important connections may not have been made. Throughout history, serendipities and / or convergences have come together to form a holistic system of emerging with more than noticeable impact. We hope that this one of those moments.
Finally, this writes an article in Scientific American that is, hopefully that can be understood by the educated lay person, but not short-change the serious scientist, too. Professional jargon will be held to a minimum. It is my hope that a more detailed review is not necessary, if there is enough interest. It would certainly be much more rewarding if interested parties would take the debate, or even start lines of inquiry that can weave the contours of these patches in a semi-integrated complete tissue of any improvement, or completely new understanding. So, here we go, more or less "coincidental.
A early times
Approximately 96% of the organic biomass of a cell consists of carbohydrates, fats, nucleotides and proteins. The four of these components can be burned as fuel to power the cell, or as building materials to replace defective parts in a cell at rest or to build a new cell, as in the case of a cell divides. In normal cells, healthy sleep, there is a balance between energy production and repair rates so that the cell is said to be in homeostasis or equilibrium. In a normal, healthy cell division, growth policies to create a cascade of an order the cell to increase both its energy production and import of raw materials and build these raw materials in the components of a new cell. In summary, RNA and DNA nucleotides, amino acids become proteins, sugars become complex carbohydrates and fatty acids in a process called lipid anabolism, while these same four materials may alternatively be burned as fuel to generate energy in a process called catabolism. The anabolic more intermediate products can be mounted on anabolism in molecular assemblies such as ribosomes, enzyme complexes etc., and even more in organelles such as mitochondria, however, make it more like an expanded version of the old cell metabolism.
Although, what has been presented so far is an oversimplification, it suffices to say that the mid-twentieth century, a fairly sophisticated scheme of hundreds Traffic of molecular pathways of catabolic and anabolic interaction of organic molecular transitions, is plotted. posters on walls in classrooms demonstrated these processes in a manner similar to see the flow of traffic on the freeway the car from an aerial view of a big city. Many discoveries have been made through observation of interruptions in the flow, like car accidents causing obstructions in exit ramps, access ramps and forms intern in the highway system.
Otto Warburg, in charge of a large research organization and a highly respected molecular researcher of his day, the first half of the twentieth century, believed see a disturbance of intermediary metabolism both unique and specific to all cancer cells. More precisely, the hypothesis that this disturbance criticism merely catabolic side burning or fuel metabolism, but also
Glucose is the primary, but by no means the only fuel that is burned by the cells of the body, and burned in two complex systems, called glycolysis and the Krebs cycle. The energy obtained by glycolysis from glucose and other sugars by an anaerobic (oxygen-using) mechanism to produce ATP, an energy carrying molecule. Krebs cycle, contained in an organelle called the mitochondria, the final product burns glycolytic pyruvate, using an aerobic (Oxygen consumption) mechanism to produce ATP. The burning of a sequential process strips hydrogen oxygen glycolytic end product, the conversion of NAD to NADH2 couples and then the NAD hydrogen to oxygen to form water, while the release of sugar to form carbon dioxide. The water formation is a gradual process in which the energy of the hydrogen atoms and electrons come together in a step by step process called electron transport, while the energy of the process is captured through the conversion of ADP into ATP, while H and O is water, in a process called oxidative phosphorylation. Anabolism is the process opposite, in which hydrogen energy NAD and ATP are used to construct cellular components. Thus, two molecules of swing in the process are the ATP and NAD as alternating among forms of energy and high and low oxidation and reduction of form, respectively.
In a healthy cell homeostasis, fuels used by many, and about 5% of the ATP is produced by glycolysis, whereas about 95% of the ATP is produced by the mitochondria. Anabolism and catabolism balance steady state with this energy mitochondria produce ATP by about 99% efficiency. In a healthy cell division, energy production system, increases the expression of energy to produce ATP and NADH reduce the power of anabolic requirements for a new cell. Otto Warburg note unique in the catabolism cancer cells, where glycolysis is considerably high, breathing was depressed and that the mitochondria in cancer cells appeared small, malformed or disorganized. He also suggested that, unlike the fetus or other cells that normally divide, the cancer cell is irreversible "stuck" in this metabolic phenotype. Although the glycolytic part of his hypothesis was not refuted, the notion of the respiratory defect was beaten in a furious debate in 1955-1956. deficiency Mitochondrial respiratory, although found in many tumor types, not found in all types of tumors, and was not considered necessary as a fundamental requirement of the condition cancer cells.
As mentioned above, Warburg was a big name in his time. He made and broke many scientific careers, and was known to have a little character irascible. Well, the bigger they are, the harder they fall. Many of the opponents of Warburg became journal editors, reviewers and laboratory directors. Oh to be apply to any person any form of mitochondrial defect and a history of cancer, even twenty five years later.
After rejection Warburg hypothesis, cancer research moved away from metabolic studies to oncovirus, oncogenes, growth factors and cell cascades, systems suppressing cell growth, apoptosis mechanisms, telomeric immortalization, cell recognition and adhesion systems etc. These studies have been enormously impact on our understanding of cancer cell normal to the transformation process. It has become clear that evolution has provided numerous impediments to carcinogenesis lethal in their attempts to keep cell division under control. Nor is there doubt that these new areas of research have been opened, regardless the results of the hypothesis of Warburg. However, it is also true that research on mitochondrial interactions in the intermediary metabolic interaction in the tumor cell, there have been almost exhausted, as the majority does.
In 1975, some twenty years after the shock Warburg, a student very politically naive graduate named G. Bambeck became fascinated with the mitochondria, in a laboratory at Kent State University, who happened to have a mouse model lymphoblastic lymphoma. Mitochondria isolated from tissues of mice and noted that many of the mitochondria lymphoma had only low ADP: O ratios. This means that these mitochondria were producing abnormally low amounts of oxygen consumed by ATP energy. This could mean that either ATP consumption was uncoupled oxygen through the respiratory chain, which reduced NAD was either being dissociated from oxygen or exported from the mitochondria in abnormally high rates, through a chemiosmotic type of transport, the anabolic effects, or some combination thereof, by some unknown mechanism (s).
So began a literature search and, among other things, he ran into the debacle of Warburg. But being socially unsophisticated, followed forward, and he went ahead because he found something very interesting, very interesting, in fact, that practically left her wet lab (held) the mental investigation of a form of research. Research in mind, a review of the work of other researchers, with the hope of "a unique synthesis of thought "or, in other words, an overview is ignored, which, in this case, could be suitable for a doctoral thesis.
First, only a few cases. What we find, in all cases where data were obtained, the net production of mitochondrial ATP per mitochondrion in terms and / or, more importantly, was by cell basis, significantly reduced compared to normal dividing cells. He further noted that mitochondrial net deficit of ATP synthesis might be due to low numbers of mitochondria per cell, inefficient electron transport, the increase in NAD / NADH transport export of reducing power, the inefficient coupling of ATP formation chemiosmotic potential hydrogen, a change in the ATP synthase dynamic ATPase balance or a fundamental change metabolic km route linking chemicals glycolytic end the cycle of Krebs. Anything that can block connection between the NAD / NADH redox coupling to the formation of ATP, could tip the balance of carbon flux for anabolism. More importantly, such deficiencies production mitochondrial ATP could change the mitochondrial glycolytically produced by the ratio of ATP production over 1000%. He suggested that this differential of forced intercourse fuel dependency of glucose while forcing other metabolites, reducing power and energy flow to ATP anabolism. In light of modern discoveries, which will be discussed later, one could say that this system of pre-adaptation of the cell, metabolically, to a format an uncontrolled growth, if not necessarily marked by a growth factor: a precancerous condition or hyperplasia nondividing growth as I could have it. If carcinogenesis is a multistep process, why not have a metabolic process or a progression toward a metabolic state that predicates terminal process when adequate mutations and their associated stimuli arrive?
G. Bambeck optimism presents its findings to the scientific community disdainful expected results. Although his thesis was of a somewhat heretical, received his doctorate because the logic was essentially good. But no place to publish and where to work on his findings, which evaporates from the darkness to nothing in the annals of cancer research. Instead, bands active in layers medical diagnostics and research technologies to the tool. 1975-1980 tools were not available to deal with a justification of the fall Mitochondrial efficiency in cells. On the one hand, there seemed to be more aspects of what happens. Gene switch systems and switching genes were only in the early days of the initial clarification. There were simply too many unknowns, and alternatives. G. Bambeck took a stab at the problem, and thé notion that species reactive oxygen (ROS), known as free radicals at the time, it might be peppering the mitochondrial and nuclear genome, resulting in a randomized sequence of mitochondria and manifests as a progressive decrease in the efficiency of burning fuel. Paraphrasing, he said, "by any means, the mitochondrial ATP per cell production deficiency is there. "We now know that this is true, not only in cancer cells, but in older cells, too. Its manifestation worst often happens in cancer cells. The relationship between aerobic anaerobic ATP production appears to exacerbate increasingly as cells age and change. Cell production of heat and adaptation to hypoxia are hallmarks of cells adapted glycolytically loosely coupled ATP formation, as evidenced by the limited success with hyperthermia, the export of lactic acid and hypobaric blocking anti-cancer therapies. G. Bambeck the hypothesis more specific blocking agents of glycolytic and mitochondrial systems, there could be more effective, either to kill the institution of differential or renormalization cancer cell. The facts now known to be glycolytic blocking agents can kill or fetal pyruvate kinase can renormalized the blocking agents cancer cells to a non-anabolic and non-growing, and that the conditions and agents that create efficient aerobic catabolism through the mitochondrial biogenesis reduce the incidence of cancer and increase cell rejuvenation, show greater support for the mechanistic. However, much of these data come from areas original research perceived as only tangentially related, or not at all related to cancer.
To Present Times
From the 1980s to the present, has been a lot of work with the ROS and its mutagenic and aging in cells. Basically, ROS are highly reactive oxygen species that contain an unshared electron that allows ROS to react with almost any organic molecule available, including DNA, RNA, proteins, etc. Naturally, ROS mutagenic and therefore carcinogenic, similar to radiation ionizing, making the highly specific and organized genome and their protein products to be more random or meaningless. Because they are immersed in an atmosphere of oxygen, either directly or through delivery of blood, the body's cells use molecules produce ROS and free radical scavenger to clean up nemesis. Antioxidants such as vitamin C, vitamin E, bioflavonoids, etc are such free radical scavengers, and experiments with high doses of antioxidants and their effects on the induction of cancer and aging rates are common. In general, the results are positive, helping organizations to achieve best possible all natural potential well nourished
The mitochondria produce more ROS than any other part of the cell, as is the headquarters of oxidative fuel burning, which uses the cascade of electrons respiratory chain increased the energy of the electrons from the Krebs cycle intermediate hydrogen for the formation of ATP, because ultimately, oxygen, to produce water. To protect their own domestically produced ROS, mitochondria and antioxidant endemic uses a special enzyme called SOD to clean ROS.
Each mitochondrion has several copies of your own DNA, and when ordered to do so, the mitochondria can multiply like cells. But unlike the cells, mitochondria can do something incredible. Through a process most unresolved, mitochondrial biogenesis (as distinct from the simple division), results in mitochondria efficient new mitochondria arise from inefficient old. Cell nuclear genomes pass on the errors that their DNA repair systems do not detect or repair faulty, like mitochondria, when simply dividing, but not when subjected to biogenesis. Maybe it is because a single cell has a single nuclear genome (or most cases, two half genomes), but up to a thousand mitochondrial genomes that can be coupled to a selection process, perhaps based on some kind of selection for the fidelity of the consensus sequence. It seems obvious that there must be some kind of renewal of the selective system, because mitochondria are passed from generation to generation through oogenesis, on average, without a single point mutation. Without this process, not take many generations of eggs containing a squiggly mitochondrial sequences, which tracks the matrilineal line to a virtual impossibility. The fact that we can follow the matrilineal line through thousands of generations, supports this notion. I imagine something like a mechanism of polytene chromosomes Sequence comparison of some sort, or perhaps the mother of a highly protected genome and isolated mitochondrial somewhere in the cell. biogenesis of real horses. In the adult body cells, the mitochondria gradually degenerate into inefficient couplings of hydrogen, electrons and oxygen to ATP and water production. And not just one thing, but a lot of things go wrong in the mitochondria, cells age adults, with one of the best causal suspects to be ROS-mediated mutagenesis. Concomitant with decreased mitochondrial efficiency over time, cells are terminally differentiated and can no longer divide, such a change relationship is not a cancer risk, like adult stem cells, which still have functional telomeres and telomerase could immortalize. Telomere shortening terminal differentiation is a well-established mechanism is supposed to prevent cancer progression in adult cells.
However, terminal differentiated adult cells and adult stem cells can divide, and usually divide to replace dead adult tissues or missing, under the directive of growth factors. In such conditions, tissues are replaced but are not rejuvenated. Instead of young new dividing cells to replace old dead cells, old cells are replaced are divided, in part because of mitochondrial biogenesis is not happening. Cells are replaced, but the tissue is not being renovated. It seems that as we age, the metabolic phenotype (metabotype) operates cellular aging more and more metabotype as a cancer cell. Somehow, I do not think there is a strong evolutionary pressure to put additional obstacles metabotype such progression, especially with the above-mentioned, long list of quality assurance mechanisms and non-metabolic in the guide. In fact, this progressive metabolic transition, probably support the evolutionary process. From an evolutionary perspective, it is preferred at any given time to dispose of the old bodies, which represent the genetic experiment yesterday, with the following experiment generational mix of genes. After all, the genome has a shot in perpetuity, and vehicles used to get there. In summary, it appears that adult tissues are aged metabotypes tissues of juvenile and adult stem cells are between metabotypes fetal stem cells, and that their progress toward metabotype metabotypes cancer cells, independent of other components of the cancer cell transformation process. There seems to be a mixture continuity metabolic between these cell types temporary basis, and recent science on cancer and aging are giving ideas to show the crossover between metabolism applications these once disparate fields of research. It seems we're starting to get a degree of control over aging and cancer, at least from a metabotype.
To a degree quite remarkable, metabotype cellular aging and cancer cells have recently been returned to normal extension with dramatic increases of life and the reduction of cancer incidence in experimental groups that share seemingly unrelated lucky seeing them only results from metabolic shared perspective. By extension of life, ie the effect of age beyond their normal well-nourished than "This is not to be confused with the achievement of the highest natural to delay the premature death, but, going beyond their natural maximum health to a considerable extent. In addition, is too early to talk about curing cancer, but the first data point to a significant renormalization cancer or death. But first, there is a need a bit of a preamble.
Until recently, the technique only known to cause true extension of life is to initiate a condition known as caloric restriction. Caloric restriction and life extension affects welcomes back seven decades, but their multiple mechanisms of action of many newly emerging to light, due to new technologies emerging from the genomics revolution. Studies have shown that calorie restriction rejuvenated cells, by virtually all respects, and in nearly all tissues and organs of the body from neuroregeneration, the delay and reverse muscle loss, visual impairment, skin wrinkling etc. These phenomena such as rejuvenation occurred in organisms, as humble as yeast, up through the evolutionary chain multicellular organism from worms mice. Just last year, a 25-year study of calorie restriction in rhesus monkeys extended these results to the order of primates, human beings which is a member. Preliminary results in humans parallel results are being obtained. In retrospect, such findings make evolutionary sense, because the cycles of scarcity and abundance dating back to the dawn of time. There is a clear survival advantage in the ability to sweat out the lean times, to the availability of nutrients of times fat allows the availability of energy to support cell division in unicellular organisms or multicellular organisms procreation. Hibernation or estivation can work for newspapers, such as the circumstances winter snow or summer drought, as it does for the bears in the north and desert toads, but variables and conditions have resulted in unforeseen a much more ancient and metabolic flexible, as noted by caloric restriction. It seems clear that many millions of generations have been improved by caloric restriction for use as a generic life extender as a means to avoid extinction.
In just the past two years, the genetic mechanisms behind the phenomenon caloric restriction have become much more clear. First, calorie restriction activates a gene called SIRT1 that activates a set of at least 745 genes that are normally active in juveniles, but off in the adult. At least, SIRT1 is becoming an extremely complex system of genes in adult cells rejuvenation operating normally only in juveniles, tempting the notion of "especially because the extension of life is the result of activation. It seems clear that this must be an old system to be composed of a number orchestrated such large components, and in such a mold specific expression, with a special inclination towards enlargement of body length imitating life, or treat mimic the juvenile period and impose the adult cells. The impact appears to be more pronounced in metabolic efficiency.
For one thing, the metabotype all of the changes in cellular aging to a metabotype becomes smaller when SIRT1. Surprisingly, not homeostatic divide adult cells undergo mitochondrial biogenesis, in that old inefficient mitochondria are replaced by new efficient mitochondria. This is not only ineffective mitochondria of dividing to produce more mitochondria inefficient, as is the case in aging adults replicating cells and cancer cells, but biogenesis behaving real young mitochondria producing cells in a juvenile metabotype. This probably helps explain the reduction in insulin resistance, dramatically reducing dependence of glucose into the cell, and a series of rejuvenating the effects caused by rebalancing the catabolic energy production, and probably reduced ROS, or ROS scavenging. There is no support for the idea that mitochondrial biogenesis can only have a major impact on cellular rejuvenation, such as direct elicitors of mitochondrial biogenesis (PGC1-alpha) in mice, reduces muscular and visual impairment. We expect to see an explosion of research in this area because mitochondria are known to be vital for cellular health, much more than previously thought in the traditional sense.
However, only 80 years. But stay tuned. There is evidence that caloric restriction may be gen systems, in large part, chemically inducible.
There is a new kid on the block, called resveratrol. In the last decade or so, resveratrol has become an acclaimed anti-aging super anti-oxidant. Originally touted as a component of lycopene / tomato, oil and omega 3/olive resveratrol / red wine mediteranian diet, resveratrol has become in a heavyweight contender in its own right, and for good reason. Affinity gene gun experiments, which measure and downregulation of more than 20,000 genes to time by measuring mRNA gene transcription annealing the leaders of the DNA sequence, show that `more than 745 genes are regulated by resveratrol the same way as does caloric restriction in mouse tissues. In fact, the number and direction of regulation shows a remarkable agreement 99.7% with caloric restriction, and the remaining 0.3%, which somehow avoids SIRT1. Similar results were obtained with other tissues. The effect occurs even in mice of fat, although the jury is still out on its impact on the longevity of these animals. Importantly, mitochondrial biogenesis and resveratrol initiated a long list of regeneration affects tissue and cytological similar if not identical to caloric restriction. The likelihood of such a high concordance of gene activation is so tiny border on the incalculable. The fact that it does so through some sort of derivation of the putative genes initiation cascade control and IGF-SIRT1 Growth Factor (IGF), is initiating a rather heated debate between pharmaceutical companies with vested interests on both sides of the issue resveratrol gene control and if this is a true calorie restriction mimetic. On the basis of the impact of mitochondrial biogenesis seen, I guess a large percentage of genes or resveratrol-induced SIRT1 is involved in mitochondrial biogenesis and its impact on aging and cancer cell metabotype.
There can no longer fit doubt that many if not most cancer cells have withdrawn some metabotype that is fundamentally more obsessed than in normal cells. In short, In vitro studies mimicking glycolytic glucose blocking agents such as glucose and glucose 2-deoxy-D 5 dude, can kill up to 99.999% of cancer cells in a few hours, leaving live normal dividing cells with cancer cells are radiation sensitive and normal cells to radiation insensitive. These agents slam glycolytic ATP production to end hunger pyruvate leaving only mitochondrial ATP production to stay. Being dependent on the product of glycolysis final, much more than most normal cells, cancer cells die, whereas normal cells can be used, or disconnect the fuel alternative, more easily. Unfortunately, these results do not translate in vivo use because the therapeutic dose is about contraindicating dose, probably because they are analogues of glucose. Brain cells are highly dependent on glucose, for example.
In cancer cells, glycolysis produces many times more often that pyruvate can assimilate the mitochondria inefficient, so the excess becomes of pyruvate to lactate for export to the liver cells, where it is converted to glucose for re-export to the tumor, in a closed loop system called Cori cycle. Other cells, such as hypoxic cells and low oxidative fast-twitch muscle cells, reversibly can use the cycle Cori, whereas cancer cells are much more entrenched in the loop CORI. Hyperacidification by lactic acid blockers has instituted differential export kills cancer cells, in many cases, but usually not eradicate tumors that are adapted to hypoxic conditions. It is also necessary, as with glucose as raw material blocking the thread of a narrow path between the efficacy and contraindications.
Import diversion systems of cells from glucose and lactate export can demonstrate effectively an alternative outcome. A recent strategy, applied in a broad spectrum of tumors in mice, using dichloroacetate (DCA) to block a fetus puruvate kinase (FPK) enzyme in these tumors, thus renormalizing metabolic flux away from anabolism, and stop cell growth. Apparently, the adult switchout PK FPK is very common in the mouse tumors such. Unfortunately, the results are so promising, and dichloroacetate, being a common reagent patentable, have led to a growing illegal market dichloroacetate, among desperate cancer victims.
Caloric restriction and antioxidants both have an impact on cancer incidence and severity. Carcinogenesis is so late, and once rates growth slowed. It would be interesting to see the results of resveratrol and dichloroacetate together. One could postulate a synergistic effect, which dichloroacetate renormalized glycolytic flux and reinforces the effect of resveratrol through anti-oxidation and / or mitochondrial biogenesis. On the other hand, things are not so simple. The system FPK could not work the same way in humans as in mice, because persons with DCA are reporting mortality rates of large cells in tumors and problems associated with dead load cell, indicating that DCA is acting more as a blocking agent for a way to change agent. If true, it could all be for the better, as killing is much more preferred than renormalization, allowing the therapy to be stopped at some point, instead of having to spend endless. In addition, the long-term use of DCA is hepatotoxic.
The DCA effect has revived the name of Otto Warburg, and rightly so. For the first time in 50 years, the metabolism is more, coming into the forefront of research cancer. Note that the metabotype other dividing cells, such as fetal cells and adult stem cells. Cancer, apparently, is not only related with aging, but may be a stepwise mutated form thereof. These integrated set of results give rise to an interesting evolutionary standpoint.
A short evolutionary perspective
Now that they have whole genomes, from bacteria to humans sequenced, many questions come first obvious. One of the most tempting is: How can something as complex as a mammal, with over 200 different types of cells, which operate in a highly integrated symphony, evolve to take a couple of times more genes than a single eukaryotic cell life form, such as yeast. What makes this even more disconcerting is that our 25,000 more or less, particularly genes appear to have arisen from a pair of double, perhaps 5000-7000 or less of the genome containing genes archaic. One idea is that the duplication complete genome creates an opportunity regulator of multicellularity, allowing differential expression of each genome in each of two cells that do not separate after division, allowing each cell to perform unique tasks that improve the survival of each one, together. Over time, this leads to multicellularity, plans and body simple words, such as segmented worms, the development of segments in the complex body parts and plans, such as insect or mammalian inner ear Mandibulata etc. Over time, the remnants of genes not transcribed, sister chromatids cross over millions of times, DNA shuffling viral transposons, evolutionary pressures selected for increases gene, losses and mutations, the gene regulatory systems advance, more and more cell types and regulatory systems do not evolve, and create an increasingly diversified range of body plans, etc, until now, the genome archaic, although statistically apparent ease, it just yet visible in the jumble. This is not enough to do more with less, because it is like doing helluva lot more with more of the same. Without taking anything away from Darwin, but the nature can take a number of existing genes to new levels of expression and function of different without having to create real "new" genes.
The new field of epigenetics is a case, since carries an apparent Lamarckian acquired characteristics, end-all, the notion linear time Darwinian survival traits resulting from mutagenesis selected genomic fitness generational series. In summary, the epigenome responds to environmental conditions as hunger in the sex cells of the parents, a selective methylation of the genes up and down so that the governing these regulatory systems are transmitted to offspring, presumably to pre-adaptation of the offspring to the conditions of the environment experienced by the father. 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 findings is even a surprise to this story. An experiment shows that scarcity and abundance Epigenomic leave a differential impact on sons and daughters that significantly affects their life expectancy. Moreover, the firm passes through epigenetic several generations before it vanishes. From a Darwinian perspective, the only way to have the appearance of a Lamarckian result is to adapt after that has been produced from numerous, widely separated, anterior or many, very selective, recent exposures to a phenomenon. The genes most affected systems in a more organized, oldest and longest of the system should be. Indefinite circular arguments apply to life, because life has "been there" before, especially in the case of famine, and because gene replicate successful systems and fan out over time. As the focus subject of this document, there seems to be much oldest and one much larger and more gene controls famine handling system that epigenetics at work.
I addressed these issues to propose the idea that older systems, such as intermediary metabolism, mitochondrial function and formerly phenomena occur, such as scarcity and abundance, grew along with the growth of the metabolic pathways themselves. a whole set of genes are involved in its control, but over time the system evolves to reach a relatively few fixed sets of treaties and true "tactics have become more or less successfully fixed response systems. Other, more flexible life components, such as the length of time a minor, or the duration of life as an adult, can operate in a spectrum intermediate time, and they are responding to events much longer than epigenetics, but much shorter than metabotype premiums, although the three systems described here, from a party standpoint and hunger, can leave their mark on the expression metabotype.
My point is this: although there are hundreds of cell growth factors, the unique combination of which, tell each cell type when and what how fast they grow and divide, there seems to be a real shortage of the system (s) the establishment of mitochondrial biogenesis in motion, with their apparent need restoration the 5 / 95 glycolytic / Krebs ratios ATP production and the resultant catabolic / anabolic rate. This system seems to rejuvenate biogenic painting with a broad brush, saying essentially "on" in cells of children, "off" in the adult cells and when in the off '" position, slowly mitochondria age (as in humans), or age quickly (as in mice), similar to the inefficient metabotype cancer. This becomes a precancerous condition or hyperplasia expected growth signal and signal-related mutations, to transform it into the cancerous state. Surprisingly, juvenile system can be converted back into adult cells, but only when the body is in great lines of a type repeatedly since the dawn of metabolic evolution. Interestingly, most mammals do not ovulate if you do not have enough supply of fat is so calorie restriction extends life leads to change for the capacity reproductive loss, allowing the number of species replacement was deferred to a future stuffed more nutrients. On the contrary, when times return party, begins a fat storage, high efficiency production of ATP is no longer a requirement for sustaining life, and after a breeding cycle few adults now shorter duration, shall be removed. Interestingly enough, nature has also found a mechanism for mitochondria do not act to a metabolic defect in cell growth, warning that, being inherent to life-saving power supply availability, on the one hand, and the potential to aid in death dealing carcinogenic process, on the other.
There does not seem to open any real need to change this old system, except to change the length of the child and adult to adapt to environmental conditions demanding such. These stages of life-long differences between mice, dogs, horses, etc. are independent of the human metabolic rate, body size, the brain-body relationship, as is the time from birth to the increased risk of cancer incidence in the curve. Instead, they seem more related to the decay rate mitochondrial as life expectancy. It is as if the vast array of environmental constraints to adjust the length of life required the agency and has no cellular metabolism a very difficult to meet by establishing length of juvenile and adult stage as needed. Of mice and men, old age or the age of three 100, several thousands of percent difference in life expectancy and 99% identical metabolic pathways. This argument buys into the notion of what is not, or doing something, but when do. Probably works the same in mice as in men, with switches that are turned off and on at different times and in different concentrations. The core system metabolism, and their key regulatory elements have not changed much since the more advanced animals was a sponge.
In retrospect, glycolysis and aerobic respiration are rooted in systems as old times, which was the land even before there was an atmosphere oxygen. When the early oxygen-producing photosynthesis first evolved in the ocean, the glycolytic anaerobic bacteria in one or more branches of life, began oxidatively extracting energy from glycolytic end products through the elimination of hydrogen and oxygen in the addition of a step step process. Over time this evolved oxidative process to extract the maximum energy obtainable through the extension of the oxidative chain all the way to carbon dioxide carbon and natural water as a waste product, period. A symbiosis was formed when a nucleus containing species housed archaeobacterial aerobic bacterial life form itself, probably abusive protection in exchange for abundant energy. This is a similar relationship to that which exists today when the algae of coral polyps home within themselves. Before the first fluffy simple forms of multicellular life evolved, one year almost one billion relationship between host and symbiont had matured. Finally, this relationship became so intractable that, by the time the first eukaryotic fungi / animal stem cell arrived, the symbiont Aerobic had mostly been reduced to slave status of its host, giving most of their genome in return for providing critical energy production of benefits to their host (except for the protruding, and the distinction is rather disturbing to maintain a host cell killing center commands, called apoptosis). We call this relic, the mitochondria. Today, the mitochondria of animal cells contains only the genes of respiratory chain and some of its synthesis protein and replication machinery, the mechanism of cell suicide, included. All other functions of the former pre-mitochondrial DNA are sequestered in the nucleus cellular and gene products imported into the mitochondria in the cytoplasm. This is true even though in most primitive forms of animal life, and even earlier forms of life such as single-celled yeast. Thus, aerobic and anaerobic systems were trapped intricate in terms of each operation and other control mechanisms for a period longer than the existence of the animal kingdom. No wonder we see the birthings of a system of control of SIRT1 in organisms that predate the animal kingdom.
It seems incredible how both deeply rooted and unchanging system of restrictions on caloric response has been maintained over time. We find in the animal kingdom, from worms through Insecta, the tree of vertebrates, the old forms of modern life. The system is also notable for its versatility, and its short, intermediate and long-term applications organismic, species and survival Kingdom. When we look at mammals, in our attempts to use similar models ourselves human, we see that SIRT1 scanning system applies to all tested tissues and organs. Although rejuvenation SIRT1 cascade "is far from being confused with the immortalization of the word "is an apt monomer, however. Among other things, the production system institutes through biogenesis mitochondrial efficient catabolism, which provides survival advantages during the energy shortage in nutrient and energy efficient rapid growth yields during growth factor led juvenile period of rapid expansion of the body. He turns adult cells to a youthful state, to the extent possible within the constraints mutagenic causing a true 30% to 80% increase in life span, depending on the model.
After puberty, in ad libitum conditions, it becomes quite clear that the system of SIRT1 is not only not needed, but not used, probably because it becomes a disadvantage in the statistical sense of evolutionary survival. In the adult stage is, it seems that cellular senescence is a mandatory rule that can only be violated if the survival of the next generation is at risk because of the risk to the survival of the current generation, through starvation. As So no matter whether in terms of party, to childbearing and fulfilled, that cancer becomes a natural result of the decreased metabolic efficiency, along with other necessary changes in systems of control of cell growth. In the adult system, inefficient catabolism diverted to storage anabolic processes fat and pushes cells to become more dependent on the Cori cycle, because they become more dependent on glucose fuel by diverting excess pyruvate lactic acid for export to the liver for gluconeogenesis. Such cells are metabotype "pre-adapted" for cancer and As for the aging body or death due to poor condition, because it really does not matter how the body may be assigned, provided they are removed, usually by predation or disease, of course, because of his age and weakened condition, only under conditions of low nutrient fuel does this process of decomposition seems natural to be interrupted. The fact that SIRT genes mice knockout age rapidly and die very soon, only underscores these conclusions.
SIRT1 to the regulation has the opposite effect. Mitochondrial biogenesis occurs, the return to a metabotype metabotype minors, the period of adult life lengthens, the decrease in the incidence of cancer, tissue recovery function, such as muscle, liver, neurological etc. runs from total output and output energy bodies and usually occurs vitality. The fact that resveratrol mimics this condition is usually a lucky discovery. The fact that pharmaceutical giants are at war by resveratrol and caloric restriction mimetic capacity, shows how far human folly can intensified when so many billions of dollars are at stake, especially if the leading candidate drug is not patentable. Although data from the chip affinity indicate that resveratrol prevents IGF SIRT and the fact that active 99 +% of its downstream cascade, at least three types of tissue, says it all. Physiological studies and cytology, which support the rejuvenating effects are due to many sources to be collusion, accident or madness.
Regardless, research continues in the current SIRT1 activators, resveratrol, SIRT1 activators or analogues cascading down, these recent developments should contribute to a tremendous amount of research basic, in both aging and cancer, and must, above all, to give new impetus to new research from the long-awaited therapeutic efficacy of cell cancer, the interventions of intermediary metabolism. This is particularly true in light of the preliminary results of the use of DCA, and central position between glycolysis and mitochondria occupied by pyruvic acid.
Currently, the list of anti-aging supplements to be taken to avoid the multitude of cellular systems in decline in aging bodies is immense, to say the least. Many of these supplements organs, tissues and cells. However, by activating a cascade of rejuvenation SIRT1 gene, it seems that life extension occurs in the absence of such supplementation. This fact alone has incredible implications because it shows that the vast majority of youth information effect of the cell remains intact, and is recoverable with the right incentive (s). The implications are enormous, as it states with certainty delicious, that aging is not normal, so much so, a process of irreversible decline, since it is a form of planned obsolescence already very controlled. The investigation of supplementation changed, along with the initiation cascade of genes and rejuvenation systems control mitochondrial biogenesis could provide fertile ground for growing a wide area of applications. It is becoming increasingly clear that the glycolytic catabolic systems and mitochondrial control, in themselves, have a profound impact on cell function, outside the governance of cell growth control signaling pathways. The idea that such a system is, at root, the control over such radical concepts, such as aging, biogenesis, rejuvenation and cancer, is almost bewildering. After all, these systems, and central control elements, predate multicellularity and the need for differential cell
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