Technical Bulletin: Life Extension (LE) Map Correctly Predicts Semi-Independent LE Target Synergies.

Gregory S. Bambeck Ph.D. and Michael Wolfson J.D., M.B.A. About a month ago (late July 2011) we published a map of the mutually opposing life extension (LE)/caloric restriction (CR) and cell growth (CG) metabolic pathways, i.e. LE/CR vs. CG, in our article entitled Life Extension Metabolic Pathway Map Reveals New Phytonutrient Candidates, which is available on the internet. Up to the present time, the only existing molecules to mimic true LE via the CR metabolic pathway have been the pharmaceuticals metformin and rapamycin, and possibly the phytonutrients curcumin, silibinin and resveratrol. Except for rapamycin, all the above listed molecules down regulate target of rapamycin (TOR) through the activation of the nutrient energy sensor adenosine monophosphate kinase (AMPK), while rapamycin stands alone as a direct TOR suppressor. The CG and LE/CR pathways operate in functional opposition to one another primarily by having antagonistic impacts upon TOR. For instance, CG activates TOR and institutes accelerated anabolism and catabolic nutrient utilization energy production inefficiency, while conversely, an activated LE/CR pathway suppresses TOR and institutes anabolic inhibition and efficient energy production catabolic frugality. CG pathway activation and/or LE/CR pathway inactivation dramatically increase(s) the risk and severity of the three major diseases of aging, while CR activation, using mimetics or CR, dramatically reduces the probability of these disease states, and promote LE. Unfortunately, all of the known LE/CR mimicry molecules activate the CR pathway and only suppress the CG pathway weakly and indirectly via cross pathway regulators. Although LE/CR mimetics do increase LE, they do so less than half as much as CR itself. In our article, we proposed that this is so because CR pathway mimicry is not equivalent to CR because it is not accompanied by nutrient fuel restriction, thereby

not being fully capable of deactivating highly fuel supplied CG drive states, as suggested by our unified dual metabolic pathway map. In our paper, we suggested that inhibiting the CG pathway at, or near the many cell growth factor common regulatory bottleneck at the protein kinase AKT (AKT) would cause cells to operate as if calorically restricted, even when abundant fuel is present. We proposed that inhibition of the CG pathway at, or near AKT would act as a semiindependent and/or additional LE factor. We also proposed that CG inhibitors used with known CR pathway activators would result in a more realistic CR mimicry, and therefore, a more impactful LE effect approaching that of genuine CR. We listed soy genistein and white/green tea EGCG as possible natural AKT inhibiting, and therefore CG inhibiting CR/LE adjuvants that could assist existing known CR mimetics. As serendipity would have it, an editors choice synopsis in the August 5, 2011 issue of Science gives strong credence to our LE vs. aging disease global unifying metabolic singularity hypothesis. In their synopsis, Science notes that SIRT1 to AKT blocking independently institutes LE, inhibits formation of cardiac hypertrophy and decreases cell growth rate in tumors, as strongly stated by our hypothesis, and as we applied it to the diseases of aging. They further note that inhibition of SIRT1 deacetylase keeps a still acetylated AKT in check, and that an activated SIRT1 deacetylated AKT has the exact opposite effects. This strongly suggests that CG suppression with LE/CR activation would be, as we continue to predict, synergistic. These data also help to resolve the conflicting results surrounding the impact of SIRT1 on the LE/CR pathway, particularly as it relates to the LE/CR pathway mimetics and their mechanisms associated with AMPK, as argued between the pharmaceutical giants Pfizer and Glaxo about a year and a half ago. This is not the first time that our LE and diseases of aging unifying metabolic hypothesis has either properly contextualized recent discoveries, resolved theoretical metabolic conflicts or predicted them as

soon to be discovered. In previous papers, we even predicted that mainstream science would reverse a half century old cancer metabolism dogma, which it did, in December of 2010. We would strongly suggest that interested parties read our aforementioned life extension metabolic map paper, as this paper has shown itself to be remarkably coherent, consistent and realistic in integrating these new concepts, discoveries and revolutions. Its narrative also contains a listing of appropriately pathway activating and inhibiting food supplements that should have life extending and anti-aging disease merit against the three greatest killers of humanity, which in turn, are also defined in terms of the metabolic map that is included within the paper. It appears that we may soon be able to add LE/anti-CG mimetics to our LE/CR mimetics, and our other newly coined lexicon of terms. It is said that a true hypothesis predicts well, and it looks like we might really have something.

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Gregory S. Bambeck Ph.D., e-mail: gregorybambeck@yahoo.com Michael Wolfson J.D., M.B.A., e-mail: mwolfson@stanfordalumni.com Copyright by Gregory S. Bambeck and Michael Wolfson, August 17, 2011