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