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11 Jan 2003

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Life Extension

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

The Resveratrol Bioavailability, Caloric Restriction and Life Extension 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 temporally cooperative 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 known as the caloric restriction pathway. Factors extrinsic to caloric restriction, such as growth hormone and thyroxine, up regulate PGC-1alpha to institute mitochondrial neogenesis. The neo/re mitochondrial biogenesis systems are best understood within 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 elevated cell replication, following the 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 (or complete) mitochondrial biogenesis is most appropriately described as a two phase operation. The first phase consists of the making of more numerous, but inefficient, mitochondria (neogenesis). A second phase can follow which consists of repairing old mitochondria or making new neogenic mitochondria efficient (regenesis). Killing cancer cells and instituting real life extension is critically dependant upon efficient mitochondria and, therefore, the regenesis function, because this function reduces the cell replication anabolic reduction drive state supported by excess NADH and elicits the autophagy and apoptosis systems concommittant with the up regulation of the ROS scavenging and ROS reducing regenesis functions of increased mitochondrial anti-oxidant superoxide dismutase (SOD) activity in tandem with the increased efficiency of respiratory transfer of NADH to ATP associated with catabolic drive states.

A similar confusion exists around the so called caloric restriction mimetic, resveratrol. The dividing of full mitochondrial biogenesis into the two phases of neogenesis and regenesis becomes very instructive here. Under low concentration, in-vivo conditions, resulting from oral administration, resveratrol's 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. Once PGC-1alpha is perceived as a temporal toggle switch, with a chronic catabolic default state toward mitochondrial regenesis, under caloric restriction conditions, the enforced default state between necessary rounds of neogenesis is revealed to be 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. The ROS can accelerate both cancer promotion and aging. These two ill effects do not occur with dietary resveratrol because low concentration resveratrol reduces the ROS load with its powerful anti-oxidant function, and its main metabolic stimulation is oriented toward catabolic rather than anabolic pathways, in a kind of caloric restriction meta-mimicry. However, in low bioavailable concentrations, its stimulation of the caloric restriction pathway is minor, if at all. It must be noted that dietary resveratrol continues to show its rejuvenative multiple tissue and organ impacts, although without actual cancer reduction, while having only a weak impact as a caloric restriction mimetic. Average life expectancy increases, but without overall life extension. This has been a real source of consternation to researchers because resveratrol is doing what it apparently cannot do at such low concentrations. The neogenesis concept resolves this conundrum when we later compare variations of mechanisms. A rapid and sure transition from neogenesis to regenesis would insure that both systems are utilized to maximum potential.

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, thereby favoring cancer incidence reduction and life extension. This is the intracellular caloric mimetic pathway induced by high concentration in-vitro resveratrol. Interestingly, cancer cells are growth factor driven to be in an anabolic and inefficient mitochondrial format. Forcing a mitochondrial efficiency format, via some form of regenesis stimulator, just might be the intracellular conflict trigger that institutes a more bioavailable in-vivo resveratrol induced cancer cell apoptosis. Later on, we will describe how a unidirectional ancient bioenergetic regulatory feedback loop, or cycle, consisting of just several regulatory control elements that interact with numerous activators and inhibitors, allows for a mechanistic description that permits us to both resolve many discrepancies and arrive at functional descriptions that provide greater insight.

With this new understanding, an extension of our logic applies to a resolving of variable results surrounding the resveratrol/caloric restriction mimetic debate, and maybe, a better way to utilize resveratrol or other caloric restriction mimetics to achieve more desired in-vivo results. For instance, recent experimental evidence shows that a moderate intermittent fasting protocol is sufficient to yield results comparable to caloric restriction, indicating that there could be a possible regenic behavioral effect synergy with the neogenic dietary resveratrol effect. Work is also afoot on the possibility of micronization, solvation, sub-lingual delivery and homogenization carriers of resveratrol to increase orally administered resveratrol bioavailability. Exercise regimens may also be designed that create an oxygen and/or glucose debt that interacts with the nutrient signaling system that is already known to facilitate a transfer from a neogenic to regenic state. We already know that resveratrol is good for us. But the real extent of the health benefits is only now beginning to surface.

Gregory S. Bambeck Ph.D. e-mail:. gregorybambeck@yahoo.com.

Michael Wolfson J.D., M.B.A. e-mail: mwolfson@stanfordalumni.org

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