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