Catalytic Longevity

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Catalytic Longevity

Carlsbad, CA, United States
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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.


In type 1 diabetics, hepatic exposure to insulin is chronically subnormal even in the context of insulin therapy; as a result, expression of glycolytic enzymes is decreased, and that of gluconeogenic enzymes is enhanced, resulting in a physiologically inappropriate elevation of hepatic glucose output. Subnormal expression of glucokinase (GK) is of particular importance in this regard. Possible strategies for correcting this perturbation of hepatic enzyme expression include administration of small molecule allosteric activators of GK, as well as a procedure known as chronic intermittent intravenous insulin therapy (CIIIT); however, side effects accompany the use of GK activators, and CIIIT is time and labor intensive. Alternatively, administration of high-dose biotin has potential for modulating hepatic enzyme expression in a favorable way. Studies in rodents and in cultured hepatocytes demonstrate that, in the context of low insulin exposure, supra-physiological levels of biotin induce increased expression of GK while suppressing that of the key gluconeogenic enzyme phosphoenolpyruvate carboxykinase. These effects may be a downstream consequence of the fact that biotin down-regulates mRNA expression of FOXO1; insulin's antagonism of the activity of this transcription factor is largely responsible for its modulatory impact on hepatic glycolysis and gluconeogenesis. Hence, high-dose biotin may compensate for subnormal insulin exposure by suppressing FOXO1 levels. High-dose biotin also has the potential to oppose hepatic steatosis by down-regulating SREBP-1 expression. Two pilot trials of high-dose biotin (16 or 2 mg per day) in type 1 diabetics have yielded promising results. There is also some reason to suspect that high-dose biotin could aid control of diabetic neuropathy and nephropathy via its stimulatory effect on cGMP production. Owing to the safety, good tolerance, moderate expense, and current availability of high-dose biotin, this strategy merits more extensive evaluation in type 1 diabetes. © 2016 Elsevier Ltd


McCarty M.F.,Catalytic Longevity
Hormone Molecular Biology and Clinical Investigation | Year: 2015

Fibroblast growth factor-21(FGF21), produced mainly in hepatocytes and adipocytes, promotes leanness, insulin sensitivity, and vascular health while down-regulating hepatic IGF-I production. Transgenic mice overexpressing FGF21 enjoy a marked increase in median and maximal longevity comparable to that evoked by calorie restriction - but without a reduction in food intake. Transcriptional factors which promote hepatic FGF21 expression include PPARa, ATF4, STAT5, and FXR; hence, fibrate drugs, elevated lipolysis, moderate-protein vegan diets, growth hormone, and bile acids may have potential to increase FGF21 synthesis. Sirt1 activity is required for optimal responsiveness of FGF21 to PPARα, and Sirt1 activators can boost FGF21 transcription. Conversely, histone deacetylase 3 (HDAC3) inhibits PPARα's transcriptional impact on FGF21, and type 1 deacetylase inhibitors such as butyrate therefore increase FGF21 expression. Glucagon-like peptide-1 (GLP-1) increases hepatic expression of both PPARα and Sirt1; acarbose, which increases intestinal GLP-1 secretion, also increases FGF21 and lifespan in mice. Glucagon stimulates hepatic production of FGF21 by increasing the expression of the Nur77 transcription factor; increased glucagon secretion can be evoked by supplemental glycine administered during post-absorptive metabolism. The aryl hydrocarbon receptor (AhR) has also been reported recently to promote FGF21 transcription. Bilirubin is known to be an agonist for this receptor, and this may rationalize a recent report that heme oxygenase-1 induction in the liver boosts FGF21 expression. There is reason to suspect that phycocyanorubin, a bilirubin homolog that is a metabolite of the major phycobilin in spirulina, may share bilirubin's agonist activity for AhR, and perhaps likewise promote FGF21 induction. In the future, regimens featuring a plant-based diet, nutraceuticals, and safe drugs may make it feasible to achieve physiologically significant increases in FGF21 that promote metabolic health, leanness, and longevity.


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.


Increased fasting serum phosphate within the normal physiological range has been linked to increased cardiovascular risk in prospective epidemiology; increased production of fibroblast growth factor 23, and direct vascular effects of phosphate, may mediate this risk. Although dietary phosphate intake does not clearly influence fasting serum phosphate in individuals with normal renal function, increased phosphate intake can provoke a rise in fibroblast growth factor 23, and in diurnal phosphate levels, and hence may adversely influence vascular health. Dietary phosphate absorption can be moderated by emphasizing plant-based dietary choices (which provide phosphate in less bioavailable forms); avoidance of processed foods containing inorganic phosphate food additives; and by ingestion of phosphate-binder drugs, magnesium supplements, or niacin, which precipitate phosphate or suppress its gastrointestinal absorption. The propensity of dietary phosphate to promote vascular calcification may be opposed by optimal intakes of magnesium, vitamin K, and vitamin D; the latter should also counter the tendency of phosphate to elevate parathyroid hormone. © 2014 Elsevier Inc.


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.


McCarty M.F.,Catalytic Longevity | Al-Harbi S.A.,Mahmoud Haidar Medical Center
Medical Hypotheses | Year: 2013

Naturally occurring T regulatory cells targeting epitopes derived from various heat shock proteins escape thymic negative selection and can be activated by vaccination with heat shock proteins; hence, vaccination with such proteins has exerted favorable effects on rodent models of autoimmune disorders. A more elegant way to achieve such vaccination, first evaluated clinically by Al-Harbi in the early 1990s, is to subject mononuclear cells to survivable heat shock ex vivo, incubate them at physiological temperature for a further 24-48. h, and then inject them subcutaneously; anecdotally, beneficial effects were observed with this strategy in a wide range of autoimmune and inflammatory conditions. There is growing evidence that M1-activated microglia play a primary or secondary role in the pathogenesis of numerous neurodegenerative diseases, as well as in major depression. T regulatory cells, by polarizing microglial toward a reparative M2 phenotype, have the potential to aid control of such disorders. It would be appropriate to test the heat-shocked mononuclear cell vaccination strategy in animal models of neurodegeneration and major depression, and to evaluate this approach clinically if such studies yield encouraging results. © 2013 Elsevier Ltd.


McCarty M.F.,Catalytic Longevity | DiNicolantonio J.J.,St Lukes Hospital
Postgraduate Medicine | Year: 2014

Vascular calcification (VC), commonly encountered in renal failure, diabetes, and aging, is associated with a large increase in the risk for cardiovascular events and mortality. Calcification of the arterial media and of heart valves clearly plays a mediating role in this regard, whereas it is less clear how calcification of plaque influences atherogenesis and risk for plaque rupture. Vascular calcification is an active process in which vascular smooth muscle cells (VSMCs) adopt an osteoblastic phenotype and deposit hydroxyapatite crystals; apoptosis of VSMCs also promotes this deposition. Drivers of this phenotypic transition, which include elevated serum phosphate, advanced glycation end-products, bone morphogenetic proteins, inflammatory cytokines, and leptin, invariably induce oxidative stress in VSMCs, which appears to be a necessary and sufficient condition for induction of the runt-related transcription factor 2 gene (RUNX2) and the shift to osteoblastic behavior. Magnesium antagonizes the impact of phosphate on VSMC osteoblastic transition, both by a direct effect within VSMCs and by suppressing absorption of dietary phosphate. Antioxidants that suppress reduced nicotinamide adenine dinucleotide phosphate oxidase activity may have the potential to block the osteoblastic transition of VSMCs. Minimizing the absorption of dietary phosphate may also be helpful in this regard, particularly in renal failure, and it can be achieved with plant-based dietary choices, avoidance of phosphate additives, and administration of pharmaceutical phosphate binders, supplemental magnesium, and niacin. Good vitamin K status opposes VC by optimizing the γ-carboxylation of matrix Gla protein, a physiological antagonist of VC. Adequate but not excessive vitamin D status also appears to discourage VC. Etidronate, a structural analogue of pyrophosphate, has shown potential for blocking VC. © Postgraduate Medicine.


McCarty M.F.,Catalytic Longevity
Age | Year: 2014

AMP-activated kinase (AMPK) is activated when the cellular (AMP+ADP)/ATP ratio rises; it therefore serves as a detector of cellular "fuel deficiency." AMPK activation is suspected to mediate some of the health-protective effects of long-term calorie restriction. Several drugs and nutraceuticals which slightly and safely impede the efficiency of mitochondrial ATP generation - most notably metformin and berberine - can be employed as clinical AMPK activators and, hence, may have potential as calorie restriction mimetics for extending healthspan. Indeed, current evidence indicates that AMPK activators may reduce risk for atherosclerosis, heart attack, and stroke; help to prevent ventricular hypertrophy and manage congestive failure; ameliorate metabolic syndrome, reduce risk for type 2 diabetes, and aid glycemic control in diabetics; reduce risk for weight gain; decrease risk for a number of common cancers while improving prognosis in cancer therapy; decrease risk for dementia and possibly other neurodegenerative disorders; help to preserve the proper structure of bone and cartilage; and possibly aid in the prevention and control of autoimmunity. While metformin and berberine appear to have the greatest utility as clinical AMPK activators - as reflected by their efficacy in diabetes management - regular ingestion of vinegar, as well as moderate alcohol consumption, may also achieve a modest degree of health-protective AMPK activation. The activation of AMPK achievable with any of these measures may be potentiated by clinical doses of the drug salicylate, which can bind to AMPK and activate it allosterically. © 2013 American Aging Association.

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