The Resveratrol Bioavailability, Caloric Restriction and Life Extension Conundrum: A New Understanding Just Might Resolve This Contentious Debate

Posted by admin on Apr 15th, 2010 | 0 comments

The Resveratrol Bioavailability, Caloric Restriction and Life Extension Conundrum: A New Understanding Just Might Resolve This Contentious Debate

The Resveratrol Bioavailability, Caloric Restriction and LifeExtension Conundrum: A New Understanding Just Might Resolve This Contentious Debate.                                                             

Gregory S. Bambeck Ph.D. and Michael Wolfson  J.D.  M.B.A.

TECHNICAL BRIEF

From a metabolic standpoint, life extension research is fraught with conflict and confusion. There are two opposing but co-operative forms of mitochondrial renewal, but the research community usually uses the single term ‘mitochondrial biogenesis’ to describe both of them. Using the term ‘neogenesis’ to describe the making of more mitochondria and the term ‘regenesis’ to describe the repair of existing mitochondria, resolves this source of confusion. For instance, the mitochondrial proliferator activator (PGC-1alpha) institutes mitochondrial regenesis when down regulated by the ‘gold standard’ of life extension, the caloric restriction pathway. Factors extrinsic to caloric restriction, such as growth hormone and thyroxine, up regulate PGC-1alpha to institute  mitochondrial neogenesis. These two systems are best understood under the metabolic context of equilibrium shifts toward catabolism or toward anabolism. Regenesis is generally associated with increased catabolism, increased mitochondrial NADH to OX/PHOS efficiency and steady state cell quiescence via up regulation of post neogenesis respiratory chain proteins, while neogenesis is mostly associated with increased anabolism, lowered NADH to OX/PHOS mitochondrial efficiency and cell replication,  following up regulation of over a thousand constituent mitochondrial proteins. This general rule is not absolute, due to independent temporal up regulation of different elements of the mitochondrial transcriptome and proteome engendered by neogenesis and regenesis. In short, the notion of full mitochondrial biogenesis is most easily described as a two phase operation, the first phase consisting of the making of more numerous, but inefficient mitochondria (neogenesis), followed by repairing old mitochondria or making those new neogenic mitochondria efficient (regenesis). Killing cancer cells and instituting real life extension is critically dependant upon efficient mitochondria.        

A similar confusion exists around the, so called, caloric restriction mimetic, resveratrol. Under low concentration, in-vivo conditions, its activity is biased toward mitochondrial neogenesis, while in high concentrations, under in vitro conditions, its activity is biased towards mitochondrial regenesis, based upon its double phase and condition pathway impact on PGC-1alpha. Perceiving PGC-1alpha as a temporal toggle switch, with a chronic catabolic default state toward mitochondrial regenesis, under caloric restriction conditions, shows that the enforced default state between necessary rounds of neogenesis, is critical to both life extension and inhibition of the cancer ‘metabotype’. In the neogenesis format, inefficient mitochondrial NADH to OX/PHOS supports anabolic reduction pathways and reactive oxygen species (ROS) production, which accelerates both cancer promotion and aging. Under the mitochondrial regenesis format, ROS induced mitochondrial autophagy destroys dysfunctional mitochondria and increases the NADH to OX/PHOS efficiency of existing mitochondria, which lowers ROS production and supports catabolic oxidation pathways, which favor cancer incidence reduction and life extension. Interestingly, cancer cells are growth factor driven to be in an anabolic and inefficient mitochondrial format. Forcing a mitochondrial efficiency format, via regenesis, just might be the intracellular conflict trigger that institutes high concentration resveratrol induced cancer cell apoptosis. With this new understanding, an extension of our logic applies to a resolving of variable results surrounding the

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