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McCarty M.F.,Catalytic Longevity
Medical Hypotheses | Year: 2014

In many common cancers, production of cAMP boosts cancer proliferation, survival, and aggressiveness, reflecting the fact that, through mechanisms that require further clarification, cAMP can promote tyrosine phosphorylation, notably transactivation of the epidermal growth factor receptor (EGFR). Hormones which activate adenylate cyclase in many cancers include PGE2 - often produced by cox-2 activity within tumors - and adrenergic hormones, acting on beta2 receptors. NSAID cyclooxygenase inhibitors, including low-dose aspirin, clearly reduce risk for many adenocarcinomas, but the impact of cox-2 inhibitors in clinical cancer therapy remains somewhat equivocal. There is increasing evidence that increased sympathetic drive, often reflecting psychic stress or tobacco usage, increases risk for, and promotes the aggressiveness of, many cancers. The non-specific beta antagonist propranolol shows cancer-retardant activity in pre-clinical rodent studies, especially in stressed animals, and a limited amount of epidemiology concludes that concurrent propranolol usage is associated with superior prognosis in breast cancer, ovarian cancer, and melanoma. Epidemiology correlating increased resting heart rate with increased total cancer mortality can be interpreted as compelling evidence that increased sympathetic drive encourages the onset and progression of common cancers. Conversely, hormones which inhibit adenylate cyclase activity in cancers may have potential for cancer control; GABA, which can be administered as a well-tolerated nutraceutical, has potential in this regard. Combination regimens intended to down-regulate cancer cAMP levels, perhaps used in conjunction with EGFR inhibitors, may have considerable potential for suppressing the contribution of cAMP/EGFR to cancer aggressiveness. This model also predicts that certain other hormones which activate adenylate cylase in various tissue may play a yet-unsuspected role in cancer induction and spread. © 2014 Elsevier Ltd.

Third World quasi-vegan cultures have been characterized by low risks for "Western" cancers, autoimmune disorders, obesity, and diabetes. The relatively low essential amino acid contents of many vegan diets may play a role in this regard. It is proposed that such diets modestly activate the kinase GCN2 - a physiological detector of essential amino acid paucity - within the liver, resulting in up-regulated production of fibroblast growth factor 21 (FGF21). FGF21, by opposing the stimulatory effect of growth hormone on hepatic IGF-I production, may be responsible for the down-regulation of plasma IGF-I observed in vegans consuming diets of modest protein content. Decreased IGF-I bioactivity throughout life can be expected to have a favorable impact on cancer risk, as observed in rodents that are calorie restricted or genetically defective in IGF-I activity. Increased FGF21 in vegans might also contribute to their characteristic leanness and low LDL cholesterol by promoting hepatic lipid oxidation while inhibiting lipogenesis. Direct trophic effects of FGF21 on pancreatic beta-cells may help to explain the low risk for diabetes observed in vegans, and the utility of vegan diets in diabetes management. And up-regulation of GCN2 in immune cells, by boosting T regulatory activity, might play some role in the reduced risk for autoimmunity reported in some quasi-vegan cultures. The fact that bone density tends to be no greater in vegans than omnivores, despite consumption of a more "alkaline" diet, might be partially attributable to the fact that FGF21 opposes osteoblastogenesis and decreases IGF-I. If these speculations have merit, it should be possible to demonstrate that adoption of a vegan diet of modest protein content increases plasma FGF21 levels. © 2014 Elsevier Ltd.

McCarty M.F.,Catalytic Longevity
Medical Hypotheses | Year: 2015

Molecular hydrogen (H2) can scavenge hydroxyl radical and diminish the toxicity of peroxynitrite; hence, it has interesting potential for antioxidant protection. Recently, a number of studies have explored the utility of inhaled hydrogen gas, or of hydrogen-saturated water, administered parenterally or orally, in rodent models of pathology and in clinical trials, oftentimes with very positive outcomes. The efficacy of orally ingested hydrogen-rich water (HW) has been particularly surprising, given that only transient and rather small increments in plasma hydrogen can be achieved by this method. A recent study in mice has discovered that orally administered HW provokes increased gastric production of the orexic hormone ghrelin, and that this ghrelin mediates the favorable impact of HW on a mouse model of Parkinson's disease. The possibility that most of the benefits observed with HW in experimental studies are mediated by ghrelin merits consideration. Ghrelin is well known to function as an appetite stimulant and secretagogue for growth hormone, but it influences physiological function throughout the body via interaction with the widely express GHS-R1a receptor. Rodent and, to a more limited extent, clinical studies establish that ghrelin has versatile neuroprotective and cognitive enhancing activity, favorably impacts vascular health, exerts anti-inflammatory activity useful in autoimmune disorders, and is markedly hepatoprotective. The stimulatory impact of ghrelin on GH-IGF-I activity, while potentially beneficial in sarcopenia or cachectic disorders, does raise concerns regarding the long-term impact of ghrelin up-regulation on cancer risk. The impact of ingesting HW water on ghrelin production in humans needs to be evaluated; if HW does up-regulate ghrelin in humans, it may have versatile potential for prevention and control of a number of health disorders. © 2015 Elsevier Ltd.

McCarty M.F.,Catalytic Longevity | DiNicolantonio J.J.,St Lukes Mid America Heart Institute | O'Keefe J.H.,St Lukes Mid America Heart Institute
Medical Hypotheses | Year: 2015

Ketogenic diets are markedly neuroprotective, but the basis of this effect is still poorly understood. Recent studies demonstrate that ketone bodies increase neuronal levels of hypoxia-inducible factor-1α (HIF-1α), possibly owing to succinate-mediated inhibition of prolyl hydroxylase activity. Moreover, there is reason to suspect that ketones can activate Sirt1 in neurons, in part by increasing cytoplasmic and nuclear levels of Sirt1's obligate cofactor NAD(+). Another recent study has observed reduced activity of mTORC1 in the hippocampus of rats fed a ketogenic diet - an effect plausibly attributable to Sirt1 activation. Increased activities of HIF-1 and Sirt1, and a decrease in mTORC1 activity, could be expected to collaborate in the induction of neuronal macroautophagy. Considerable evidence points to moderate up-regulation of neuronal autophagy as a rational strategy for prevention of neurodegenerative disorders; elimination of damaged mitochondria that overproduce superoxide, as well as clearance of protein aggregates that mediate neurodegeneration, presumably contribute to this protection. Hence, autophagy may mediate some of the neuroprotective benefits of ketogenic diets. Brain-permeable agents which activate AMP-activated kinase, such as metformin and berberine, as well as the Sirt1 activator nicotinamide riboside, can also boost neuronal autophagy, and may have potential for amplifying the impact of ketogenesis on this process. Since it might not be practical for most people to adhere to ketogenic diets continuously, alternative strategies are needed to harness the brain-protective potential of ketone bodies. These may include ingestion of medium-chain triglycerides or coconut oil, intermittent ketogenic dieting, and possibly the use of supplements that promote hepatic ketogenesis - notably carnitine and hydroxycitrate - in conjunction with dietary regimens characterized by long daily episodes of fasting or carbohydrate avoidance. © 2015 Elsevier Ltd.

McCarty M.F.,Catalytic Longevity | DiNicolantonio J.J.,Mid America Heart Institute At St Lukes Hospital
Medical Hypotheses | Year: 2015

The recent Trial to Assess Chelation Therapy (TACT) study, enrolling subjects who had previously experienced a myocardial infarction, has provided strong evidence that intravenous chelation therapy can markedly reduce risk for mortality and vascular events in diabetics, whereas no discernible benefit was observed in non-diabetics. It has plausibly been suggested that this reflects a role for transition metal ions - iron or copper - in the genesis of advanced glycation end products, key mediators of diabetic complications that can destabilize plaque. Since phlebotomy therapy fails to prevent vascular events in diabetics, we hypothesize that labile copper may be the chief culprit whose removal by chelation mediated the benefit observed in TACT. If so, strategies less time and labor intensive than chelation therapy might provide comparable benefit. A number of recent studies report that the copper-specific orally-active chelator trientine can reduce risk for range of diabetic complications in rodents; a clinical trial with this agent demonstrated some decrease in left ventricular mass in diabetics with ventricular hypertrophy. However, until this agent becomes less expensive, supplementation with high-dose zinc may represent a more feasible alternative. Zinc opposes the absorption and redox activity of copper via induction of the antioxidant protein metallothionein, which binds copper tightly. A great many studies demonstrate that increased expression of metallothionein decreases risk for tissue damage in diabetic rodents, and in some of these studies metallothionein expression was boosted by supplemental zinc. Zinc supplementation also modestly improves glycemic control in type 2 diabetics, and might reduce risk for diabetes by protecting pancreatic beta cells from oxidative stress. A long term study assessing the impact of supplementing diabetics with high-dose zinc, assessing risk for mortality, vascular events, and diabetic complications, may be warranted. Histidine, which readily forms complexes with copper that possess superoxide dismutase activity, also has potential for alleviating the contribution of loosely bound copper to AGE formation; moreover, in a recent clinical study, supplemental histidine improved insulin sensitivity and exerted anti-inflammatory and antioxidant effects in women with metabolic syndrome. Since ascorbate can reduce labile copper and thereby enhance its pathogenicity, the impact of high-dose ascorbate supplementation on cardiovascular risk in diabetics should receive further study. © 2015 Elsevier Ltd.

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