Categories:

Protective Glycine

Also see:
Gelatin, stress, longevity
Thyroid peroxidase activity is inhibited by amino acids
Gelatin, Glycine, and Metabolism
Gelatin > Whey
Health Benefits of Glycine
Gelatin, stress, longevity
The anticatabolic effect of glycine
Enzyme to Know: Tryptophan Hydroxylase
Whey, Tryptophan, & Serotonin
Omega -3 “Deficiency” Decreases Serotonin Producing Enzyme
Hypothyroidism and Serotonin
Estrogen Increases Serotonin
Role of Serotonin in Preeclampsia
Maternal Ingestion of Tryptophan and Cancer in Female Offspring
Tryptophan Metabolism: Effects of Progesterone, Estrogen, and PUFA
Anti-Serotonin, Pro-Libido

“The selection of proteins should minimize the amino acids tryptophan (which is the precursor of serotonin) and cysteine (which, like tryptophan, suppresses thyroid function, by including gelatin and fruits. Gelatin is 22% glycine, which protects the lungs and other organs against toxins and inflammatory agents, and many fruits are “deficient” in tryptophan and cysteine.” -Ray Peat, PhD

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Am J Physiol. 1999 Nov;277(5 Pt 1):L952-9.
Production of superoxide and TNF-alpha from alveolar macrophages is blunted by glycine.
Wheeler MD, Thurman RG.
Glycine blunts lipopolysaccharide (LPS)-induced increases in intracellular calcium concentration ([Ca(2+)](i)) and tumor necrosis factor-alpha (TNF-alpha) production by Kupffer cells through a glycine-gated chloride channel. Alveolar macrophages, which have a similar origin as Kupffer cells, play a significant role in the pathogenesis of several lung diseases including asthma, endotoxemia, and acute inflammation due to inhaled bacterial particles and dusts. Therefore, studies were designed here to test the hypothesis that alveolar macrophages could be inactivated by glycine via a glycine-gated chloride channel. The ability of glycine to prevent endotoxin [lipopolysaccharide (LPS)]-induced increases in [Ca(2+)](i) and subsequent production of superoxide and TNF-alpha in alveolar macrophages was examined. LPS caused a transient increase in intracellular calcium to nearly 200 nM, with EC(50) values slightly greater than 25 ng/ml. Glycine, in a dose-dependent manner, blunted the increase in [Ca(2+)](i), with an IC(50) less than 100 microM. Like the glycine-gated chloride channel in the central nervous system, the effects of glycine on [Ca(2+)](i) were both strychnine sensitive and chloride dependent. Glycine also caused a dose-dependent influx of radiolabeled chloride with EC(50) values near 10 microM, a phenomenon which was also inhibited by strychnine (1 microM). LPS-induced superoxide production was also blunted in a dose-dependent manner by glycine and was reduced approximately 50% with 10 microM glycine. Moreover, TNF-alpha production was also inhibited by glycine and also required nearly 10 microM glycine for half-inhibition. These data provide strong pharmacological evidence that alveolar macrophages contain glycine-gated chloride channels and that their activation is protective against the LPS-induced increase in [Ca(2+)](i) and subsequent production of toxic radicals and cytokines.

Am J Physiol Regul Integr Comp Physiol. 2004 Dec;287(6):R1387-93. Epub 2004 Aug 26.
Glycine intake decreases plasma free fatty acids, adipose cell size, and blood pressure in sucrose-fed rats.
El Hafidi M, Pérez I, Zamora J, Soto V, Carvajal-Sandoval G, Baños G.
The study investigated the mechanism by which glycine protects against increased circulating nonesterified fatty acids (NEFA), fat cell size, intra-abdominal fat accumulation, and blood pressure (BP) induced in male Wistar rats by sucrose ingestion. The addition of 1% glycine to the drinking water containing 30% sucrose, for 4 wk, markedly reduced high BP in sucrose-fed rats (SFR) (122.3 +/- 5.6 vs. 147.6 +/- 5.4 mmHg in SFR without glycine, P < 0.001). Decreases in plasma triglyceride (TG) levels (0.9 +/- 0.3 vs. 1.4 +/- 0.3 mM, P < 0.001), intra-abdominal fat (6.8 +/- 2.16 vs. 14.8 +/- 4.0 g, P < 0.01), and adipose cell size were observed in SFR treated with glycine compared with SFR without treatment. Total NEFA concentration in the plasma of SFR was significantly decreased by glycine intake (0.64 +/- 0.08 vs. 1.11 +/- 0.09 mM in SFR without glycine, P < 0.001). In control animals, glycine decreased glucose, TGs, and total NEFA but without reaching significance. In SFR treated with glycine, mitochondrial respiration, as an indicator of the rate of fat oxidation, showed an increase in the state IV oxidation rate of the beta-oxidation substrates octanoic acid and palmitoyl carnitine. This suggests an enhancement of hepatic fatty acid metabolism, i.e., in their transport, activation, or beta-oxidation. These findings imply that the protection by glycine against elevated BP might be attributed to its effect in increasing fatty acid oxidation, reducing intra-abdominal fat accumulation and circulating NEFA, which have been proposed as links between obesity and hypertension.

Am J Physiol Lung Cell Mol Physiol. 2000 Aug;279(2):L390-8.
Dietary glycine blunts lung inflammatory cell influx following acute endotoxin.
Wheeler MD, Rose ML, Yamashima S, Enomoto N, Seabra V, Madren J, Thurman RG.
Mortality associated with endotoxin shock is likely mediated by Kupffer cells, alveolar macrophages, and circulating neutrophils. Acute dietary glycine prevents mortality and blunts increases in serum tumor necrosis factor-alpha (TNF-alpha) following endotoxin in rats. Furthermore, acute glycine blunts activation of Kupffer cells, alveolar macrophages, and neutrophils by activating a glycine-gated chloride channel. However, in neuronal tissue, glycine rapidly downregulates chloride channel function. Therefore, the long-term effects of a glycine-containing diet on survival following endotoxin shock were investigated. Dietary glycine for 4 wk improved survival after endotoxin but did not improve liver pathology, decrease serum alanine transaminase, or effect TNF-alpha levels compared with animals fed control diet. Interestingly, dietary glycine largely prevented inflammation and injury in the lung following endotoxin. Surprisingly, Kupffer cells from animals fed glycine for 4 wk were no longer inactivated by glycine in vitro; however, isolated alveolar macrophages and neutrophils from the same animals were sensitive to glycine. These data are consistent with the hypothesis that glycine downregulates chloride channels on Kupffer cells but not on alveolar macrophages or neutrophils. Importantly, glycine diet for 4 wk protected against lung inflammation due to endotoxin. Chronic glycine improves survival by unknown mechanisms, but reduction of lung inflammation is likely involved.

Glycine protects against fat accumulation in the alcohol-induced liver injury (Senthilkumar, et al., 2003), suggesting that dietary gelatin would complement the protective effects of saturated fats. -Ray Peat, PhD

Both proline and glycine (which are major amino acids in gelatin) are very protective for the liver, increasing albumin, and stopping oxidative damage. -Ray Peat, PhD

Pol J Pharmacol. 2003 Jul-Aug;55(4):603-11.
Glycine modulates hepatic lipid accumulation in alcohol-induced liver injury.
Senthilkumar R, Viswanathan P, Nalini N.
We studied the effect of administering glycine, a non-essential amino acid, on serum and tissue lipids in experimental hepatotoxic Wistar rats. All the rats were fed standard pellet diet. Hepatotoxicity was induced by administering ethanol (7.9 g kg(-1)) for 30 days by intragastric intubation. Control rats were given isocaloric glucose solution. Glycine was subsequently administered at a dose of 0.6 g kg(-1) every day by intragastric intubation for the next 30 days. Average body weight gain at the end of the total experimental period of 60 days was significantly lower in rats supplemented with alcohol, but improved on glycine treatment. Feeding alcohol significantly elevated the levels of cholesterol, phospholipids, free fatty acids and triglycerides in the serum, liver and brain as compared with those of the control rats. Subsequent glycine supplementation to alcohol-fed rats significantly lowered the serum and tissue lipid levels to near those of the control rats. Microscopic examination of alcohol-treated rat liver showed inflammatory cell infiltrates and fatty changes, which were alleviated on treatment with glycine. Alcohol-treated rat brain demonstrated edema, which was significantly lowered on treatment with glycine. In conclusion, this study shows that oral administration of glycine to alcohol-supplemented rats markedly reduced the accumulation of cholesterol, phospholipids, free fatty acids and triglycerides in the circulation, liver and brain, which was associated with a reversal of steatosis in the liver and edema in the brain.

Eur Rev Med Pharmacol Sci. 2012 Jun;16(6):728-36.
Glycine alleviates liver injury induced by deficiency in methionine and or choline in rats.
Barakat HA, Hamza AH.
OBJECTIVES:
Nonalcoholic steatohepatitis (NASH) is an advanced stage of non-alcoholic fatty liver disease (NAFLD) from steatosis. Methionine and choline are important amino acids play a key role in many cellular functions. Glycine is a non-essential amino acid having multiple roles in many reactions. This study aimed to investigate liver damage induced by feeding male albino rats either methionine deficient (MD), choline deficient (CD), or MCD diets. And to clarify the alleviatory effect of dietary glycine supplementation (5%) on reduced complications caused by feeding each of the deficient diets.
MATERIAL AND METHODS:
Nutritional status, liver functions, lipids profile, hepatic oxidative stress, hepatic antioxidant enzymes, tumor markers and hepatic fatty acid transport protein gene were assessed.
RESULTS:
Rats fed with either MD or MCD diet had less body weight gain unlike rats fed the CD diet. Liver injury was detected in deficient groups by elevating plasma ALT, AST, ALP, total and direct bilirubin, albumin and protein levels. Lipid accumulation was more prominent in rats fed the MCD or CD diet than in those fed the MD diet. Fatty acid transport protein (FATP) was significantly elevated in the different glycine supplemented groups.
CONCLUSION:
Oral administration of glycine confers a significant protective effect by optimizing all the assessed parameters and gene expression.

Hepatology. 2000 Sep;32(3):542-6.
Glycine prevents apoptosis of rat sinusoidal endothelial cells caused by deprivation of vascular endothelial growth factor.
Zhang Y, Ikejima K, Honda H, Kitamura T, Takei Y, Sato N.
Apoptosis of sinusoidal endothelial cells (SECs) is one of the initial events in the development of ischemia-reperfusion injury of the liver. Glycine has been shown to diminish ischemia-reperfusion injury in the liver and improve graft survival in the rat liver transplantation model. Here, we investigated the effect of glycine on apoptosis of primary cultured rat SECs induced by vascular endothelial growth factor (VEGF) deprivation. Isolated rat SECs were cultured in EBM-2 medium supplemented with 10% fetal bovine serum (FBS) and growth factors including 20 ng/mL VEGF for 3 days. SECs at 3 days of culture showed spindle-like shapes; however, cells started shrinking and detaching from dishes by VEGF deprivation. Apoptosis was detected by terminal deoxynucleotidyl transferase (TdT)-mediated d-uridine triphosphate (dUTP)-biotin nick end labeling (TUNEL) staining in these conditions. Control SECs contained only a few percent of TUNEL-positive cells; however, they started increasing 4 hours after VEGF deprivation, and the percentage of TUNEL-positive cells reached about 50% at 8 hours and almost 100% at 16 hours after VEGF deprivation. Interestingly, this increase in TUNEL-positive cells after VEGF deprivation was prevented significantly when glycine (1-10 mmol/L) was added to the medium, the levels being around 60% of VEGF deprivation without glycine. Furthermore, strychnine (1 micromol/L), a glycine receptor antagonist, inhibited this effect of glycine, suggesting the possible involvement of the glycine receptor/chloride channel in the mechanism. Moreover, Bcl-2 protein levels in SECs were decreased 8 hours after VEGF deprivation, which was prevented almost completely by glycine. It is concluded that glycine prevents apoptosis of primary cultured SECs under VEGF deprivation.

Glycine, like carbon dioxide, protects proteins against oxidative damage (Lezcano, et al., 2006), so including gelatin (very rich in glycine) in the diet is probably protective. -Ray Peat, PhD

Rev Alerg Mex. 2006 Nov-Dec;53(6):212-6.
Effect of glycine on the immune response of the experimentally diabetic rats.
Lezcano Meza D, Terán Ortiz L, Carvajal Sandoval G, Gutiérrez de la Cadena M, Terán Escandón D, Estrada Parra S.
BACKGROUND:
Hyperglycemia induces protein glycation, disturbing its function, additionally, the glycated products (AGEs) induce by themselves proinflammatory cytokine release that are responsible for insulin resistance. Glycine has been successfully used in diabetic patients to competitively reduce hemoglobin glycation.
OBJECTIVES:
To assess hyperglycemia impact on the immune response and to evaluate if it is possible to reverse it by means of glycine administration.
MATERIAL AND METHODS:
Streptozotocin-induced diabetic rats, with and without glycine administration were challenged with sheep red blood cells, and specific antibody producing cells were accounted. Normal rats were challenged as controls.
RESULTS:
Induced diabetes modifies significantly the humoral immune response capacity versus sheep red blood cells. Also, glycine administration prevents against this deleterious effect.
CONCLUSIONS:
Glycine could be an important therapeutic resource among diabetics to avoid the characteristic immunodeficiencies of this disease.

Infect Immun. 2001 Sep;69(9):5883-91.
Dietary glycine prevents peptidoglycan polysaccharide-induced reactive arthritis in the rat: role for glycine-gated chloride channel.
Li X1, Bradford BU, Wheeler MD, Stimpson SA, Pink HM, Brodie TA, Schwab JH, Thurman RG.
Peptidoglycan polysaccharide (PG-PS) is a primary structural component of bacterial cell walls and causes rheumatoid-like arthritis in rats. Recently, glycine has been shown to be a potential immunomodulator; therefore, the purpose of this study was to determine if glycine would be protective in a PG-PS model of arthritis in vivo. In rats injected with PG-PS intra-articularly, ankle swelling increased 21% in 24 to 48 h and recovered in about 2 weeks. Three days prior to reactivation with PG-PS given intravenously (i.v.), rats were divided into two groups and fed a glycine-containing or nitrogen-balanced control diet. After i.v. PG-PS treatment joint swelling increased 2.1 +/- 0.3 mm in controls but only 1.0 +/- 0.2 mm in rats fed glycine. Infiltration of inflammatory cells, edema, and synovial hyperplasia in the joint were significantly attenuated by dietary glycine. Tumor necrosis factor alpha (TNF-alpha) mRNA was detected in ankle homogenates from rats fed the control diet but not in ankles from rats fed glycine. Moreover, intracellular calcium was increased significantly in splenic macrophages treated with PG-PS; however, glycine blunted the increase about 50%. The inhibitory effect of glycine was reversed by low concentrations of strychnine or chloride-free buffer, and it increased radiolabeled chloride influx nearly fourfold, an effect also inhibited by strychnine. In isolated splenic macrophages, glycine blunted translocation of the p65 subunit of NF-kappaB into the nucleus, superoxide generation, and TNF-alpha production caused by PG-PS. Further, mRNA for the beta subunit of the glycine receptor was detected in splenic macrophages. This work supports the hypothesis that glycine prevents reactive arthritis by blunting cytokine release from macrophages by increasing chloride influx via a glycine-gated chloride channel.

Clin Nutr. 2014 Jun;33(3):448-58. doi: 10.1016/j.clnu.2013.06.013. Epub 2013 Jun 26.
Glycine administration attenuates skeletal muscle wasting in a mouse model of cancer cachexia.
Ham DJ1, Murphy KT1, Chee A1, Lynch GS1, Koopman R2.
BACKGROUND AND AIMS:
The non-essential amino acid, glycine, is often considered biologically neutral, but some studies indicate that it could be an effective anti-inflammatory agent. Since inflammation is central to the development of cancer cachexia, glycine supplementation represents a simple, safe and promising treatment. We tested the hypothesis that glycine supplementation reduces skeletal muscle inflammation and preserves muscle mass in tumor-bearing mice.
METHODS:
To induce cachexia, CD2F1 mice received a subcutaneous injection of PBS (control, n = 12) or C26 tumor cells (n = 32) in accordance with the protocols developed by Murphy et al. [Murphy KT, Chee A, Trieu J, Naim T, Lynch GS. Importance of functional and metabolic impairments in the characterization of the C-26 murine model of cancer cachexia. Dis Models Mech 2012;5(4):533-545.]. Subcutaneous injections of glycine (n = 16) or PBS (n = 16) were administered daily for 21 days and at the conclusion of treatment, selected muscles, tumor and adipose tissue were collected and prepared for Real-Time RT-PCR or western blot analysis.
RESULTS:
Glycine attenuated the loss of fat and muscle mass, blunted increases in markers of inflammation (F4/80, P = 0.01 & IL-6 mRNA, P = 0.01) and atrophic signaling (MuRF, P = 0.047; atrogin-1, P = 0.04; LC3B, P = 0.06 and; BNIP3, P = 0.10) and tended to attenuate the loss of body mass (P = 0.07), muscle function (P = 0.06), and oxidative stress (GSSG/GSH, P = 0.06 and DHE, P = 0.07) seen in tumor-bearing mice. Preliminary studies that compared the effect of glycine administration with isonitrogenous doses of alanine or citrulline showed that the observed protective effect was specific to glycine.
CONCLUSIONS:
Glycine protects skeletal muscle from cancer-induced wasting and loss of function, reduces the oxidative and inflammatory burden, and reduces the expression of genes associated with muscle protein breakdown in cancer cachexia. Importantly, these effects were glycine specific.

Front Neurol. 2012 Apr 18;3:61. doi: 10.3389/fneur.2012.00061. eCollection 2012.
The effects of glycine on subjective daytime performance in partially sleep-restricted healthy volunteers.
Bannai M1, Kawai N, Ono K, Nakahara K, Murakami N.
Approximately 30% of the general population suffers from insomnia. Given that insomnia causes many problems, amelioration of the symptoms is crucial. Recently, we found that a non-essential amino acid, glycine subjectively and objectively improves sleep quality in humans who have difficulty sleeping. We evaluated the effects of glycine on daytime sleepiness, fatigue, and performances in sleep-restricted healthy subjects. Sleep was restricted to 25% less than the usual sleep time for three consecutive nights. Before bedtime, 3 g of glycine or placebo were ingested, sleepiness, and fatigue were evaluated using the visual analog scale (VAS) and a questionnaire, and performance were estimated by personal computer (PC) performance test program on the following day. In subjects given glycine, the VAS data showed a significant reduction in fatigue and a tendency toward reduced sleepiness. These observations were also found via the questionnaire, indicating that glycine improves daytime sleepiness and fatigue induced by acute sleep restriction. PC performance test revealed significant improvement in psychomotor vigilance test. We also measured plasma melatonin and the expression of circadian-modulated genes expression in the rat suprachiasmatic nucleus (SCN) to evaluate the effects of glycine on circadian rhythms. Glycine did not show significant effects on plasma melatonin concentrations during either the dark or light period. Moreover, the expression levels of clock genes such as Bmal1 and Per2 remained unchanged. However, we observed a glycine-induced increase in the neuropeptides arginine vasopressin and vasoactive intestinal polypeptide in the light period. Although no alterations in the circadian clock itself were observed, our results indicate that glycine modulated SCN function. Thus, glycine modulates certain neuropeptides in the SCN and this phenomenon may indirectly contribute to improving the occasional sleepiness and fatigue induced by sleep restriction.

The FASEB Journal. 2011;25:528.2
Dietary glycine supplementation mimics lifespan extension by dietary methionine restriction in Fisher 344 rats
Joel Brind, Virginia Malloy, Ines Augie, Nicholas Caliendo, Joseph H Vogelman, Jay A. Zimmerman, and Norman Orentreich
Dietary methionine (Met) restriction (MR) extends lifespan in rodents by 30–40% and inhibits growth. Since glycine is the vehicle for hepatic clearance of excess Met via glycine N-methyltransferase (GNMT), we hypothesized that dietary glycine supplementation (GS) might produce biochemical and endocrine changes similar to MR and also extend lifespan. Seven-week-old male Fisher 344 rats were fed diets containing 0.43% Met/2.3% glycine (control fed; CF) or 0.43% Met/4%, 8% or 12% glycine until natural death. In 8% or 12% GS rats, median lifespan increased from 88 weeks (w) to 113 w, and maximum lifespan increased from 91 w to 119 w v CF. Body growth reduction was less dramatic, and not even significant in the 8% GS group. Dose-dependent reductions in several serum markers were also observed. Long-term (50 w) 12% GS resulted in reductions in mean (±SD) fasting glucose (158 ± 13 v 179 ± 46 mg/dL), insulin (0.7 ± 0.4 v 0.8 ± 0.3 ng/mL), IGF-1 (1082 ± 128 v 1407 ± 142 ng/mL) and triglyceride (113 ± 31 v 221 ± 56 mg/dL) levels compared to CF. Adiponectin, which increases with MR, did not change in GS after 12 w on diet. We propose that more efficient Met clearance via GNMT with GS could be reducing chronic Met toxicity due to rogue methylations from chronic excess methylation capacity or oxidative stress from generation of toxic by-products such as formaldehyde. This project received no outside funding.

J Am Heart Assoc. 2015 Dec 31;5(1). pii: e002621. doi: 10.1161/JAHA.115.002621.
Plasma Glycine and Risk of Acute Myocardial Infarction in Patients With Suspected Stable Angina Pectoris.
Ding Y, Svingen GF, Pedersen ER, Gregory JF, Ueland PM, Tell GS, Nygård OK.
Abstract
BACKGROUND:
Glycine is an amino acid involved in antioxidative reactions, purine synthesis, and collagen formation. Several studies demonstrate inverse associations of glycine with obesity, hypertension, and diabetes mellitus. Recently, glycine-dependent reactions have also been linked to lipid metabolism and cholesterol transport. However, little evidence is available on the association between glycine and coronary heart disease. Therefore, we assessed the association between plasma glycine and acute myocardial infarction (AMI).
METHODS AND RESULTS:
A total of 4109 participants undergoing coronary angiography for suspected stable angina pectoris were studied. Cox regression was used to estimate the association between plasma glycine and AMI, obtained via linkage to the CVDNOR project. During a median follow-up of 7.4 years, 616 patients (15.0%) experienced an AMI. Plasma glycine was higher in women than in men and was associated with a more favorable baseline lipid profile and lower prevalence of obesity, hypertension, and diabetes mellitus (all P<0.001). After multivariate adjustment for traditional coronary heart disease risk factors, plasma glycine was inversely associated with risk of AMI (hazard ratio per SD: 0.89; 95% CI, 0.82-0.98; P=0.017). The inverse association was generally stronger in those with apolipoprotein B, low-density lipoprotein cholesterol, or apolipoprotein A-1 above the median (all Pinteraction≤0.037).
CONCLUSIONS:
Plasma glycine was inversely associated with risk of AMI in patients with suspected stable angina pectoris. The associations were stronger in patients with apolipoprotein B, low-density lipoprotein cholesterol, or apolipoprotein A-1 levels above the median. These results motivate further studies to elucidate the relationship between glycine and lipid metabolism, in particular in relation to cholesterol transport and atherosclerosis.

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By Team FPS – June 29, 2012

Estrogen’s Role in Seizures

Also see:
Estrogen, Progesterone, and Epilepsy: What’s the Relationship?
Menstrual Cycle Related Epilepsy (Catamenial Epilepsy)
The Brain – Estrogen’s Harm and Progesterone’s Protection
Estrogen, Glutamate, & Free Fatty Acids
Women, Estrogen, and Circulating DHA
Brain Swelling Induced by Polyunsaturated Fats (PUFA)
Fish Oil Toxicity
PUFA, Fish Oil, and Alzheimers
The Randle Cycle

“Seizures are known to be promoted by estrogen, by unsaturated fats, and by lipid peroxidation, and to cause an increase in the size of the free fatty acid pool in the brain. Prolonged seizures cause nerve damage in certain areas, especially the hippocampus, thalamus, and neocortex (Siesjo, et al., 1989). Dementia is known to be produced by prolonged seizures.” -Ray Peat, PhD

“If progesterone’s antiepileptic effectiveness were not enough (and it is very effective even in irrational pharmaceutical formulations), the fact that it reduces birth defects, and promotes brain development and nerve repair should assure its general use in women with a history of seizures, until it is established that they are no longer “epileptic.” Although thyroid, progesterone, and a high quality protein diet will generally correct the epilepsy problem, it is important to mention that the involvement of unsaturated fats and free radicals in seizure physiology implies that we should minimize our consumption of the unsaturated fats. Even years after eliminating them from the diet, their release from tissue storage can prolong the problem, and during that time the use of vitamin E is likely to reduce the intensity and frequency of seizures. Coconut oil lowers the requirement for vitamin E, and reduces the toxicity of the unsaturated fats (see Cleland, et al.), favoring effective respiration and improving thyroid and progesterone production. Endotoxin formed in the bowel can block respiration and cause hormone imbalances contributing to instability of the nerves, so it is helpful to optimize bowel flora, for example with a carrot salad; a dressing of vinegar, coconut oil and olive oil, carried into the intestine by the carrot fiber, suppresses bacterial growth while stimulating healing of the wall of the intestine. The carrot salad improves the ratio of progesterone to estrogen and cortisol, and so is as appropriate for epilepsy as for premenstrual syndrome, insomnia, or arthritis.” -Ray Peat, PhD

Endocrinology. 1992 Aug;131(2):662-8.
Estradiol selectively regulates agonist binding sites on the N-methyl-D-aspartate receptor complex in the CA1 region of the hippocampus.
Weiland NG.
Estradiol alters cognitive function and lowers the threshold for seizures in women and laboratory animals. Both of these activities are modulated by the excitatory neurotransmitter glutamate in the hippocampus. To assess the hypothesis that estradiol increases the sensitivity of the hippocampus to glutamate activation by increasing glutamate binding sites, the densities of N-methyl-D-aspartate (NMDA) agonist sites (determined by NMDA displaced glutamate), competitive antagonist sites (CGP 39653), noncompetitive antagonist sites (MK801) as well as the non-NMDA glutamate receptors for kainate and AMPA (using kainate and CNQX, respectively) were measured using autoradiographic procedures. Two days of estradiol treatment increased the density of NMDA agonist, but not of competitive nor noncompetitive NMDA antagonist binding sites exclusively in the CA1 region of the hippocampus. The density of noncompetitive NMDA antagonist sites, however, was decreased in the dentate gyrus by estradiol treatment. Ovarian steroids had no effect on the density of kainate or AMPA receptors in any region of the hippocampus examined. These data indicate that the agonist and antagonist binding sites on the NMDA receptor/ion channel complex are regulated independently by an as yet unidentified mechanism, and that this regulation exhibits regional specificity in the hippocampus. The increase in NMDA agonist sites with ovarian hormone treatment should result in an increase in the sensitivity of the hippocampus to glutamate activation which may mediate some of the effects of estradiol on learning and epileptic seizure activity.

Epilepsia. 1985 May-Jun;26(3):252-7.
Comparative effects of estradiol benzoate, the antiestrogen clomiphene citrate, and the progestin medroxyprogesterone acetate on kainic acid-induced seizures in male and female rats.
Nicoletti F, Speciale C, Sortino MA, Summa G, Caruso G, Patti F, Canonico PL.
We have investigated the comparative effects of estradiol benzoate (EB), the antiestrogen clomiphene citrate (CC), and the progestin medroxyprogesterone acetate (MPA) on seizures induced by systemic injection of kainic acid (15 mg/kg i.p.) in male and female rats. Subcutaneous administration for 10 days of EB (10 micrograms/kg) or high doses of CC (50 mg/kg) significantly potentiated kainate-induced seizures, with this effect being more pronounced in male animals. Doses of 2.5 mg/kg of CC potentiated kainate-induced seizures in male rats but were ineffective in female rats. Low doses of CC (0.5 mg/kg) exhibited a mild anticonvulsant effect in both sexes. Repeated administration of MPA (2.5 mg/kg) partially protected female animals against kainate-induced seizures; in male animals, MPA induced a 30% increase in the seizure severity score, although the difference from the score of control male rats was not significant. These data suggest that sex steroids influence kainate-induced seizures in a sex-dependent manner and that the effects of the antiestrogen CC are dose dependent. This should be taken into account in view of a possible use of CC and MPA in hormonal therapy for seizure disorders.

Epilepsia. 2000 May;41(5):510-5.
Estradiol facilitates kainic acid-induced, but not flurothyl-induced, behavioral seizure activity in adult female rats.
Woolley CS.
PURPOSE:
This study was designed to determine whether previously demonstrated increases in hippocampal axospinous synapse density and NMDA receptor function induced by estradiol are paralleled by increased susceptibility to limbic (kainic acid induced) or generalized (flurothyl induced) behavioral seizures.
METHODS:
Kainic acid was injected systemically to ovariectomized adult female rats treated with either estradiol or oil vehicle. The latencies to each of five stages of seizure-related behaviors (staring, wet-dog shakes, head waving and chewing, forelimb clonus, rearing, and falling) were recorded for each animal. Flurothyl was administered by inhalation to ovariectomized adult female rats treated with estradiol alone, estradiol followed by short-term progesterone, or oil vehicle. The latencies to each of three stages of seizure-related behaviors (first myoclonic jerk, forelimb clonus, wild running and bouncing) were recorded for each animal.
RESULTS:
Estradiol treatment decreased the latency to seizure-related behaviors induced by kainic acid, but neither estradiol alone nor estradiol followed by progesterone had any effect on flurothyl-induced seizure-related behaviors.
CONCLUSIONS:
The same estradiol treatment paradigm known to induce structural and functional changes in the excitatory circuitry of the hippocampus facilitates the progression of kainic acid-induced seizures, which are known to involve the hippocampus, but has no effect on flurothyl-induced seizures. The lack of an effect of estradiol alone or estradiol followed by progesterone on flurothyl-induced seizures indicates that estradiol’s effects on seizure susceptibility do not result from increased neuronal excitability throughout the brain, but rather involve action within the limbic system. The data suggest that structural and functional changes in hippocampal circuitry induced by estradiol may contribute to increased susceptibility to limbic seizure activity.

Epilepsy Res. 1993 May;15(1):47-52.
Patterns of seizure occurrence in catamenial epilepsy.
Herkes GK, Eadie MJ, Sharbrough F, Moyer T.
The pattern of seizure occurrence was analysed over 44 menstrual cycles in 12 epileptic women who considered they had menstrually related seizures. Two peaks in the daily seizure rate were apparent. A significant increase in seizures occurred during the days of menstrual flow and the two days preceding it, with a second peak in the four days at midcycle. The lowest seizure rate was in the late phase of the menstrual cycle. Daily salivary progesterone levels were assayed in 11 women, and 12 ovulatory and eight anovulatory cycles were identified on this basis. No increase in seizures occurred at midcycle if ovulation did not occur, but the perimenstrual increase took place irrespective of ovulatory status.

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By Team FPS – June 29, 2012

Estrogen’s Role in Asthma

Also see:
Phospholipases, PUFA, and Inflammation
Unsaturated Fats and Lung Function
Women, Estrogen, and Circulating DHA

Am J Respir Crit Care Med. 1995 Oct;152(4 Pt 1):1183-8.
Menopause, postmenopausal estrogen preparations, and the risk of adult-onset asthma. A prospective cohort study.
Troisi RJ, Speizer FE, Willett WC, Trichopoulos D, Rosner B.
We prospectively evaluated the association of hormone replacement therapy and asthma incidence in a cohort of pre- and postmenopausal women 34 to 68 yr of age. During 582, 135 person-years of follow-up between 1980 and 1990, 726 new cases of asthma were documented. Postmenopausal women who were never users of replacement hormones had a significantly lower age-adjusted risk of asthma than premenopausal women (relative risk = 0.65; 95% confidence interval [CI] = 0.46 to 0.92). Among naturally menopausal women, the age-adjusted relative risk of asthma for ever use of postmenopausal hormones was 1.49 (95% CI = 1.10 to 2.00); for current use of hormones (conjugated estrogens with or without progesterone), 1.50 (95% CI = 0.98 to 2.30); and for past use, 1.52 (95% CI = 1.08 to 2.13), compared with never use of hormones. Ever users of 10 or more years’ duration had twice the age-adjusted risk of asthma compared with women who never used postmenopausal hormones (95% CI = 1.39 to 2.87). Among current users of conjugated estrogens, there was a positive dose-response demonstrated between daily dose and asthma risk (p for trend = 0.007). While confirmatory studies are warranted, these data suggest that estrogen plays a role in the pathophysiology of asthma and that long-term use and/or high doses of postmenopausal hormone therapy increase subsequent risk of asthma.

Am Rev Respir Dis. 1989 Aug;140(2):358-62.
Influence of the menstrual cycle on airway function in asthmatic and normal subjects.
Pauli BD, Reid RL, Munt PW, Wigle RD, Forkert L.
Investigations of premenstrual asthma (PMA) have been based on studies of asthmatics already aware of a deterioration of asthma premenstrually. Little is known, therefore, about relationships between the menstrual cycle and airway function in asthmatics who do not complain of PMA or in normal subjects. We investigated airway function in both of these groups for three or four consecutive menstrual cycles. Daily records of asthma symptoms and peak expiratory flow rates were maintained by 11 asthmatics and 29 normal control subjects. Standard spirometry and serum estradiol and progesterone levels were measured during the follicular, midluteal, and late luteal phases of the menstrual cycle. Airway reactivity to methacholine was tested during the follicular and luteal phases. The normal group showed no significant changes in symptoms, peak flow rates, spirometric parameters, or airway reactivity. Although the asthmatic group also demonstrated no significant changes in spirometry and airway reactivity, asthma symptoms (shortness-of-breath, cough, wheeze, and chest tightness) deteriorated significantly (p less than 0.001) from the follicular to the luteal phase, as did the morning peak flows of the asthmatics (p = 0.045). Airway function and reactivity were not related to hormone levels in either group. This study indicates that asthmatics not previously aware of PMA will record a premenstrual worsening of asthma symptoms and peak expiratory flow rates. These changes are not related to a deterioration in spirometry and airway reactivity or to the absolute levels of circulating progesterone and estradiol.

Lancet. 1988 Aug 13;2(8607):370-2.
Severe premenstrual exacerbations of asthma: effect of intramuscular progesterone.
Beynon HL, Garbett ND, Barnes PJ.
Three patients with severe premenstrual exacerbations of asthma are reported. None had responded to conventional treatment, including high-dose corticosteroids. In all cases there was a striking fall premenstrually in peak flow rate. The addition of intramuscular progesterone (100 mg daily in two cases and 600 mg twice a week in one) to the regimen eliminated the premenstrual dips in peak flow, and daily doses of prednisolone were reduced in the three patients.

Maturitas. 1995 Feb;21(2):153-7.
Sub-clinical worsening of bronchial asthma during estrogen replacement therapy in asthmatic post-menopausal women.
Lieberman D, Kopernik G, Porath A, Lazer S, Heimer D.
BACKGROUND:
Changes in asthma activity, in part related to the female hormonal profile, have been observed during pre-menstrual periods and during pregnancy. Estrogen replacement therapy (ERT) is an accepted routine treatment for post-menopausal women. The effect of ERT on disease activity in post-menopausal asthmatic women has not been investigated in the past and is the subject of the present study.
METHODS:
Fifteen post-menopausal women with mild to moderate asthma completed two 30-day periods in which they measured peak expiratory flow (PEF) at home and filled in a daily diary of asthma-related symptoms. The first monitoring period was pre-ERT and the second was during ERT. In addition spirometry was performed on each woman three times, twice pre-ERT and once during ERT.
RESULTS:
The average daily PEF decreased from 241 (57.9, S.D.) l/min pre-ERT to 226.7 (62.7) l/min during ERT (P < 0.004). Significant differences between the two study periods were also found in morning and evening PEF values. Diurnal variation, measured as the difference between morning and evening PEF values, decreased significantly from 22.3 (26.7) l/min pre-ERT to 17.5 (26.8) l/min during ERT (P < 0.007). The average daily consumption of bronchodilator inhalers increased significantly from 3.7 puffs/day pre-ERT to 4.3 puffs/day during ERT (P < 0.006). Although the differences in spirometry between the two periods did not reach statistical significance, a trend towards a worsening of the obstructive disorder during ERT was observed. However, the general feeling of well-being of the asthmatics did not change during the two periods.
CONCLUSIONS:
During ERT a sub-clinical worsening of disease activity was found in postmenopausal women with mild to moderate asthma. We also detected a decrease in diurnal variation. Our findings should be substantiated by additional studies.

Chest. 1993 Oct;104(4):1300-2.
Bronchospasm secondary to replacement estrogen therapy.
Collins LC, Peiris A.
A postmenopausal woman with severe obstructive airways disease and bronchospasm developed increased airflow limitation with the reintroduction of estrogen therapy for osteoporosis. Discontinuation of the estrogen caused symptomatic improvement and decreased her corticosteroid requirement. Readministration of estrogen caused recrudescence of her symptoms and a decline in her peak expiratory flow rate and spirometric data, which reversed with withdrawal of the estrogen therapy. Bronchospasm during the luteal phase of the menstrual cycle is well known, but exacerbation of reactive airways disease with the administration of exogenous estrogen has not previously been reported; however, with the increasing practice of reintroducing estrogen in postmenopausal women to reduce the risk of symptomatic osteoporosis, other susceptible women may suffer clinically significant deterioration of their underlying pulmonary disease.

Pediatr Allergy Immunol. 1997 Nov;8(4):200-4.
Is asthma an endocrine disease?
Wjst M, Dold S.
The prevalence of pediatric asthma has increased in many parts of the world. This increase started more than 30 years ago and is particularly obvious in studies which document the onset of asthma in native populations when they change to a “Western” lifestyle. Besides a genetic influence, numerous environmental factors have been described for the development of asthma. Genetic factors are unlikely to explain the sharp increase within the short time period and also allergen and pollution exposure or any specific infection does not actually seem to be the main cause for this phenomenon. Another factor, however, that fits well into the geographical and temporal background of the asthma epidemic is the mother’s oral contraceptive use. We therefore review the epidemiological association with later asthma in the children, give a summary of estrogen effects on immune function and develop a preliminary theory how oral contraception could influence later pregnancy.

J Microbiol Immunol Infect. 1998 Sep;31(3):197-9.
Premenstrual asthma: report of a case with hormonal studies.
Lam SM, Huang SC.
We report a 39-year-old female non-smoker who has history of asthma since the age of 29 and history of allergic rhinitis at age 13. No symptomatic characteristics of premenstrual tension were reported. Forced expiratory peak flow rate (PEFR) readings showed striking falls 24 hours before menses, with the peak flows dropping from a baseline of 350 L/min to 200 L/min. The patient received 10 mg prednisolone daily which was increased to 40 mg prednisolone in the menstrual week in an attempt to maintain a normal peak flow. Daily peak flow readings and every other day hormonal studies of progesterone and estrogen both demonstrated a positive correlation between the serum progesterone and the peak flow readings. The addition of intramuscular progesterone (75 mg daily) to the bronchodilators eliminated the premenstrual dips in peak flow, and daily doses of prednisolone were reduced to 5-10 mg. We suggest that a rapid fall in serum progesterone may play an important role in the pathogenesis of premenstrual asthma.

Ann Allergy Asthma Immunol. 1998 Sep;81(3):243-6.
Exacerbation of premenstrual asthma caused by an oral contraceptive.
Derimanov GS, Oppenheimer J.
BACKGROUND:
The relationship between sex hormones and asthma has not been clarified. Studies have suggested a potential beneficial effect of exogenous sex hormones and/or contraceptive pills on asthma in premenopausal females whereas the data for postmenopausal females are inconsistent.
CASE REPORT:
A 33-year-old woman suffering from asthma with premenstrual exacerbations had a stable course until she began taking oral contraceptives. At that time she experienced clinical deterioration of her asthma associated with decline of pulmonary function tests. No other precipitating factors were identified. After discontinuing the contraceptives, her condition returned to baseline.
CONCLUSION:
We found only two reports of worsening of asthma related to hormonal therapy (estrogen in one case, contraceptive pills in the other) in premenopausal women. Our report, together with these observations, suggests that in some premenopausal women exogenous sex hormones and/or contraceptive pills may, contrary to expected, produce exacerbation of asthma.
PIP:
Although the mechanism of premenstrual asthma has not been established, hormonal variations during the menstrual cycle are believed to play an important role. About 30-40% of female asthmatics report worsening of asthma symptoms during the premenstrual and/or menstrual period. This article presents a case in which oral contraceptives (OCs) appeared to precipitate an asthma attack. The patient, a 33-year-old White US woman, first developed asthma at age 27 years. The strongest trigger to her asthma attacks was her menstrual period. All periods were associated with a worsening of asthma, typically extending from 1 week before to 2-3 days after the onset of menstrual bleeding. Subsequently, the patient’s asthma was stabilized by continuous inhaled steroids. However, clinical deterioration of asthma and a decline of pulmonary function occurred immediately after the woman initiated OC use. There was a rapid stabilization in clinical status once OC use was discontinued. Although the weight of scientific evidence points to a possible beneficial effect of OCs or exogenous sex hormones on premenstrual asthma, this case suggests there may be a subset of women in whom sex hormones exacerbate asthma.

Compr Ther. 2001 Spring;27(1):65-71.
Menstrual cycle effects on common medical conditions.
Case AM, Reid RL.
Menstrual cycle-related exacerbation of common medical conditions such as migraine, epilepsy, asthma, irritable bowel syndrome, and diabetes, is a well-recognized phenomenon. Accurate documentation of symptoms on a menstrual calendar allows identification of women with cyclic alterations in disease activity.

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By Team FPS – June 29, 2012

Excess Dietary Phosphorus Lowers Vitamin D Levels

Also see:
Calcium to Phosphorus Ratio, PTH, and Bone Health
Fatty Acid Synthase (FAS), Vitamin D, and Cancer

J Clin Invest. 1986 Jan;77(1):7-12.
Oral intake of phosphorus can determine the serum concentration of 1,25-dihydroxyvitamin D by determining its production rate in humans.
Portale AA, et al.
Changes in the oral intake of phosphorus could induce the reported changes in the serum concentration of 1,25-dihydroxyvitamin D (1,25-(OH)2D) by inducing changes in its production rate (PR) or metabolic clearance rate (MCR), or both. To investigate these possibilities, we employed the constant infusion equilibrium technique to measure the PR and MCR of 1,25-(OH)2D in six healthy men in whom the oral intake of phosphorus was initially maintained at 1,500 mg/70 kg body weight per d for 9 d, then restricted to 500 mg/d (coupled with oral administration of aluminum hydroxide) for 10 d, and then supplemented to 3,000 mg/d for 10 d. With phosphorus restriction, the serum concentration of 1,25-(OH)2D increased by 80% from a mean of 38 +/- 3 to 68 +/- 6 pg/ml, P less than 0.001; the PR increased from 1.8 +/- 0.2 to 3.8 +/- 0.6 micrograms/d, P less than 0.005; the MCR did not change significantly. The fasting serum concentration of phosphorus decreased from 3.5 +/- 0.2 to 2.6 +/- 0.2 mg/dl, P less than 0.01. With phosphorus supplementation, the serum concentration of 1,25-(OH)2D decreased abruptly, reaching a nadir within 2 to 4 d; after 10 d of supplementation, the mean concentration of 27 +/- 4 pg/ml was lower by 29%, P less than 0.01, than the value measured when phosphorus intake was normal. The PR decreased to 1.3 +/- 0.2 micrograms/d, P less than 0.05; the MCR did not change significantly. The fasting serum concentration of phosphorus increased significantly, but only initially. These data demonstrate that in healthy men, reductions and increases in the oral intake of phosphorus can induce rapidly occurring, large, inverse, and persisting changes in the serum concentration of 1,25-(OH)2D. Changes in the PR of 1,25-(OH)2D account entirely for the phosphorus-induced changes in serum concentration of this hormone.

Vitamin D3 positively affected by calcium intake:
Am J Clin Nutr. 2004 Dec;80(6 Suppl):1717S-20S.
Vitamin D status, 1,25-dihydroxyvitamin D3, and the immune system.
Cantorna MT, Zhu Y, Froicu M, Wittke A.
Vitamin D is an important immune system regulator. The active form of vitamin D, 1,25-dihydroxyvitamin D3 [1,25(OH)2D3], has been shown to inhibit the development of autoimmune diseases, including inflammatory bowel disease (IBD). Paradoxically, other immune system-mediated diseases (experimental asthma) and immunity to infectious organisms were unaffected by 1,25(OH)2D3 treatment. There are similar paradoxical effects of vitamin D deficiency on various immune system functions. Vitamin D and vitamin D receptor (VDR) deficiency resulted in accelerated IBD. Experimental asthma was unaffected by 1,25(OH)2D3 treatment and was less severe among VDR-deficient mice. Vitamin D is a selective regulator of the immune system, and the outcome of 1,25(OH)2D3 treatment, vitamin D deficiency, or VDR deficiency depends on the nature of the immune response (eg, infectious disease, asthma, or autoimmune disease). An additional factor that determines the effect of vitamin D status on immune function is dietary calcium. Dietary calcium has independent effects on IBD severity. Vitamin D-deficient mice on low-calcium diets developed the most severe IBD, and 1,25(OH)2D3 treatment of mice on low-calcium diets improved IBD symptoms. However, the best results for IBD were observed when the calcium concentration was high and 1,25(OH)2D3 was administered. Both the type of immune response and the calcium status of the host determine the effects of vitamin D status and 1,25(OH)2D3 on immunity.

Low Phophosphate Intake, Increases Vitamin D, Lowers Prostate Disease:
Indian J Exp Biol. 1999 Jul;37(7):623-6.
Phosphorus balance and prostate cancer.
Kapur S.
Prostatic diseases affect men over the age of 45 and increase in frequency with age so that by the eighth decade more than 90% of men have Benign Prostatic Hyperplasia, (BPH), of which some progress to Carcinoma of Prostate (CaP). CaP, the most common malignancy in men, is also the second most common cause of death in men. Over the last three decades the mortality rate for CaP has steadily increased. There, however, are scant clues to the aetiology/pathogenesis of CaP. As treatment failures of advanced carcinoma continue to frustrate clinicians, emphasis has recently been focused on possible preventive strategies. Several studies support the view that higher levels of 1,25-(OH)2D, the active metabolite of vitamin D, reduce the risk of BPH and CaP. Men with high serum levels of 1,25-(OH)2D have a reduced risk of poorly differentiated and clinically advanced CaP. Hypercalcemic activity of 1,25-(OH)2D or its analogues, however, thwart their use for therapy in humans. Incidentally, a low dietary intake of phosphorus has been reported to increase serum levels of 1,25-(OH)2D. In addition, dietary fructose reduces plasma phosphate levels by 30 to 50% for more than 3 hr. Fruit intake has, indeed, been shown to be associated with reduced risk of CaP, particularly the advanced type. These observations, taken together, support that dietary determinants of hypophosphatemia, leading to increased plasma levels of 1,25-(OH)2D, could reduce the risk of ageing men to develop prostatic diseases, both BPH and/or carcinoma of Prostate.

Phosphorus intake over 1400 mg per day raises all-cause mortality.

Am J Clin Nutr February 2014 vol. 99 no. 2 320-327
High dietary phosphorus intake is associated with all-cause mortality: results from NHANES III
Alex R Chang, Mariana Lazo, Lawrence J Appel, Orlando M Gutiérrez, and Morgan E Grams
Background: Elevated serum phosphorus is associated with all-cause mortality, but little is known about risk associated with dietary phosphorus intake.
Objective: We investigated the association between phosphorus intake and mortality in a prospective cohort of healthy US adults (NHANES III; 1998–1994).
Design: Study participants were 9686 nonpregnant adults aged 20–80 y without diabetes, cancer, or kidney or cardiovascular disease. Exposure to dietary phosphorus, which was assessed by using a 24-h dietary recall, was expressed as the absolute intake and phosphorus density (phosphorus intake divided by energy intake). All-cause and cardiovascular mortality was assessed through 31 December 2006.
Results: Median phosphorus intake was 1166 mg/d (IQR: 823–1610 mg/d); median phosphorus density was 0.58 mg/kcal (0.48–0.70 mg/kcal). Individuals who consumed more phosphorus-dense diets were older, were less often African American, and led healthier lifestyles (smoking, physical activity, and Healthy Eating Index). In analyses adjusted for demographics, cardiovascular risk factors, kidney function, and energy intake, higher phosphorus intake was associated with higher all-cause mortality in individuals who consumed >1400 mg/d [adjusted HR (95% CI): 2.23 (1.09, 4.5) per 1-unit increase in ln(phosphorus intake); P = 0.03]. At <1400 mg/d, there was no association. A similar association was seen between higher phosphorus density and all-cause mortality at a phosphorus density amount >0.35 mg/kcal [adjusted HR (95% CI): 2.27 (1.19, 4.33) per 0.1-mg/kcal increase in phosphorus density; P = 0.01]. At <0.35 mg/kcal (approximately the fifth percentile), lower phosphorus density was associated with increased mortality risk. Phosphorus density was associated with cardiovascular mortality [adjusted HR (95% CI): 3.39 (1.43, 8.02) per 0.1 mg/kcal at >0.35 mg/kcal; P = 0.01], whereas no association was shown in analyses with phosphorus intake. Results were similar by subgroups of diet quality and in analyses adjusted for sodium and saturated fat intakes.
Conclusions: High phosphorus intake is associated with increased mortality in a healthy US population. Because of current patterns in phosphorus consumption in US adults, these findings may have important public health implications.

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By Team FPS – June 29, 2012

Vegetarians have smaller brains

by Barry Groves

If you want to get ahead, get a brain

There is overwhelming evidence that we can not be a vegetarian species. In 1972 the publication of two independent investigations confirmed this.[1] [2] They concerned fats. About half our brain and nervous system is composed of complicated, long-chain, fatty acids. These are also used in the walls of our blood vessels. Without them we cannot develop normally. These fatty acids do not occur in plants, although fatty acids in a simpler form do. This is where plant-eating herbivores come in. Over the year, the herbivores convert the simple fatty acids found in grasses and seeds into intermediate, more complicated forms. By eating the herbivores we can convert their stores of these fatty acids into the ones we need.

About 2.5 million years ago animal foods began to occupy an increasingly prominent place in our ancestors’ menus. Smaller molar size, less robust facial muscles and alterations in incisor shape from that time all suggest a greater emphasis on foods such as meat that require less grinding and more tearing.

An increasing proportion of meat in the diet would obviously have provided more animal protein, a factor perhaps related to the increase in stature which appears to have accompanied the transition from Australopithecines through Homo habilis to Homo erectus.[3] But greater availability of animal fat was probably a more important dietary alteration. Crude stone tools allowed early humans to break bones and allowed them access to brain and marrow fats from a broad range of animals obtained by scavenging or hunting. These and other carcass fats were probably as prized by early hominids as they are by modern human hunter-gatherers.[4] Not only did more animal fat in the diet mean considerably more energy, it was also a source of ready-made, long-chain, polyunsaturated fatty acids, including omega-6 arachidonic acid (AA), omega-3 docosatetraenoic acid (DTA) and omega-3 docosahexaenoic acid (DHA). These 3 fatty acids together make up over 90% of the fatty acids found in the brain matter of all mammalian species.[5]

Our brain is considerably larger than that of any ape. Looking back at the fossil records from early hominids to modern man, we see a remarkable increase in brain size from 375-550 ml at the time of Australopithecus, to 500-800 ml in Homo habilis, 775-1,225 ml in Homo erectus, and 1,350 cc in modern humans (Homo sapiens). While there is still speculation about why this should have happened, this increase in brain size could not have been supported physiologically without an increased intake of preformed long-chain fatty acids which are an essential component in the formation of brain tissue.[6] It would never have occurred if our ancestors had not eaten meat — with its fat. Human breast milk contains the fatty acids needed for large brain development, cow’s milk does not. It is no coincidence that, in relative terms, our brain is some 50 times the size of a cow’s.

Where does the energy for our brain come from?

Between 20% and 25% of all the energy we use, is used by our brain. This is in contrast to the great apes whose brains use only about 8%. This makes our brains very expensive in energy terms. It means that our energy use compared to our body size should be considerably higher than that of other animals. Yet it isn’t. This presents something of a puzzle: where do we humans get the extra energy to spend on our large brains? Researchers WR Leonard and ML Robertson concluded that the evolution of brain size imply changes in diet quality during hominid evolution. They say,

‘The shift to a more calorically dense diet was probably needed in order to substantially increase the amount of metabolic energy being used by the hominid brain. Thus, while nutritional factors alone are not sufficient to explain the evolution of our large brains, it seems clear that certain dietary changes were necessary for substantial brain evolution to take place.'[7]

This confirms the Crawfords’ work. While our enlarged brain was made necessary by our banding together into tighter communities with more individuals and, thus, a necessity to remember more individuals, what made it possible was a diet of sufficient quality to allow that brain expansion.

But there is another aspect. Two scientists, Aiello and Wheeler, measured the sizes of brains and other body organs against organ size relative to body size predictions.[8] What they found was that the larger-than-expected size of the human brain was compensated for by a smaller-than-expected gut size. Measuring the other energy-expensive organs in the body: heart, kidneys, liver, and gastrointestinal tract, as these use the most energy after the brain, and comparing those of a 65-kg non-human primate with the organ sizes of an average 65-kg human, they found dramatic differences between the expected and actual sizes of the human brain, and gut: ‘the splanchnic [abdominal/gut] organs were approximately 900g less than expected’. Almost all of this shortfall was due to our gut being only about 60% of that expected for a similar-sized primate.

We have a carnivore gut

Not only is our gut smaller than predicted compared with other primates, it is also configured very differently. Our small intestine is the major organ used to digest food and extract its nutrients for absorption into our bodies. Not surprisingly, it is more than 50% of the total volume of our gut. Our colon (large intestine) plays little part in the process of digestion: it is used mainly to extract and, so conserve, water. For this reason, it represents only around 20% of our gut’s volume. In contrast, the ratios in other primates are exactly the opposite: The small intestines of orangs and chimps, which play a minor role in digestion, are around 25% of gut volume, and their colons, where bacteria are used to ferment plant fibre and where most digestion takes place, are around 53% by volume.[9]

This is not the only measurement that matters. So far I have compared our gut to that of our primate cousins which eat mostly plant food. If we also compare them to the great carnivores, we find that our gut is actually very much like theirs. The comparisons are done with respect to body weight as weight is closely related to the metabolic energy requirements of an animal. This ratio, known as Kleiber’s Law, expresses the relationship between body mass (weight) and the body’s metabolic energy requirements. The size of any organ that is directly concerned with metabolic turnover should comply with Kleiber’s law. If we measure the size of these and they are in accordance with Kleiber’s law, each part’s gastrointestinal (GI) quotient should be 1.00. A GI greater than 1.00 means the organ is larger than expected, and GI less than 1.00 indicates a size smaller than expected.

In the gut, it is the surface area of various parts of the digestive tract which determines their relative absorptive ability. A test of major areas of the human digestive tract was published in 1985 with the following results:[10]

Stomach quotient 0.31
Small intestine quotient 0.76
Caecum quotient 0.16
Colon quotient 0.58

As these values are all considerably less than 1.00, it can only mean one thing: for the absorption of sufficient energy and nutrients for the body to function properly, food must be very energy and nutrient dense. Fat meat is the only universal class of food that falls into this category, thus there can be no doubt that humans fall into the carnivore class.

Brain quotient

Our gut is not the only part of our bodies to be analysed in this way. It is in our brain size and high intelligence that we humans are unique. Relative to our body size, our brains are truly enormous. If we measure our brain quotient in the same way we did for the gut, we can get some idea of just how big it really is.

In order to measure encephalization as it is called, statistical models were developed which compared brain size and body size in a wide range of species. This allowed an accurate estimation of the brain size for a given species based on its body mass. This is important because it allows the quantitative study and comparison of brain sizes between different species by automatically adjusting for body size. For example, elephants, which are plant eaters, and whales whether herbivores or carnivores, have larger brains than we do — but they also have much larger bodies. In this exercise it was noticed that the brain sizes of these animals also followed Kleiber’s law.

When this test was conducted on humans, it put humans right at the very top of the primate scale. Our Encephalization Quotient was an outstanding 28.8.

With a brain so out of proportion to the rest of our bodies, it’s not surprising that it uses such a large proportion of our total energy. As brain size and energy use is so high, and our gut size so small, the amount of energy available to the brain is dependent not only on how the body’s total energy budget is allocated between the brain and other energy-intensive organs and systems, but on the ability of our gut to extract sufficient energy from our food. That also confirms that the kind of diet we should eat must have the high nutrient density found in foods such as meat and fat.

Our brains are now getting smaller

With such a small gut with which to absorb all the nutrients and energy our bodies need, a modern low-calorie, low-fat, fibre-rich, plant-based diet is woefully inadequate as an energy source for our energy-hungry system to function at peak efficiency. That lack has begun to show.

Since the advent of agriculture, there has been a worrying trend as our brains have actually decreased in size. A recently updated and rigorous analysis of changes in human brain size found that our ancestors’ brain size reached its peak with the first anatomically modern humans of approximately 90,000 years ago. That then remained fairly constant for a further 60,000 years.[11] Over the next 20,000 years there was a slight decline in brain size of about 3%. Since the advent of agriculture about 10,000 years ago, however, that decline has quickened significantly, so that now our brains are a further 8% smaller. That is a total of 11% smaller than at their peak size.

This suggests some kind of recent historical deficiency in some aspect of overall human nutrition. The most obvious and far-reaching dietary change during the last 10,000 years is, of course, the enormous drop in consumption of high-energy, fat-rich foods of animal origin which formed probably over 90% of the diet, to as little as 10% today, coupled with a large rise in less energy-dense grain consumption.[12] This pattern still persists; it is even advocated today: it is the basis of our so-called ‘healthy’ diet.

Vitamin B-12

If any more convincing that we have to be a meat-eating species is needed, there is one other essential nutrient that is not found in any plant food. That nutrient is Vitamin B-12.

Vitamin B-12 is unique among vitamins in that while it is found universally in foods of animal origin, where it is derived ultimately from bacteria, there is no active vitamin B-12 in anything which grows out of the ground. Where trace amounts of vitamin B-12 are found on plants it is there only fortuitously in bacterial contamination of the soil. And even that is lost if plants are washed thoroughly before eating them.

Bacteria in the human colon make prodigious amounts of vitamin B-12. Unfortunately, this is useless as it is not absorbed through the colon wall. Dr. Sheila Callender tells of treating vegans with severe vitamin B-12 deficiency by making water extracts of their stools which she fed to them, thus affecting a cure.[13] An Iranian vegan sect unwittingly also makes use of this fact. Investigators could not understand how members of this sect remained healthy, until their investigations showed that they grew their vegetables in human manure — and then ate the vegetables without being too fussy about washing them first.[14]

To enable vegans to survive, vitamin B-12 is added artificially to breakfast cereals in Britain and may be bought in pill form. This is hardly a natural way to get food and in many cases it is self-defeating. Unlike most other vitamins, Vitamin B-12 occurs as a number of analogues, very few of which are active for humans. In collecting human stools for analysis Dr. Victor Herbert found that of each 100 micrograms of vitamin B-12 extracted, only 5 micrograms were analogues active for humans.[15] Thus even in this most prodigious source of the vitamin, 95% was composed of analogues which were useless.

Several fermented products such as tempeh, a soya bean product and spirulinas, used by strict vegans as a source of vitamin B-12, either do not contain significant amounts of the vitamin or contain analogues of the vitamin which are not active for humans.[16] Over half of the adults from a macrobiotic community tested in New England had low concentrations of vitamin B-12. Children were short in stature and low in weight. The community relied on sea vegetables for the vitamin.

This reliance on vegetables sources gives a false sense of security and could actually bring on the symptoms of B-12 deficiency more quickly.

The amount of vitamin B-12 we need is tiny: about 1 microgram per day. Eating more than this results in a reserve being built up in the body. When a person becomes a vegan, those stores are depleted — but only gradually. Thus it can be several years before the onset of symptoms. In England a carefully conducted study carried out on vegans showed that they all got vitamin B-12 deficiency eventually.[17]

Brain shrinkage among vegetarians

But, getting back to brain size, the decline which started with the advent of agriculture and our greater reliance on foods of plant origin has now seen a dramatically greater decline in those who have adopted a ‘healthy’, vegetarian diet.

Scientists at the Department of Physiology, Anatomy and Genetics, University of Oxford, recently discovered that changing to a vegetarian diet could be bad for our brains — with those on a meat-free diet six times more likely to suffer brain shrinkage.[18]

Using tests and brain scans on community-dwelling volunteers aged 61 to 87 years without cognitive impairment at enrolment, they measured the size of the participants’ brains. When the volunteers were retested five years later the scientists found those with the lowest levels of vitamin B12 intake were the most likely to have brain shrinkage. Not surprisingly, vegans who eschew all foods of animal origin, suffered the most brain shrinkage. This confirms earlier research showing a link between brain atrophy and low levels of B12.

Vegans are the most likely to be deficient because the best sources of the vitamin are meat, particularly liver, milk and fish.

There were two other worrying aspects to this trial. The first was at the start of the trial, the biggest brain in a vegan, at 1455 ml, was already smaller than smallest brain of someone on a ‘normal diet’, at 1456 ml.

The other aspect was even more worrying. It was that all participants had Vit B-12 which was within the ‘normal’ range. This suggests that the normal range is too low – and by quite large margin. I understand that, based on this study, the Japanese have raised their normal level.

Confirmation of the above study was provided the following year by another study by the Oxford Project to Investigate Memory and Ageing, the Department of Physiology, Anatomy and Genetics, University of Oxford, UK.[19] Noting that vitamin B-12 deficiency is often associated with cognitive deficits, they reviewed evidence that cognition in the elderly may also be adversely affected at concentrations of vitamin B-12 above the traditional cutoffs for deficiency. Their suggestion is that the elderly in particular should be encouraged to maintain a good, rather than just an adequate, vitamin B-12 status by dietary means.

Conclusion

It is obvious that we need to be eating more, not less, meat and animal-sourced foods.

If vegetarians — and vegans in particular — berate you for ‘murdering’ and eating animals, please be kind to them. They are almost certainly suffering from self-inflicted brain atrophy, and have little recognition of both the damage they are doing to themselves and the harm that are doing to others who follow their advice.

References

[1]. Crawford M, Crawford S. The Food We Eat Today. Spearman, London, 1972.
[2]. Leopold AC, Ardrey R. Toxic Substances in Plants and Food Habits of Early Man. Science 1972; 176(34): 512-4.
[3]. McHenry HM. How big were early hominids? Evol Anthropol 1992; 1: 15-20.
[4]. Stefansson V. The fat of the land. MacMillan, New York, 1960. 15-39.
[5]. Sinclair AJ. Long-chain polyunsaturated fatty acids in mammalian brain. Proc Nutr Soc 1975; 34: 287-91.
[6]. Crawford MA, Cunnane SC, Harbige LS. A new theory of evolution: quantum theory. In: Sinclair A, Gibson R, eds. Essential fatty acids and eicosanoids. American Oil Chemists Society, Champlaign, Ill, 1992. 87-95.
[7]. Leonard WR, Robertson ML. Evolutionary perspectives on human nutrition: the influence of brain and body size on diet and metabolism. Am J Human Biol 1994; 6: 77-88.
[8]. Aiello LC, Wheeler P. The expensive tissue hypothesis: the brain and the digestive system in human and primate evolution. Current Anthropology, 1995; 36: 199-221.
[9]. Milton K. Primate diets and gut morphology: implications for hominid evolution. In: Food and Evolution: Toward a Theory of Food Habits, eds. Harris M, Ross EB; Temple University Press, Philadelphia, 1987, 93-115.
[10]. Martin RD, et al. Gastrointestinal allometry in primates and other mammals. In: Size and Scaling in Primate Biology. Jungers WL ed., Plenum Press, New York, 1985, 61-89.
[11]. Ruff CB, Trinkaus E, Holliday TW. Body mass and encephalization in Pleistocene Homo. Nature 1997; 387: 173-176.
[12]. Eaton, S Boyd, Eaton, Stanley B III. Evolution, diet and health. Presented in association with the scientific session, Origins and Evolution of Human Diet. 14th International Congress of Anthropological and Ethnological Sciences, Williamsburg, Virginia, 1998.
[13]. Callender ST, Spray GH. Latent pernicious anaemia. Br J Haematol 1962; 8: 230.
[14]. Halstead JA, et al. Serum and tissue concentration of vitamin B 12 in certain pathologic states. N Eng J Med 1959; 260: 575.
[15]. Herbert V. Vitamin B-12: plant sources, requirements and assay. Am J Clin Nutr 1988; 48: 852.
[16]. Miller DR, et al. Vitamin B-12 status in a macrobiotic community. Am J Clin Nutr 1991; 53: 524-9.
[17]. Chanarin I, O’Shea AM, Malkowska V, Rinsler MG. Megaloblastic anaemia in a vegetarian Indian community. Lancet 1985; ii: 1168.
[18] Vogiatzoglou A, et al. Vitamin B12 status and rate of brain volume loss in community-dwelling elderly. Neurology 2008; 71(11): 826-32
[19] Smith AD, Refsum H. Vitamin B-12 and cognition in the elderly. Am J Clin Nutr 2009; 89: 707S-11S.

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By Team FPS – June 28, 2012

Synergistic Effect of Creatine and Baking Soda on Performance

Also see:
Protective Carbon Dioxide, Exercise, and Performance
Benefits of Aspirin
Exercise Induced Stress
Lactate Paradox: High Altitude and Exercise
Ray Peat, PhD on Carbon Dioxide, Longevity, and Regeneration
Carbohydrate Lowers Exercise Induced Stress
Protective Altitude
Bicarbonate For Strength Athletes: 25g of Baking Soda Up Your Squat (+27%) & Bench Press (+6%) Within 60 Min

J Strength Cond Res. 2004 May;18(2):306-10.
Combined creatine and sodium bicarbonate supplementation enhances interval swimming.
Mero AA, Keskinen KL, Malvela MT, Sallinen JM.
This study examined the effect of simultaneous supplementation of creatine and sodium bicarbonate on consecutive maximal swims. Sixteen competitive male and female swimmers completed, in a randomized order, 2 different treatments (placebo and a combination of creatine and sodium bicarbonate) with 30 days of washout period between treatments in a double-blind crossover procedure. Both treatments consisted of placebo or creatine supplementation (20 g per day) in 6 days. In the morning of the seventh day, there was placebo or sodium bicarbonate supplementation (0.3 g per kg body weight) during 2 hours before a warm-up for 2 maximal 100-m freestyle swims that were performed with a passive recovery of 10 minutes in between. The first swims were similar, but the increase in time of the second versus the first 100-m swimming time was 0.9 seconds less (p < 0.05) in the combination group than in placebo. Mean blood pH was higher (p < 0.01-0.001) in the combination group than in placebo after supplementation on the test day. Mean blood pH decreased (p < 0.05) similarly during the swims in both groups. Mean blood lactate increased (p < 0.001) during the swims, but there were no differences in peak blood lactate between the combination group (14.9 +/- 0.9 mmol.L(-1)) and placebo (13.4 +/- 1.0 mmol.L(-1)). The data indicate that simultaneous supplementation of creatine and sodium bicarbonate enhances performance in consecutive maximal swims.

Journal of Strength & Conditioning Research: POST AUTHOR CORRECTIONS, 23 March 2012
Original Investigation: PDF Only
Effects of combined creatine and sodium bicarbonate supplementation on repeated sprint performance in trained men
Barber, James J; McDermott, Ann Y; McGaughey, Karen J; Olmstead, Jennifer D; Hagobian, Todd A
Creatine and sodium bicarbonate supplementation independently increase exercise performance, but it remains unclear whether combining these two supplements is more beneficial on exercise performance. The purpose of this study was to evaluate the impact of combining creatine monohydrate and sodium bicarbonate supplementation on exercise performance. Thirteen healthy, trained men (21.1 +/- 0.6 yr, 23.5 +/- 0.5 kg/m2, 66.7 +/- 5.7 ml/kg-min) completed 3 conditions in a double-blinded, crossover fashion: 1) Placebo (Pl; 20 g maltodextrin + 0.5 g/kg maltodextrin), 2) Creatine (Cr; 20 g + 0.5 g/kg maltodextrin), and 3) Creatine plus sodium bicarbonate (Cr+Sb; 20g + 0.5 g/kg sodium bicarbonate). Each condition consisted of supplementation for 2 days followed by a 3-week washout. Peak power, mean power, relative peak power, and bicarbonate concentrations were assessed during six 10-second repeated Wingate sprint tests on a cycle ergometer with a 60-second rest period between each sprint. Compared to Pl, relative peak power was significantly higher in Cr (4%) and Cr+Sb (7%). Relative peak power was significantly lower in sprints 4-6, compared to sprint 1, in both Pl and Cr. However, in Cr+Sb, sprint 6 was the only sprint significantly lower compared to sprint 1. Pre-Wingate bicarbonate concentrations were significantly higher in Cr+Sb (10%), compared to Pl and Cr, and mean concentrations remained higher after sprint 6, although not significantly. Combining creatine and sodium bicarbonate supplementation increased peak and mean power, and had the greatest attenuation of decline in relative peak power over the six repeated sprints. These data suggest that combining these two supplements may be advantageous for athletes participating in high-intensity, intermittent exercise.

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By Team FPS – June 28, 2012

PUFA, Inflammation, and Rheumatoid Arthritis

Eur J Med Res. 2003 Aug 20;8(8):381-7.
Dietary fatty acids and immune reactions in synovial tissue.
Adam O.
Inflammation of the synovial membrane in rheumatoid arthritis is mediated by specialized cells necessary for immune response. The most prominent features are the accumulation of mononuclear phagocytes, lymphocytes and leukocytes in the proliferating tissue. Pro-inflammatory and proliferative signals are transmitted to the bone marrow and to the synovial membrane. The result is a monoclonal stimulation of specific cell lines, and synovial proliferation in the inflamed joint. Angiogenesis, synovial hypertrophy, and increased perfusion facilitate the accumulation of inflammatory cells. Components of the autoimmune reaction are described in the international system of classification, the CD-System (cluster of differentiation). Pro-inflammatory signals are mediated by metabolites of arachidonic acid. Prostaglandins, leukotrienes, lipoxines and hydroxy fatty acids, derived from this PUFA, stimulate the formation and the activity of adhesion molecules (integrines), cytokines (gamma-interferon, interleukin-1, interleukin-6, tumor-necrosis factor), chemokines (interleukine-8, macrophage-chemotactic peptide, RANTES and colony -stimulating factors ((CSF, granulocytes/ monocytes-CSF, Multi-CSF (= IL-3)). Dietary means to mitigate inflammation comprise reduction of arachidonic acid, and increased intake of eicosapentaenoic acid and antioxidants. In the literature 12 randomized, placebo-controlled double-blind studies, fulfilling GCP-criteria, demonstrate a moderate but consistent improvement of clinical findings and laboratory parameters in patients with RA. A dose-response relationship was established up to an daily dose of 2.6 gram fish oil, equivalent to about 1.6 gram EPA. In these experiments EPA was the omega-3 fatty acid responsible for improvement, with distinct effects on inhibition of cytokines formation (IL-1 to IL-6, IL-8, TFN-alpha, GM-CSF), decreased induction of proinflammatory adhesion molecules (selectines, intercellular adhesions molecule-1 (ICAM-1)), and degrading enzymes (e.g. phospholipase A2, cyclooxygenase-2, inducible NO-synthetase). Only one study reports the relevance of the background diet. From this study it became apparent that reduction of dietary arachidonic acid improves the incorporation and the clinical benefit of EPA.

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By Team FPS – June 28, 2012

The Streaming Organism

Also see:
Gershom Zajicek’s Website
Diabetes: Conversion of Alpha-cells into Beta-cells
Research by Zajicek, et al. on Pubmed
Nutrition and Brain Growth in Chick Embryos
The Brain – Estrogen’s Harm and Progesterone’s Protection

Quotes by Ray Peat, PhD:
“Even the liver and adrenal gland are now known to be continuously renewed by “cell streaming,” though at a slower rate than the skin, conjunctiva, and intestine.”

“Choosing the right foods, the right atmosphere, the right mental and physical activities, and finding the optimal rhythms of light, darkness, and activity, can begin to alter the streaming renewal of cells in all the organs. Designing a more perfect environment is going to be much simpler than the schemes of the genetic engineers.”

“For almost the entire 20th century, the medical experts completely ignored the work of experimenters such as Polezhaev, and their excuse was that when a brain was sliced, dividing cells were never seen, and they could be seen in the skin and liver, which they knew could regenerate. The reason, for which the absence of evidence was the excuse, for denying regeneration in the heart and brain was that they were committed to the world-view of August Weismann. Since the brain isn’t in a chemically exposed situation, such as the skin, gut, and liver, there’s no need for it to make new cells every day. Polezhaev showed that a degenerating brain cell was the stimulus for producing a new cell. In the absence of evidence showing that medical education is radically less stupid than previously, I will ignore their present doctrines, as I ignored their previous opinions.”

“As the metabolic rate decreases, things become more rigid, but with renewal of the metabolic pattern, more sugar, thyroid, and CO2, the course can be shifted. The need for a tissue evokes expansion of that tissue, and I think that’s the main issue in brain plasticity, that with stabilizing neurosteroids and efficient sugar oxidation, the frontal lobes in particular will grow. The amount of DNA in a human brain was found to keep increasing up to the age of 90, but that would include glia.”

“Partly, it’s that the environmental conditions that advance puberty also inhibit brain development, namely, the low CO2/O2 ratio and high PUFA environments. But estrogen’s effect, increasing the average amount of free fatty acids in the circulation, works with the bad environment. With a different environment, estrogen’s function would probably include increasing brain plasticity.”

Med Hypotheses. 1981 Oct;7(10):1241-51.
The histogenesis of glandular neoplasia.
Zajicek G.
Tissues in the organism may be divided according to their proliferative capacities into three categories: 1. Fast replicators (FR) e.g., epidermis; 2. Slow replicators (SR) e.g., liver and 3. Non replicators (NR) e.g., nerve cells. Evidence is presented that FR as well as SR tissues continuously proliferate exhibiting two distinct histomorphological structures; a progenitor region in which cells are formed and a functional region into which they enter. Throughout their displacement, the cells cover a typical path denominated as tissue radius. The SR tissues e.g., parotid gland, mammary gland, liver and prostate, exhibit similar ontogenies, and proceed during regeneration and neoplasia through similar stages. All are compound glands with two distinct stem cell types, one residing in the excretory duct epithelium and the second in the intercalated duct. Each stem cell gives rise to its typical neoplasm. Excretory duct originating neoplasms consist of papillomas, epidermal and adenocarcinomas, while intercalated stem cell bound neoplasms embrace the canalicular adenoma, oncocytoma acinic cell and lobular carcinomata. All tissues continuously stream along the tissue radius. Evidence is presented that even the liver cords are continuously displaced from the limiting lamina toward the terminal hepatic (or central) vein. The histological image of these tissues actually reflects an instantaneous picture of cells in a continuous flux.

Brain Neurogensis:
J Cereb Blood Flow Metab. 2007 Aug;27(8):1417-30. Epub 2007 Mar 28.
Regeneration and plasticity in the brain and spinal cord.
Johansson BB.
The concept of brain plasticity covers all the mechanisms involved in the capacity of the brain to adjust and remodel itself in response to environmental requirements, experience, skill acquisition, and new challenges including brain lesions. Advances in neuroimaging and neurophysiologic techniques have increased our knowledge of task-related changes in cortical representation areas in the intact and injured human brain. The recognition that neuronal progenitor cells proliferate and differentiate in the subventricular zone and dentate gyrus in the adult mammalian brain has raised the hope that regeneration may be possible after brain lesions. Regeneration will require that new cells differentiate, survive, and integrate into existing neural networks and that axons regenerate. To what extent this will be possible is difficult to predict. Current research explores the possibilities to modify endogenous neurogenesis and facilitate axonal regeneration using myelin inhibitory factors. After apoptotic damage in mice new cortical neurons can form long-distance connections. Progenitor cells from the subventricular zone migrate to cortical and subcortical regions after ischemic brain lesions, apparently directed by signals from the damaged region. Postmortem studies on human brains suggest that neurogenesis may be altered in degenerative diseases. Functional and anatomic data indicate that myelin inhibitory factors, cell implantation, and modification of extracellular matrix may be beneficial after spinal cord lesions. Neurophysiologic data demonstrating that new connections are functioning are needed to prove regeneration. Even if not achieving the goal, methods aimed at regeneration can be beneficial by enhancing plasticity in intact brain regions.

Science. 2003 Aug 8;301(5634):805-9.
Requirement of hippocampal neurogenesis for the behavioral effects of antidepressants.
Santarelli L, Saxe M, Gross C, Surget A, Battaglia F, Dulawa S, Weisstaub N, Lee J, Duman R, Arancio O, Belzung C, Hen R.
Various chronic antidepressant treatments increase adult hippocampal neurogenesis, but the functional importance of this phenomenon remains unclear. Here, using genetic and radiological methods, we show that disrupting antidepressant-induced neurogenesis blocks behavioral responses to antidepressants. Serotonin 1A receptor null mice were insensitive to the neurogenic and behavioral effects of fluoxetine, a serotonin selective reuptake inhibitor. X-irradiation of a restricted region of mouse brain containing the hippocampus prevented the neurogenic and behavioral effects of two classes of antidepressants. These findings suggest that the behavioral effects of chronic antidepressants may be mediated by the stimulation of neurogenesis in the hippocampus.

Liver. 1985 Dec;5(6):293-300.
The streaming liver.
Zajicek G, Oren R, Weinreb M Jr.
Twenty male adult rats weighing 200 g were injected with tritiated thymidine (3HTdR). The animals were then killed in groups of five, at the following times: 1 h, 1, 3 and 5 weeks. Autoradiograms of sections through the liver were prepared. The distances between labelled cells and the portal space rim were measured. One hour after labelling most labelled cells were confined to a region extending from the portal space rim up to a distance of 700 micron, which roughly corresponds to Rappaport’s hepatic acinus zones-1 and -2. Throughout the experiment lasting 5 weeks labelled cells entered zone-3 and advanced toward the terminal hepatic vein. Hepatocytes travelled at a daily velocity of 1.44 micron, covering daily 0.324% of the acinus diameter. During the experiment acinus size did not change appreciably. The estimated mean hepatocyte cell cycle time was 37 days and its life expectation, 201 days. These experiments show that the liver is essentially a slowly renewing cell population. Hepatocytes nascent at the portal space gradually stream toward the terminal hepatic vein where they are probably eliminated by apoptosis. Their journey lasts 201 days. Since hepatocytes are glued together with tight junctions, all have to advance toward their terminal hepatic veins en masse. During their voyage, they traverse the three acinus zones, and since in each they produce different enzymes, each zone represents a differentiation state of the advancing cell. It is suggested further that the streaming hepatocyte carries with it its nerve supply and is accompanied by sinusoidal endothelium and Kupffer cells.

Diabetes Res. 1990 Mar;13(3):121-5.
Streaming pancreas: islet cell kinetics.
Zajicek G, Arber N, Schwartz-Arad D, Ariel I.
Thirty male young adult rats aged 7 weeks, weighing 200 g, were injected with 0.5 microCi/g body weight tritiated thymidine (specific activity 5.0 Ci/mM). The rats were then killed in groups of five, at the following times: 1 hour, and 14, 28, 42, 56, 90, and 120 days. The pancreata were dissected, embedded in paraffin, and cut into 5 microns thick sections which were then dipped into liquid emulsion. The labelling index of acini and islet cells was estimated in each autoradiogram, and their distance from intercalated duct was measured. Acini and islet cells streamed away from the intercalated duct at a daily velocity of 0.52 microns. Acinus labelling index which was initially 0.78% declined with time. Islet cell labelling index was initially 0.38%. In the following days it climbed upward reaching on the 42nd day its peak value of 0.78%. From then onward it declined to a low of 0.38%. Since cells were labelled only once, and labelling was instantaneous, it is concluded that labelled acinus cells entered the islet, and that acinus cells are actually islet cell precursors. The pancreas is structured kinetically like other exocrine glands, being a two compartment cell renewal system which continuously renews its cells. The pancreocyte is a descendant of an intercalated duct progenitor. After leaving the duct it turns into an acinus cell, gradually approaching the Langerhans islet. After crossing its border it becomes an islet cell, and proceeds toward the islet center. Its population size dwindles exponentially until at islet center all cells are eliminated.

In the adrenal glands, renewing cells stream from the capsule on the surface of the gland toward the center of the gland. The first cells to be produced in a regenerating gland are those that produce aldosterone, the next in the stream are the cortisol producing cells, and the last to be formed are the cells that produce the sex hormones, the androgens including DHEA, and progesterone. In aging, after the age of thirty, the renewal slows, but the dissolution of the sex hormone zone continues, so the proportion shifts, increasing the ratio of aldosterone and cortisol producing cells to the layer that produces the protective androgens and progesterone (Parker, et al., 1997). -Ray Peat, PhD

Also see: Stress and Aging: The Glucocorticoid Cascade Hypothesis

J Endocrinol. 1986 Dec;111(3):477-82.
The streaming adrenal cortex: direct evidence of centripetal migration of adrenocytes by estimation of cell turnover rate.
Zajicek G, Ariel I, Arber N.
Thirty adult male rats were injected with 0.5 microCi [3H]thymidine/g body weight (specific activity 5 Ci/mmol) and killed, in groups of five, 1 h and 14, 30, 60, 90 and 120 days after injection. The displacement of labelled adrenocytes with time was estimated in autoradiograms of adrenal sections. The radial distance of the labelled cell from the capsule was measured with an eyepiece micrometer and expressed in cell location units, i.e. the number of cells separating the labelled cell from the capsule. One hour after labelling, 95% of labelled cells were confined to the outer quarter of the cortex. During the following days, adrenocytes were displaced inwardly, approaching the medulla at a velocity of 0.24 locations/day. They traversed the three cortex zones, reaching the medulla after 104 days. The three adrenal zones represent three differentiation states of the adrenocyte. When young, the adrenocyte secretes aldosterone, after leaving the glomerulosa it produces corticosteroids and on reaching the reticularis it produces sex hormones. The adrenal cortex is a cell renewal system made of two compartments. A progenitor compartment extending between locations 1 and 15, and a functional compartment, covering locations 16-64. The first compartment produces 0.47 cells daily, which enter the second. Half of them die on their way while the rest are eliminated in the reticular zone. The cell stream is nourished by a subcapsular stem cell.

J Clin Endocrinol Metab. 1997 Nov;82(11):3898-901.
Aging alters zonation in the adrenal cortex of men.
Parker CR Jr, Mixon RL, Brissie RM, Grizzle WE.
Whereas aging has been shown to be associated with striking reductions in circulating levels of adrenal androgens in humans, the alteration in adrenal function that occurs in aging has not been identified. We sought to determine if there are changes in the zonation of the adrenal in aging men by performing histomorphologic analyses of adrenal specimens that had been obtained at autopsy following sudden death due to trauma. We evaluated adrenals from 21 young men (20-29 yrs) and 12 older men (54-90 yrs); inclusion criteria required the presence of medullary tissue in the specimen and fixation within the first 24 hrs postmortem. Sections stained with H/E were examined microscopically and areas of the cortex that included adjacent medullary tissue were chosen for quantitative evaluation by use of a computerized image analysis system. The average width (arbitrary units, pixels) of the zona reticularis and that of the combined zonae fasciculata/glomerulosa were determined from sections stained for reticulum fibers. The zona reticularis represented 37.1 +/- 1.9% of the total cortical width in the young men, which was significantly greater than that of the older men (27.1 +/- 3.3%, P = 0.0082). The zona fasciculata/glomerulosa to zona reticularis ratio in the young men (1.84 +/- 0.15) was significantly less that that of the older men (3.29 +/- 0.47, P = 0.0011). There was no significant difference in the total width of the cortex in young compared to older men. These data suggest that aging results in alterations within the cortex of the adrenals in men such that there is a reduction in the size of the zona reticularis and a relative increase in the outer cortical zones. A reduced mass of the zona reticularis could be responsible for the diminished production of dehydroepiandrosterone and dehydroepiandrosterone sulfate that occurs during aging.

Gershom Zajicek and his colleagues have demonstrated an organized renewal of tissues, in which new cells are born with the division of stem cells, and “stream” away from their origin as they mature, and finally are shed or dissolved. A few studies have demonstrated a similar kind of migration of cells in the brain (Eriksson, et al., 1998; Gould, et al., 1999), a process which differs by the absence of systematic dissolution of mature brain cells. -Ray Peat, PhD

Nature Medicine 4, 1313 – 1317 (1998)
Neurogenesis in the adult human hippocampus
Peter S. Eriksson, Ekaterina Perfilieva, Thomas Björk-Eriksson, Ann-Marie Alborn, Claes Nordborg, Daniel A. Peterson & Fred H. Gage
The genesis of new cells, including neurons, in the adult human brain has not yet been demonstrated. This study was undertaken to investigate whether neurogenesis occurs in the adult human brain, in regions previously identified as neurogenic in adult rodents and monkeys. Human brain tissue was obtained postmortem from patients who had been treated with the thymidine analog, bromodeoxyuridine (BrdU), that labels DNA during the S phase. Using immunofluorescent labeling for BrdU and for one of the neuronal markers, NeuN, calbindin or neuron specific enolase (NSE), we demonstrate that new neurons, as defined by these markers, are generated from dividing progenitor cells in the dentate gyrus of adult humans. Our results further indicate that the human hippocampus retains its ability to generate neurons throughout life.

Science. 1999 Oct 15;286(5439):548-52.
Neurogenesis in the neocortex of adult primates.
Gould E, Reeves AJ, Graziano MS, Gross CG.
In primates, prefrontal, inferior temporal, and posterior parietal cortex are important for cognitive function. It is shown that in adult macaques, new neurons are added to these three neocortical association areas, but not to a primary sensory area (striate cortex). The new neurons appeared to originate in the subventricular zone and to migrate through the white matter to the neocortex, where they extended axons. These new neurons, which are continually added in adulthood, may play a role in the functions of association neocortex.

Hair Regeneration:
Nature 447, 316-320 (17 May 2007) | doi:10.1038/nature05766; Received 30 August 2006; Accepted 20 March 2007
Wnt-dependent de novo hair follicle regeneration in adult mouse skin after wounding
Mayumi Ito1, Zaixin Yang1, Thomas Andl1, Chunhua Cui1, Noori Kim1, Sarah E. Millar1 & George Cotsarelis1
The mammalian hair follicle is a complex ‘mini-organ’ thought to form only during development1; loss of an adult follicle is considered permanent. However, the possibility that hair follicles develop de novo following wounding was raised in studies on rabbits2, 3, mice4 and even humans fifty years ago5. Subsequently, these observations were generally discounted because definitive evidence for follicular neogenesis was not presented6. Here we show that, after wounding, hair follicles form de novo in genetically normal adult mice. The regenerated hair follicles establish a stem cell population, express known molecular markers of follicle differentiation, produce a hair shaft and progress through all stages of the hair follicle cycle. Lineage analysis demonstrated that the nascent follicles arise from epithelial cells outside of the hair follicle stem cell niche, suggesting that epidermal cells in the wound assume a hair follicle stem cell phenotype. Inhibition of Wnt signalling after re-epithelialization completely abrogates this wounding-induced folliculogenesis, whereas overexpression of Wnt ligand in the epidermis increases the number of regenerated hair follicles. These remarkable regenerative capabilities of the adult support the notion that wounding induces an embryonic phenotype in skin, and that this provides a window for manipulation of hair follicle neogenesis by Wnt proteins. These findings suggest treatments for wounds, hair loss and other degenerative skin disorders.

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By Team FPS – June 28, 2012

Nutrition and Brain Growth in Chick Embryos

Also see:
Progesterone: Essential to Your Well-Being
Harm of Prenatal Exposure to Radiation
Metabolism, Brain Size, and Lifespan in Mammals
Sodium Improves Premature Infant Development
The Brain – Estrogen’s Harm and Progesterone’s Protection
Gelatin, Glycine, and Metabolism
PUFA, Development, and Allergy Incidence
Maternal Ingestion of Tryptophan and Cancer Risk in Female Offspring
PUFA, Development, and Allergy Incidence
Role of Serotonin in Preeclampsia
Sodium Deficiency in Pre-eclampsia
Childhood conditions influence adult progesterone levels

Quotes by Ray Peat, PhD:
“In the spring, with increased day length, the brains of song-birds grow, with an increased proliferation of cells in the part of the brain involved in singing. The production of progesterone increases in most animals in the spring, and it is the main hormone responsible for the birds’ brain growth”.

“The use of adequate protein and saturated fats during pregnancy will prevent many of the problems of pregnancy and infancy, but since the unsaturated fats remain stored in the tissues for many years, and are mobilized during stress, it’s important to eat correctly long before pregnancy. The requirement for vitamin E remains high for years after the diet has contained an excess of the polyunsatured fats. The diet which protects the developing fetus happens to be the diet that protects adults from all sorts of stress, and prevents many of the worst symptoms of aging.”

“The hormone progesterone participates in practically every physiological process, in both men and women. Its tremendous increase during pregnancy serves to stabilize the organisms, both mother and child, during that crucial time. At levels reached just before delivery, progesterone produces anesthesia and contributes to tissue elasticity. The fetus requires large amounts of glucose, and progesterone makes it possible to be provided in abundance for ideal brain growth, by promoting the mother’s ability to use fat for her own energy.”

“In the fetus and newborn baby, sodium promotes growth. Progesterone, sodium, and glucose are limiting factors in the growth of the baby’s brain; whey they are deficient, cells die instead of growing.”

“A bird developing inside its eggshell illustrates the way organs and the environment interact. The chicken created a very good environment for the early development of its young. When the egg is formed, it contains everything needed to produce a chicken, except for oxygen and a steady warm temperature. But before the chick’s body has finished developing, using yolk fat for energy, the glucose contained in the egg has been consumed, and at that point the chick’s brain stops growing. A researcher who knew that brain growth in other kinds of animals requires glucose, injected glucose (or glycine) into the developing eggs when the original glucose had been depleted. The supplemental glucose allowed the chick’s brain to continue growing until it hatched. These chicks had larger brains, containing more numerous cells. The same experimenters also found that progesterone increases brain size, while corticosterone decreases it. Although the egg is a very good environment for the development of chickens, these experiments showed that it isn’t the best that can be achieved. If the hen’s environment had been different, it might have been able to provide as much glucose and progesterone as the experimenters did.

Mammals were able to develop bigger brains than birds, by gestating their offspring internally, allowing a continuous supply of nutrients, such as glucose, and hormones such as progesterone. But the environment of the mother still can profoundly affect the development of the offspring, by influencing her physiology.”

“Estrogen’s brain toxic effects have been known since the 1950s, or earlier. Text-books in the 1960s discussed experiments in which either estrogen or insulin stopped growth of the fetus’s brain, and also in the 1960s experiments were showing that progesterone fosters brain growth and intelligence. Zamenhoff’s work showed that the prenatal abundance of glucose is a central factor in brain growth. Since estrogen and insulin lower blood sugar, and progesterone and thyroid sustain it, Zamenhoff’s work showed that the level of glucose was a common factor in many of the previous experiments, though other factors, including blood volume and body temperature, are also important. The epidemiological evidence is clear that women with toxemia of pregnancy, which involves inadequate delivery of glucose to the fetus, have babies with subnormal intelligence. Among obstetricians, it used to be common knowledge (before insulin treatment became common) that diabetic women were likely to have intellectually precocious children. As the work of Shanklin, Hodin, and the Brewers shows, there is a large group of Americans with neurological damage resulting from their mothers’ treatment during pregnancy.”

In “The Biological Generality of Progesterone” (1979) I proposed that the life-long trajectory of energy production and longevity was strongly influenced by prenatal nutrition and progesterone. This idea was based on work by people such as Marion Diamond, who showed that prenatal progesterone enlarges the cortex of the brain, and that estrogen makes it smaller, and Leonell Strong, who showed that a treatment that lowered the estrogen function in a young mouse could produce cancer-free offspring for several generations. Strong’s work was very encouraging, because it showed that biological problems that had been “bred in” over many generations could be corrected by some simple metabolic treatments.

More here from Dr. Peat in a short interview excerpt.

Growth. 1979 Mar;43(1):58-61.
The effect of progesterone on brain and body growth of chick embryos.
Ahmad G, Zamenhof S.
It has been suggested that in the embryo hormonal steroids may act also as control factors for the growth of neural systems. In the present work progesterone was introduced onto the chorioallantoic membrane of the chick embryo on day 7 or days 7 and 10 of incubation. The embryo, dissected at day 10, showed significant increases in body weight and cerebral hemispheres weight. The response at day 13 was less pronounced; male embryos responded to progesterone more than the female embryos. Progesterone is a precursor to other corticosteroids, but corticosterone itself had a significant harmful effect on embryonal growth. Several possible explanations of these results have been offered. It appears that progesterone itself promotes the growth of the early embryo, but the effect depends on its age and sex.

Growth. 1979 Sep;43(3):160-6.
The effects of exogenous nutrients on growth of chick embryo brain.
Zamenhof S, Ahmad G.
The effect of an early addition of exogenous nutrients on brain growth has been investigated in chick embryo. The nutrients were introduced onto chorioallantoic membrane at day 6 or 7 of embryonal life, and the cerebral hemispheres examined at the end of neuronal proliferation for the following parameters: weight, DNA content (index of cell number) and protein content. L-Tryptophan produced significant inhibition, probably by creating amino acid imbalance and interference with the transport of other amino acids. D-Tryptophan (slower transport) was inactive. 5-Methyltryptophan produced significant inhibition, probably by causing deficiency of tryptophan utilization and of production of serotonin, which is a growth factor for early brain. Glycine stimulated brain growth, probably by conversion to glucose which is the main energy source for the embryo in this period. Brain weight and DNA were found to be significantly correlated with blood glucose level. It is concluded that, within genetic limits, early brain growth might be manipulated in both directions (inhibition or stimulation) by addition of proper nutrients during sensitive period of neuronal proliferation.

High Salivary Cortisol in Humans and Decreased Memory:
Neurobiol Aging. 2006 Nov;27(11):1705-14. Epub 2005 Nov 4.
Salivary cortisol and memory function in human aging.
Li G, Cherrier MM, Tsuang DW, Petrie EC, Colasurdo EA, Craft S, Schellenberg GD, Peskind ER, Raskind MA, Wilkinson CW.
OBJECTIVE:
To examine the association of salivary cortisol with cognitive changes in a 3 year longitudinal study. Previous studies have suggested that elevated glucocorticoid concentrations alter hippocampal neuronal morphology, inhibit neurogenesis, and impair cognition.
METHODS:
Salivary cortisol samples were collected at home by 79 cognitively intact older persons (mean age 78+/-7 years) at 08:00, 15:00 and 23:00h, and collections were repeated annually for 3 years. Cognitive function was also assessed annually.
RESULTS:
The mean cortisol level of samples taken at three times of day and the cortisol concentration at 23:00h were significantly associated with poorer performance on tasks of declarative memory and executive function. Of 46 subjects who completed the entire 3 year study, higher initial cortisol concentration at 23:00h predicted a decline in performance of delayed paragraph recall.
CONCLUSION:
These results partially confirm previous findings that high cortisol is associated with impaired declarative memory function in non-demented older persons. In addition, our data show that high salivary cortisol concentrations predict a decline in memory function over the next 3 years.

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By Team FPS – June 28, 2012

Towards a morphogenetic perspective on cancer

Riv Biol. 2002 Jan-Apr;95(1):35-61.
Towards a morphogenetic perspective on cancer.
Aranda-Anzaldo A.
The purpose of this paper is to present a critique of the current view that reduces cancer to a cellular problem caused by specific gene mutations and to propose, instead, that such a problem might become more intelligible, if it is understood as a phenomenon which results from the breakdown of the morphological plan or Gestalt of the organism. Such an organism, in Aristotelian terms, is characterised for presenting a specific morpho or logos (form) and for having a telos (end) to fulfill. A malignant tumour represents an entity separated from both, the organic logos and the organic telos. According to the basic postulates of Semiophysics–a blend of Aristotelian physics and Catastrophe Theory developed by René Thom–an organism is a source (original) form individuated by a dominant pregnancy which corresponds to its morphogenetic field. Here it is suggested that cancer in aged individuals may result from the progressive exhaustion of the developmental constraints that regulate the process of ontogeny, that is expected to go from the fertilised non-differentiated zygote to the mature fully-developed organism, because there is no further point ahead in the developmental pathway past the reproductive age. Cancer in young individuals (before their reproductive maturity) may then be consequence of premature derangement of such fundamental developmental constraints. In all cases the result is the loss of morphological coherence within the organism. Thus representing a conflict between an organised morphology (the organism) and a part of such a morphology that drifts towards an amorphous state (the tumour).

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By Team FPS – June 28, 2012