Glycine Is An Endotoxin (TLR4) Antagonist

[Dan W]

I've always thought Tumor Necrosis Factor Alpha would be a perfect name for a Japanese death metal band.

I keep meaning to look into the amount of endotoxin we might expect from gelatin products, but I hadn't thought of how the glycine might cancel out any risk.

 

[Amazoniac]

https://www.researchgate.net/publication/21106103_The_glycine_story

"In the Caribbean, one of the most notable features of children who die from malnutrition is the massive fatty infiltration of the liver (Waterlow, 1948). The development of a fatty liver is to an extent nonspecific, with the final common pathway for a number of insults being apparent at the level of the liver. The ability of the liver to clear a xenobiotic, such as indocyanine green (ICG), has been used as a sensitive test of hepatic function. In rats, a fatty liver induced by feeding a diet deficient in choline is not associated with any change in ICG clearance, whereas with a fatty liver produced by a low protein diet ICG clearance is significantly impaired (Johoor & Jackson, 1982)." "As the extent of fatty liver on a low protein diet is influenced by the availability of dietary cysteine (Davis, Hibbert & Jackson, 1988), either the hepatic level of glutathione or the activity of the glutathione-S-transferase enzymes may be particularly important."

"One important function performed by glycine is that it is used to conjugate with a range of xenobiotics, making them more amenable to excretion."

"Neuberger (1981) suggests that there is a requirement for the endogenous synthesis of glycine that is between 10 and 50 times the dietary intake."

"The evidence shows that in normal adults on either a low protein diet, or one that is limited in the intake of non-essential nitrogen, the de novo synthesis of glycine is insufficient to satisfy the metabolic demand (Gersovitz et al., 1980; Yu et al., 1985)."
"These observations are entirely consistent with the earlier work on rats, which shows that despite a considerable ability for endogenous glycine synthesis, this ability does have a finite upper limit and the limit can be exceeded under an appropriate combination of diet and physiological or pathological stress. In these circumstances it has to be acknowledged that glycine is in effect acting as a conditionally essential amino acid."

Spoiler: Table 1

"There are two major pathways through which glycine may be derived, but the evidence does not allow for quantitative estimates to be made of the relative importance of either pathway (Neuberger, 1981):
a) by transamination of the carbon skeleton, glyoxylic acid; this route needs an adequate source of glyoxylate, which is as yet undefined.
b) by interchange with serine through glycine cleavage system, a route requiring net synthesis of serine (Snell, 1986)."

"There are a range of physiological states in which the metabolic demand for glycine would be expected to increase, thereby creating a greater likelihood of a shortfall in supply."

"During infection or trauma the body develops an acute phase response which is mediated by cytokines released from macrophages and other cells. This response is characterised by co-ordinated changes in a number of tissues and includes a shift in the type and pattern of protein synthesised. Grimble (1989) has shown that a number of the acute phase proteins are particularly rich in glycine and serine residues (Table 2). Patients with severe inflammatory conditions, being teated with total parenteral nutrition for intestinal failure, were found to have significantly elevated urinary 5OP[*] levels."
*"Glutathione synthetase deficiency is an inborn error of metabolism in which an inability to synthesise glutathione from y-glutamylcysteine results in excessive production of 5-oxoproline (SOP)"

Spoiler: Table 2

"In the past, functional demand has been expressed in a rather crude way, in terms of nitrogen balance or weight gain. Increasingly we should try to be more specific about the functional demand for individual amino acids in relation to metabolic state. So far as glycine is concerned, there is a close relationship between the metabolism of this amino acid and serine, and also with the sulphur amino acids methionine and cysteine. Cysteine and glycine contribute to the formation of glutathione, which plays a fundamental role in a wide range of cellular functions and protective mechanisms. Cellular multiplication places a heavy demand on the need for serine, glycine and methyl groups; thus factors that interfere with this area of metabolism are going to have an impact not only upon normal growth, but also upon the propensity for neoplastic tissues to grow, invade and metastasise (Snell, 1983; Snell & Riches, 1989)."​

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https://www.hindawi.com/journals/omcl/2017/1716701/

"French chemist H. Braconnot was the first to isolate glycine from acid hydrolysates of protein in 1820 [1]. The taste of glycine is sweet like glucose, because of its sweet nature, and its name was derived from Greek word “glykys.” Glycine is produced by alkaline hydrolysis of meat and gelatin with potassium hydroxide. A. Cahours chemically synthesized glycine from monochloroacetic acid and ammonia and established the structure of glycine [2]. Glycine is the simple amino acid with no L or D chemical configuration.The extracellular structural proteins such as elastin and collagen are made up of glycine. For mammals such as pigs, rodents, and human beings, glycine is treated as nutritionally nonessential amino acid. But some of the reports state that the quantity of glycine produced in vivo in pigs, rodents, and human beings is not adequate for the metabolic activity of them [3]. Shortage of glycine in small quantities is not harmful for health but severe shortage may lead to failure of immune response, low growth, abnormal nutrient metabolism, and undesirable effects on health [4]."

"In collagen, glycine is located at every third position; glycine residues bring together the triple helix of the collagen.The flexibility of active sites in enzymes is provided by glycine [5]. In central nervous system, glycine plays a crucial role as neurotransmitter, thereby controlling intake of food, behavior, and complete body homeostasis [6]. Glycine regulates the immune function, production of superoxide, and synthesis of cytokines by altering the intracellular Ca2+ levels [7]. The conjugation of bile acids in humans and pigs is facilitated by glycine; thereby glycine indirectly plays a crucial role in absorption and digestion of lipid soluble vitamins and lipids. Are NA, the NA, creatine, serine, and haem are generated by several pathways which utilize glycine. Collectively, glycine has crucial function in cytoprotection, immune response, growth, development, metabolism, and survival of humans and many other mammals."

"The biochemical studies on rats proved that glycine is synthesized from threonine (through threonine dehydrogenase pathway), choline (via formation of sarcosine), and serine (through serine hydroxymethyltransferase [SHMT]). Later on, in other investigations it was proved that the glycine synthesis in pigs, humans, and other mammals is through the abovementioned three pathways [8]. From the recent studies it was stated that hydroxyproline and glyoxylate are substrates for glycine synthesis in humans and mammals [9, 10]." [?]

"Methyl groups are generated in the mammalian tissues during degradation of choline to glycine. Generally in adult rats around 40– 45% of the choline uptake is converted to glycine and this value can sometimes increases up to 70% when the choline uptake is very low." @Mito

"The reactions involving the transfer of methyl group in cells are largely affected by S-adenosylhomocysteine to S-adenosylmethionine. If the content of choline in diet is very low, then glycine synthesis is quantitatively very low in mammals."

"Metabolic acidosis, high protein diets, and glucagon increase glycine degradation and hepatic glycine cleavage activity in different mammals. But in the case of humans, high level of fatty acids in plasma suppresses the amount of glycine appearance and does not appear to influence glycine oxidation [34]."

"It was reported that glycine is very effective to optimize the activities of g-glutamyltranspeptidase, alkaline phosphatases, asparatate transaminases, tissue fatty acid composition, and alanine transaminase, so oral supplementation of glycine can be very effective in protecting the alcohol-induced hepatotoxicity. Moreover glycine can optimize or change the lipid levels on chronic alcohol feeding by maintaining the integrity of membranes [35]. It was demonstrated that the rats supplemented with glycine showed very low blood alcohol levels. Iimuro et al. (2000) stated glycine as excellent preventive to reduce the alcohol levels in blood. Glycine has multiple effects such as reduction of accumulation of free fatty acids and regulates the individual free fatty acid composition in brain and liver of rats on chronic alcohol feeding. From the above evidences and reports it was proved that glycine is very effective and successful as a significant protective agent to fight against ethanol induced toxicity [36–38]."

"Glycine can also fight against free radical-mediated oxidative stress in hepatocytes, plasma, and erythrocyte membrane of humans and animals suffering from alcohol-induced liver injury [39]. From an in vivo study, it was demonstrated that certain melanomas like B16 and hepatic cancer can be prevented by glycine as it suppresses the endothelial cell proliferation and angiogenesis."

"Some of the other benefits of glycine are that it has cryoprotective effect in lethal cell injuries such as anoxia as it inhibits Ca[2+]- dependent degradation by nonlysosomal proteases including calpains [40].

"Benign prostatic hyperplasia, schizophrenia, stroke, and some of the rare inherited metabolic disorders can be cured by glycine supplementation."

"The harmful effects of certain drugs on kidneys after organ transplantation can be protected by glycine diet."

"Glycine can be applied to skin to cure some wounds and ulcers in legs and it is most commonly used in treating ischemic stroke."

"Glycine exhibits prophylactic effect against hepatotoxicity."

"Tumor necrosis factor, inflammation, and activation of macrophages are inhibited by glycine."

"Jacob et al. (2003) reported that glycine protects the stomach from damage during the mesenteric ischemia by suppressing the apoptosis [46]."

"GLYT1 receptor is present in the basolateral membrane of enterocytes and its main function is to import glycine into the cells." "If glycine is given before the oxidative challenge, it protects the intracellular glutathione levels without disturbing the rate of glycine uptake. Protection of intracellular glutathione levels depends on the unique activity of GLYT1 receptor. GLYT1 receptor provides the necessary requirements for intracellular glycine accumulation."

"The ability of glycine to change the multiple cell types further highlights the difficulty in dissecting the several modes of glycine function in reducing injury and inflammation."

"Glycine has an ability to control the immunological reaction and will help to suppress the rejections after [organ] transplantation."

"glycine has moderate immunosuppressive properties."

"Endotoxic and hemorrhagic shock are commonly seen in critically ill patients. Hypoxia, activation of inflammatory cells, disturbance in coagulation, and release of toxic mediators are main factors that lead to failure of multiple organs. The abovementioned events reasonable for multiple organ failure can be significantly inhibited by glycine; therefore glycine can be effectively used in therapy for shock [61]."
"endotoxin treatment triggers hepatic necrosis, lung injury, increased serum transaminase levels, and mortality which can be cured by short term glycine treatment. Constant treatment with glycine for four weeks decreases inflammation and enhances survival after endotoxin but does not improve liver pathology [63]"

"Glycine improves function of liver, cures liver injury, and prevents mortality in experimental sepsis caused by cecal puncture and ligation. From the scientific literature it is clear that glycine is very potent in protecting septic, endotoxin, and hemorrhagic shock [64]."

"Glycine possesses effective cytoprotective and antiulcer activity."

"PG-PS is a very crucial structural component of Gram-positive bacterial cell walls and it causes rheumatoid like arthritis in rats. In rats injected with PG-PS which suffer from infiltration of inflammatory cells, synovial hyperplasia, edema, and ankle swelling, these effects of PG-PS model of arthritis can be reduced by glycine supplementation [66]."

"Polyunsaturated fatty acids and peroxisomal proliferators are very good tumor promoters as they increase cell proliferation. Kupffer cells are very good sources of mitogenic cytokines such as TNF. Glycine taken in diet can suppress cell proliferation caused by WY-14,643 which is a peroxisomal proliferator and by corn oil [67, 68]. The synthesis of TNF by Kupffer cells and activation of nuclear factor B are blocked by glycine. The 65% of tumor growth of implanted B16 melanoma cells is inhibited by glycine indicating that glycine has anticancer property [69]."

"The authors declare that they have no competing interests."​

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https://www.researchgate.net/figure...egradation-and-cellular-effects-AGEs-advanced

Where does plasma methylglyoxal originate from? - ScienceDirect

https://ars.els-cdn.com/content/image/1-s2.0-S0168822712004263-gr1.jpg​

 

[Amazoniac]

Op:
"
- Glycine N-Methyltransferase and Regulation of S-Adenosylmethionine Levels
- Effect of Glycine and Serine on Methionine Metabolism in Rats Fed Diets High in Methionine
- Suppression of Methionine-Induced Hyperhomocysteinemia by Glycine and Serine in Rats
- Effect of Dietary Glycine on Methionine Metabolism in Rats Fed a High-Methionine Diet
- https://www.westonaprice.org/health-topics/abcs-of-nutrition/beyond-good-and-evil/ ("glycine")
- Valtsu's: Health Benefits of Glycine
- A weak link in metabolism: the metabolic capacity for glycine biosynthesis does not satisfy the need for collagen synthesis
- Dietary Glycine Supplementation Mimics Lifespan Extension By Dietary Methionine Restriction
- Effect of glycine and vitamin supplementation on sulphur amino acid utilization by growing cattle. - PubMed - NCBI
- Effects of dietary protein, glycine, and tryptophan on iron metabolism in the growing chick. - PubMed - NCBI

I don't know for sure about the relevance of plasma amino acids, but the fact that vegans have greater levels of glycine circulating is interesting since most vegetarians and omnivores consume plenty of methionine.
Plasma concentrations and intakes of amino acids in male meat-eaters, fish-eaters, vegetarians and vegans: a cross-sectional analysis in the EPIC-Oxford cohort
"
- The role of glycine in regulated cell death

 

[Amazoniac]

Diet and Inflammation Part 1-4 - By Joel Brind, Ph.D - One Radio Network

"Joel Brind, Ph.D

Diet and Inflammation Part 1
Diet and Inflammation
Jul 24, 2014

There’s no shortage of info out there about inflammation’s being the root cause of most of what makes people sick and die these days–from arthritis to diabetes to cardiovascular disease to cancer—and what to eat and not eat to put your body into an “anti-inflammatory” state.
But there is a shortage of real knowledge about inflammation itself: What its proper role is in the body and why it is so often out of control. Once you know that, the rest is easy.
Back in the day (some 35 years ago), I studied immunology at NYU Medical School as part of my graduate training in Basic Medical Science. You would think that inflammation, as a major function of the immune system—innate immunity, to be precise—would occupy a substantial proportion of the course material. Nope! Everyone in the field, it seemed, wanted to win the Nobel Prize for figuring out acquired immunity: How does the body figure out how to make a specific antibody against the chemical signature of a microbe it has never encountered before? That was one of the great mysteries of the day; the principle behind vaccination and all manner of specific immunity. Well, that mystery was eventually solved, and I don’t even remember who got the credit. Are we making better vaccines and saving more lives because of it? You be the judge.
But if you go back to the days when infectious disease killed most people; when great plagues swept through human populations with some regularity, it wasn’t acquired immunity that saved most of the survivors. It was innate immunity. After all, acquired immunity takes weeks to develop after the first exposure, and the body can succumb to infection in a few days. So the real life saver is the first response system, the aggressive, non-specific attack against the offending microbes. Of course, such attack can and does do lots of damage to normal tissues in the process, but it might just save your life.
It’s really just like society’s first responders; like the fire department. When your fire alarm detects a fire, the fire department is summoned, and quickly the firemen show up with their axes and their hoses. They put the fire out, all right, but they do lots of damage in the process. Once the fire is out, you bring in the repair contractor to fix the damage. In your body, once the threat of infection has been neutralized, healing begins.
But for some odd reason, inflammation—the basic operation of innate immunity—is still viewed by the medical and scientific community as part of the healing response. In fact, the opposite is true: it inhibits healing quite effectively.
Two years ago, this is how Wendy Weber, A National Center for Complementary and Alternative Medicine (one of the NIH Institutes) program director, was quoted in the Wall Street Journal (wsj.com; the section entitled “The Informed Patient”, article author Laura Landro). ‘”You need to have inflammation when you have a wound and the immune system goes in to heal it. Yet we don’t want too much inflammation in our system causing damage to our arteries” and other harm’.
The prevailing dogma, unfortunately, does not really distinguish the separate roles of immune defense and tissue repair.
To take a simple example, say you sprain your ankle. It gets all swollen and painful and immobilized from what process? Inflammation. In fact, everyone knows that the immediate treatment of choice is to put ice on it. To do what? To suppress inflammation!
Why? Because the inflammation prevents healing from taking place.
OK, so why does inflammation happen at all when you sprain your ankle? Because, it is generally believed, inflammation is the body’s natural response to tissue injury; to distress signals released from damaged cells and tissues. But why? If you sprain your ankle, where is the route of infection? There are no invading microbes to destroy, and if inflammation happens anyway and does more harm than good, why does your body do it? Why do you have to interfere with your body’s natural response to the blunt injury, for optimal healing to occur?
The answer is quite simple: Your body is not acting appropriately, because it is laboring under a nutritional imbalance. Actually, the typical Western diet tends to be deficient and/or imbalancedin 3 key nutrients: salicylic acid, omega-3 fatty acids (vs. omega 6), and glycine (vs. methionine). The third is the most important and the least well known (although Vladimir Heiskanen’s excellent recent post on this blog gives a pretty good introduction). I’ll get to the specifics of how all this works—down to the cellular and molecular level–in my next post.

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Diet and Inflammation Part 2
Diet and Inflammation
Aug 11, 2014

My last post—part 1 of Diet and Inflammation—left off with my conclusion that the answer to the widespread prevalence of chronic inflammation was a nutritional imbalance incurred by the typical Western diet, specifically deficiencies or imbalances in 3 key nutrients: omega-3 (v. omega 6) fatty acids, salicylic acid and glycine (v. methionine).
What exactly happens in inflammation? Inflammation is the basic action of the innate immune system to destroy potentially pathogenic microbes that get into the internal body tissues. It is a non-specific aggressive action by amoeba-like cells called macrophages (derived from the Greek and meaning “big eaters”), the immune system’s first responders, which can literally gobble up bacteria and other microbes. Several types of these cells—called granulocytes—have long been recognized as circulating in the blood as a type of white blood cell. More recently, macrophages have been recognized as populating all sorts of organs and tissues.
But all these diverse types of macrophages are immune system cells, and all of them originate in the bone marrow. If there is tissue injury, injured cells and cell debris will be gobbled up by these macrophages. But if there is infection—the recognition of the generic signature of bacteria, for example—these macrophages get activated, producing toxins such as hydrogen peroxide in order to kill the bacteria. In order to amplify the reaction, these macrophages release chemical signals called prostaglandins to recruit and activate other macrophages, the purpose being to destroy the infecting microbes before they can destroy the host. Of course, like other first responders, the macrophages will put down the infection just like the firemen will put out the fire, but they will also do lots of damage to normal tissues.
Unfortunately, there is still lots of confusion out there about the role of inflammation and innate immunity; most medical authorities believing that inflammation is part of the healing response and a normal response to tissue injury. Why? Because it always seems to happen with tissue injury. You sprain your ankle, and it gets swollen and painful and immobilized; i.e., inflamed. But why should this happen if there is no route of infection? There are no microbes to kill. And we all know that, contrary to healing, the inflammation inhibits healing, which is why we have to put ice on the injury, to suppress inflammation. So why does your body do it?
Here’s where nutrition comes in. The activation of macrophages is affected by an electrochemical switch mechanism on the cell surface membrane. When these cells are at rest, they are, so to speak, switched off, there is a resting voltage between the outside and the inside of the cell (positive outside; negative inside). Just like a light switch on your wall, when it is off, there is a resting voltage (120 volts in the US) between the hot wire attached to the switch and the light fixture. When the light is switched on, the voltage drops as the energetic electrons flow through the switch and activate the fixture. The electrochemical switches in cells are channels in the membrane which allow positively charged ions (calcium or sodium ions) to flow across the membrane. The voltage drops when these channels open up momentarily, activating the cell. That’s how nerve impulses (called action potentials) activate muscles, for example. But it’s also how macrophages get activated.
However, the cell surface membrane is a very dynamic envelope, like a constantly moving, constantly changing, highly sophisticated soap bubble. In the course of ordinary activity, lots of leakage of ions occurs, and there are specialized channels in the membrane that let negatively charged chloride ions in to maintain the resting voltage of 0.07 volts. A substantial proportion of these chloride channels are operated—i.e., maintained in an open position—by the amino acid glycine. Glycine is ordinarily present in body fluids at high concentrations. But if they are not high enough, the glycine-gated chloride channels (aka glycine receptors) are not open enough to allow adequate chloride entry. Thus, the voltage between the outside and inside of the cell deteriorates and the cell is too easily activated, like when there is tissue injury but no infection. Once a macrophage is activated, the extent to which it recruits and activates other macrophages to the site of inflammation is related to the levels of the two other key nutrients: salicylic acid and omega-3 v. omega-6 fatty acids.
How the balance—or imbalance—in the intake of these types of polyunsaturated fatty acids (PUFAs) will be the subject of Part 3 in this series.

Ray Peat states this about this very topic…

A generous supply of glycine/gelatin, against a balanced background of amino acids, has a great variety of anti-stress actions. Glycine is recognized as an “inhibitory” neurotransmitter, and promotes natural sleep. Used as a supplement, it has helped to promote recovery from strokes and seizures, and to improve learning and memory. But in every type of cell, it apparently has the same kind of quieting, protective anti-stress action. The range of injuries produced by an excess of tryptophan and serotonin seems to be prevented or corrected by a generous supply of glycine. Fibrosis, free radical damage, inflammation, cell death from ATP depletion or calcium overload, mitochondrial damage, diabetes, etc., can be prevented or alleviated by glycine.

Some types of cell damage are prevented almost as well by alanine and proline as by glycine, so the use of gelatin, rather than glycine, is preferable, especially when the gelatin is associated with its normal biochemicals. For example, skin is a rich source of steroid hormones, and cartilage contains “Mead acid,” which is itself antiinflammatory.

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Diet and Inflammation Part 3
diet and inflammation
Aug 25, 2014

In my last post—Part 2 of this diet and inflammation series—I discussed the cells—called macrophages—which actually affect the inflammatory response, and how the amino acid glycine is crucial in regulating the activation of the macrophages at the level of the cell surface membrane. In the present installment, I’ll be discussing the propagation and amplification of the inflammatory response, and the key roles played by two other nutrients: salicylic acid and omega-3 (v. omega-6) fatty acids.
The cell membrane itself is made up mainly of molecules called phospholipids; natural soap-like molecules which each contain two fatty acids. Upon cellular activation, some of these phospholipid molecules are broken down such that one of the fatty acids is enzymatically converted to a messenger molecule—a prostaglandin—which diffuses away to activate—or inhibit the activation of—other cells it reaches (Such local messenger molecules are known as paracrine factors.) The enzyme that catalyzes the key step in the process is called a cyclooxygenase 2 (COX2). Salicylic acid inhibits the activity of COX2. (The synthetic drug aspirin, or acetylsalicylic acid, is a much more potent COX2 inhibitor; more on this later.)
The type of prostaglandin molecule released reflects the composition of the type of fatty acids that make up the membrane, which in turn reflects the fatty acid composition of the diet. The prostaglandins that amplify the inflammatory activation are made from the omega-6 fatty acid, arachidonic acid (AA); whereas prostaglandins that inhibit this activation are made from the omega-3 fatty acid, eicosapentaenoic acid (EPA).
Hence, the greater the preponderance of omega-6 fatty acids in the diet (largely from seed oils, e.g., corn, soybean, sunflower, peanut) as opposed to omega-3 (fish or krill oil, flaxseed oil), the greater the amplification of the pro-inflammatory prostaglandin signal. (The optimal dietary ratio of omega-6 to omega-3 is about 3 or 4 to one; although whether either type of these polyunsaturated fatty acid types—”PUFAs”—are even essential to the human diet is still debated. Oils that seem to have a perfect balance of fatty acid types include walnut and olive oils [Hemp Seed Oil ~JP].) Since the mass campaign to replace saturated fats with PUFAs over the latter half of the 20th century was largely successful in saturating the Western diet (and that of its livestock) with omega-6 PUFAs, it has clearly contributed to the high prevalence of chronic inflammation.
Meanwhile, the extent of COX2 activity is largely controlled by the concentration of salicylic acid. For some reason, salicylic acid is often viewed as a “nutraceutical”, rather than an everyday nutrient. In fact, it is often not viewed as a nutrient at all, although aspirin is viewed as something middle-aged and older individual are encouraged to take daily to prevent thrombotic events such as heart attacks and strokes. Aspirin, however, is a potent synthetic drug. Although it acts like salicylic acid (as well as increasing the actual salicylic acid content of the blood), it has potentially dangerous side-effects, like excess bleeding. Meanwhile, salicylic acid itself is a widespread botanical compound, particularly high in berry fruits, grapes and kiwis, and also present in significant amounts in nuts like almonds and walnuts. (It is also a key component of EVOO that is removed when olive oil is refined.)
It is my belief that it is salicylic acid, rather than the much touted polyphenols in fruits and nuts which are key to “anti-inflammatory diets”, and which lower risk of cardiovascular disease, for example. These polyphenols (e.g., resveratrol, quercetin) are great anti-oxidants, but the value of anti-oxidants is largely to mitigate the effects of inflammation. I think it’s better to stop inappropriate inflammation from getting started. I also believe, for example, that the “French paradox”—why French people eat such a high-fat diet but suffer a low rate of heart disease—is not due to the polyphenols in the wine they drink daily, but from the high salicylic acid content of grapes, and therefore, wine.
So it’s pretty clear how the typical Western diet that is low in fruits and vegetables, and low in omega-3—but high in omega-6 fats—contributes to excess inflammation, by helping to amplify—and therefore exaggerate—the inflammatory response. But getting back to the initiation of inflammation in the first place, why should glycine levels be low in the first place, and allow inflammation to develop inappropriately? After all, glycine is a non-essential amino acid, so you really should not have to eat any of it, right? And if the diet is rich in high-protein foods (meat, fish, poultry, eggs, dairy), we are also eating plenty of it.
The answer turns out to be quite simple: Although we discovered a century ago that we need to eat whole grains to avoid devastating deficiency diseases like pellagra, we never thought that we also need to eat whole cows, pigs, chickens and fish! But it turns out that the key to a healthy omnivorous diet is to balance the content of essential amino acid methionine that predominates in muscle with the glycine that predominates in the bones and connective tissues, the parts we usually throw away.
The specifics of the biochemistry—the metabolic interactions of glycine and methionine and key intermediate metabolites and cofactors—are now understood, and present a fascinating picture of how our bodies’ metabolic machinery works as best it can with what we feed it to keep us alive and healthy. That will be the focus of my next post.

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Diet and Inflammation Part 4
Diet and Inflammation Part 4 - 180 Degree Health
Sep 20, 2014

My last post focused on the propagation of the inflammatory signal, and how nutrients such as omega-6 PUFAs and the lack of salicylic acid results in amplification of that signal, thus contributing to the overall increase in inflammation-related disease we currently experience.

Collagen

But what about the initiation of the inflammatory signal in the first place? That often turns out to be due to a widespread deficiency in the amino acid glycine, which I described in an earlier post. Glycine acts as a sort of “cellular voltage regulator”, preventing the inappropriate initiation of inflammation in response to cellular injury. (Inflammation is really only appropriate when there is infection taking place.)

But if glycine is the most abundant amino acid in the body, and it is nonessential—i.e., the human body can make it from scratch—why should anyone be deficient, especially nowadays, when the dietary intake of protein is usually so high?

As Matt Stone often says, it is really a matter of context; a matter of balance, rather than a matter of absolutes. Glycine is so abundant that it comprises about 22% by weight of the most abundant protein in the body. That protein would be collagen, the tough, extracellular fibrous protein that makes up the bones, cartilage and all the connective tissues. Hence, the collagen—and therefore most of the glycine—is the part of the meat, fish and poultry that we usually throw away. Bone broth is one way to recover it in the diet, and when the collagen is boiled out of the bones and purified, it is called gelatin.

But even though we discard most of the glycine from our animal flesh foods, we are still taking some in with our muscle meats, so that still doesn’t explain a widespread glycine deficiency. But in fact, the consumption of muscle meats actually exacerbates the deficiency because of the amino acid content of the muscle meats. Specifically, muscle meats are very rich in the essential amino acid methionine, and it is an understanding of the intimate relationship between methionine and glycine that provides the answer to this question of balance.

A problem with traditional nutritional thinking on amino acids is the rigid classification of those which are essential, as opposed to those which are non-essential; in particular, a disproportionate interest in the former v. the latter. Methionine, in particular, has long been known to play key roles in metabolism independent of its role as a constituent of proteins. Specifically, methionine—when activated to form S-adenosylmethionine (SAMe), is the universal methyl group donor, which adds a one-carbon methyl group (CH3 group) to a variety of important metabolic intermediates, including DNA bases and neurotransmitters.

So fundamental is this role of methylation, that the body (essentially, the liver) has numerous pathways of conserving, recycling, and salvaging methionine, so that it can withstand long periods of reduced methionine intake. So intense has been the emphasis on the essentiality of methionine, that methionine deficiencies have been hypothesized to underlie a number of pathologies, including cancer. But nothing could be further from the truth. In fact, typical Westerners consume about 10 times more methionine than is needed to support good health. (We really only need about 300 – 500 mg per day of methionine: more like the daily requirement for a B vitamin than a bulk nutrient!) Over 20 years’ worth of animal research has shown that laboratory animals (rats and mice) live substantially longer and healthier lives if their normal methionine intake is reduced by 80%. Moreover, it is now understood that metabolically, far from salvaging, recycling and regenerating methionine, the body switches gears and gets rid of most of the methionine absorbed from a typical high-protein meal.

What’s that got to do with glycine? The answer is remarkably simple: There is only one metabolic pathway that exists in the human body to get rid of excess methionine. That pathway—via the enzyme glycine-N-methyltransferase (GNMT)—uses up glycine in the process.

In Figure “a” below, we see a typical description of what is called the methionine cycle. It is my own version (I originally published these diagrams at the Annual Meeting of the Federation of American Societies for Experimental Biology [FASEB] in 2011.), but it typically shows how methionine is recycled, in order to conserve it maximally. I say typical, because this is the only metabolic picture generally shown in textbook descriptions of the methionine cycle. And it is accurate insofar as it applies when methionine levels are low, like when there is no methionine coming in from the diet, so methionine needs to be conserved.



In this metabolic diagram, the green arrows refer to active metabolic pathways, and the dotted black arrows refer to inactive or minimally active pathways; the red, upper case abbreviations stand for enzymes (e.g., GNMT), whereas the names and abbreviations in black are metabolic intermediates (e.g., SAMe). The heavy red dotted line shows a metabolic brake or inhibition (i.e., an “off switch”) of GNMT by an intermediate called MeTHF. MeTHF is a form of folic acid which recharges the intermediate amino acid homocysteine (Hcy) by adding a methyl group to it, thus regenerating methionine. The presence of MeTHF is a signal that methionine is being regenerated because it is scarce, and it specifically turns off GNMT so that methionine is not wasted in this time of need. The SAMe that is generated is available for essential processes, such as the methylation of DNA bases, as shown by the green arrow across the top of the diagram.

But what is not generally appreciated by biochemists and nutritionists is that when methionine is abundant, especially when methionine is being absorbed after a high-protein meal, the liver’s metabolic machinery switches gears (like it does in the transition after a high carb meal, when it switches from regenerating glucose to getting rid of glucose), working maximally to get rid of the excess methionine.

This situation is illustrated in Figure “b” below. In this diagram are also shown the two metabolic “on switches” (Solid yellow arrows with star points) for enzymes. Specifically, the high concentration of methionine itself cranks up the activity of MAT, which turns methionine into SAMe at a much higher rate. Most of this SAMe is not needed for essential methylation reactions, such as making DNA bases, but is instead deliberately wasted by GNMT, which has been turned on by the release of the braking action of MeTHF (shown in figure “a”). That’s because MeTHF is no longer being made, because SAMe itself shuts off MTHFR, the enzyme that makes MeTHF. Meanwhile, SAMe also turns on the enzyme CBS, which diverts homocysteine (“used” methionine) into the production of downstream sulfur-containing compounds (a pathway called “transulfuration”), including cysteine and glutathione, now that the remethylation (regeneration) of methionine has been turned off.



Note especially that in this high-methionine condition, glycine is required both for the action of GNMT (a pathway called “transmethylation”) and for the transsulfuration pathway, to make glutathione. In this mode, glycine can be made both from serine and from scratch (i.e., from CO2 and ammonia), through the operation of a glycine-serine cycle. However, the liver cannot keep up with the need for glycine when methionine intake is too high relative to glycine intake (i.e., when we eat lots of muscle meat without the accompanying collagen from the bones and connective tissues), and glycine levels end up being inadequate to properly regulate the immune system. The result: chronic inappropriate and/or excessive inflammation. The antidote: Eat enough glycine to balance the high intake of methionine. 8 grams per day is about right for the typical omnivorous diet.

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Glycine Methionine Balance Revisited: A Matter of Timing
Glycine Methionine Balance
Apr 23, 2015

In one of my earlier posts on this blog, I discussed the largely reciprocal nature of the amino acids glycine and methionine. Specifically, too much dietary methionine depletes glycine, because your body uses up glycine in order to get rid of the excess methionine. This is a common condition these days, because the typical diet is high in methionine-rich muscle meats, but low in glycine-rich bone and connective tissue. Many are waking up to the benefits of getting more glycine by eating more wholesome meats by supplementing with bone broths, or gelatin (collagen) products. (I take the easy way out, by simply supplementing with the glycine product “sweetamine” which I formulated and sell myself.)

The key to understanding the complex relationship between glycine and methionine is to be aware that, in addition to the role of both of them in serving as protein building blocks, they also both have many critical metabolic and other roles as free amino acids. As free amino acids—which are small, water soluble molecules—both glycine and methionine cycle very quickly through the body in a matter of hours, compared to the weeks-to-months turnover time of protein molecules.

The key difference between glycine and methionine which has been the traditional focus of nutritional and metabolic research, is the fact that methionine is essential, i.e., you’ll eventually die if you don’t get adequate dietary intake, because your body cannot make it from simpler materials; but glycine is non-essential, i.e., your body can make it from simpler compounds. Hence, the importance of glycine in the diet has been largely ignored.

Methionine—when activated to form S-adenosylmethionine, or SAMe—is the universal methyl donor. As such, it performs the critical function of adding one-carbon methyl groups, an operation necessary to form and modify DNA bases, detoxify drugs, and make certain key molecules like the hormone adrenalin, to name a few examples. Since methionine is so important, the body—mainly the liver—has a number of pathways to reuse, regenerate and recycle methionine. Best known is the methionine cycle, whereby the methyl group—once donated by SAMe—gets added back to the “spent” SAMe (the amino acid homocysteine) to reform methionine. The result of all these pathways is to render the minimal methionine daily dietary requirement very small, i.e., a few hundred milligrams; more like a vitamin than a protein amino acid.

But the dark side of methionine—long ignored—is that too much is toxic, so that after eating that methionine-rich steak, your liver is not operating the methionine cycle to conserve methionine, but rather, getting rid of it as fast as it can. To do that, the liver needs to use up glycine. Therefore, the more methionine in the diet, the more glycine is needed to help get rid of it.

Although glycine is non-essential, your liver can’t make an unlimited amount, and the typical diet usually comes up short 8-10 grams of glycine per day. Meanwhile, glycine has critical functions in the body only recently discovered. Most relevant to human diet and health is the fact that glycine is the most important endogenous regulator of inflammation. In fact, I’m convinced that glycine deficiency lies at the core of most conditions that make people sick and die these days, from diabetes and arthritis to heart disease and cancer. That’s because they’re all traceable to chronic excess inflammation. If you are glycine-deficient, it will show up as chronic inflammation sooner or later, one way or another.

So that’s why I have been quick to say that most people eat too much methionine, and really should avoid supplements such as SAMe, TMG, etc, which boost methylating power. But in one of the comments after one of my posts on this site a few months ago, the suggestion that some people are “under-methylators” prompted me to have another look at what is going on. After all, it is well known that mutations of the gene for the enzyme MTHFR—which is critical for the regeneration of methionine from homocysteine—are quite common in all human populations (between 10 and 20%). People with defective forms of MTHFR do not regenerate methionine efficiently. Consequently, during periods of fasting (or even shorter periods of say, 4-6 hours between meals), they may actually be somewhat methionine-deficient, precisely because excess methionine is so efficiently removed after absorbing a meal’s worth of high protein.

Therefore, such people may endure chronic health problems by being both glycine AND methionine-deficient! So as a simple, harmless experiment, I suggested that one could eat a rich natural source of methionine for a snack between meals. Brazil nuts are the perfect such snack, comprised of 1% methionine by weight. That means a snack of 3 Brazil nuts provides about 100mg of methionine.

Then I looked further into the topic of “under-methylation” and realized that one of my own daughters fit the profile perfectly: prone to hypoglycemia between meals and always needing a high-protein snack to tide her over, and more seriously, suffering from recurrent bronchitis—a borderline asthmatic since childhood. Of course, being my kid, she’s been taking her sweetamine glycine supplement for a couple of years now, and although feeling somewhat better, the respiratory problems persisted.

So I suggested she try a few Brazil nuts as a snack between meals. The first sign that this suggestion was on the right track was the fact that she has always loved Brazil nuts (Talk about intuitive eating!), but had avoided them because they are relatively expensive compared to other high protein snacks (peanuts, string cheese, etc.).

But the most encouraging sign of spring (literally), is that for the first time I can remember, my daughter has gotten through a northeast winter (and this year was the worst in a long time) without a single major respiratory infection!

So at this point, my working hypothesis seems to be gathering some evidence for the advantage —at least for undermethylators—of supplementing with both glycine and methionine, starting the day with the former and taking Brazil nut snacks for methionine in between meals. [: idi] (And btw, Brazil nuts are also a rich source of usable selenium, in the form of the rare but also essential amino acid, selenocysteine. Selenocysteine is essential for the formation of glutathione reductase, the enzyme which regenerates the key anti-oxidant glutathione.)

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About the Author: Joel Brind, Ph.D. has been a Professor of Biology and Endocrinology at Baruch College of the City University of New York for 28 years and a medical research biochemist since 1981. Long specializing in steroid biosynthesis and metabolism and endocrine-related cancers, he has specialized in amino acid metabolism in recent years, particularly in relation to glycine and one-carbon metabolism. In 2010 he founded Natural Food Science, LLC to make and market glycine supplement products via Sweetamine"

- glycine and cancer
- Glutathione: Is More Better? - 180 Degree Health
- http://180degreehealth.com/amino-acids-metabolic-syndrome/

 

[X3CyO]

Just fyi for people who haven't come across this info yet, but if using gelatin that isn't hydrolyzed, definitely remember to activate it with boiling water. Its similar to resistant starch otherwise and can cause a major endotoxin spike.

Regular gelatin works pretty well in any kind of soup/stew, whereas hydrolyzed is what you're supposed to be looking for if you just wanna toss it back with juice.

One could argue that hydrolyzed gelatin should be cooked as well in case of residual bacteria already on the gelatin.

I also highly recommend against storing extra already cooked gelatin in the fridge since it can easily get eaten up by bacteria yet still appear solid. One test would be just to leave it covered and out of the fridge. If it turns to liquid that ***t is contaminated as ****. 100% do not eat that. You will get super sick guaranteed.


Another way of telling if you digested the gelatin completely is if your bristol measurement is a solid 3-4. If its like 5,6,7, yeah it got hit with teh bacterials.

 

[Kartoffel]

Just fyi for people who haven't come across this info yet, but if using gelatin that isn't hydrolyzed, definitely remember to activate it with boiling water. Its similar to resistant starch otherwise and can cause major endotoxin overload.

Regular gelatin works pretty well in any kind of soup/stew, whereas hydrolyzed is what you're supposed to be looking for if you just wanna toss it back with juice.

One could argue that hydrolyzed gelatin should be cooked as well in case of residual bacteria already on the gelatin.

I also highly recommend against storing extra already cooked gelatin in the fridge since it can easily get eaten up by bacteria yet still appear solid. One test would be just to leave it covered and out of the fridge. If it turns to liquid that ***t is contaminated as ****. 100% do not eat that. You will get super sick guaranteed.


Another way of telling if you digested the gelatin completely is if your bristol measurement is a solid 3-4. If its like 5,6,7, yeah it got hit with teh bacterials.

Gelatine, hydrolyzed or not, is full of endotoxin and probably other dangerous junk. I wouldn't buy any product and go with oxtail, etc instead

 

[Wagner83]

Gelatine, hydrolyzed or not, is full of endotoxin and probably other dangerous junk. I wouldn't buy any product and go with oxtail, etc instead

And even that can give issues like headache, neck/upper back tension etc..

@haidut had told me that glycine/gelatin seemed to work just as well as fresh OJ to control the insulin response to a starchy meal, in the case of the former perhaps working against endotoxin and methionine overload helps.

 

[haidut]

And even that can give issues like headache, neck/upper back tension etc..

@haidut had told me that glycine/gelatin seemed to work just as well as fresh OJ to control the insulin response to a starchy meal, in the case of the former perhaps working against endotoxin and methionine overload helps.

There is a human study on that somewhere on the forum. A single dose of about 6g halved the glycemic response from food.

 

[Wagner83]

There is a human study on that somewhere on the forum. A single dose of about 6g halved the glycemic response from food.

Ordered.

 

[Nokoni]

Diet and Inflammation Part 1-4 - By Joel Brind, Ph.D - One Radio Network

"Joel Brind, Ph.D

Diet and Inflammation Part 1
Diet and Inflammation
Jul 24, 2014

There’s no shortage of info out there about inflammation’s being the root cause of most of what makes people sick and die these days–from arthritis to diabetes to cardiovascular disease to cancer—and what to eat and not eat to put your body into an “anti-inflammatory” state.
But there is a shortage of real knowledge about inflammation itself: What its proper role is in the body and why it is so often out of control. Once you know that, the rest is easy.
Back in the day (some 35 years ago), I studied immunology at NYU Medical School as part of my graduate training in Basic Medical Science. You would think that inflammation, as a major function of the immune system—innate immunity, to be precise—would occupy a substantial proportion of the course material. Nope! Everyone in the field, it seemed, wanted to win the Nobel Prize for figuring out acquired immunity: How does the body figure out how to make a specific antibody against the chemical signature of a microbe it has never encountered before? That was one of the great mysteries of the day; the principle behind vaccination and all manner of specific immunity. Well, that mystery was eventually solved, and I don’t even remember who got the credit. Are we making better vaccines and saving more lives because of it? You be the judge.
But if you go back to the days when infectious disease killed most people; when great plagues swept through human populations with some regularity, it wasn’t acquired immunity that saved most of the survivors. It was innate immunity. After all, acquired immunity takes weeks to develop after the first exposure, and the body can succumb to infection in a few days. So the real life saver is the first response system, the aggressive, non-specific attack against the offending microbes. Of course, such attack can and does do lots of damage to normal tissues in the process, but it might just save your life.
It’s really just like society’s first responders; like the fire department. When your fire alarm detects a fire, the fire department is summoned, and quickly the firemen show up with their axes and their hoses. They put the fire out, all right, but they do lots of damage in the process. Once the fire is out, you bring in the repair contractor to fix the damage. In your body, once the threat of infection has been neutralized, healing begins.
But for some odd reason, inflammation—the basic operation of innate immunity—is still viewed by the medical and scientific community as part of the healing response. In fact, the opposite is true: it inhibits healing quite effectively.
Two years ago, this is how Wendy Weber, A National Center for Complementary and Alternative Medicine (one of the NIH Institutes) program director, was quoted in the Wall Street Journal (wsj.com; the section entitled “The Informed Patient”, article author Laura Landro). ‘”You need to have inflammation when you have a wound and the immune system goes in to heal it. Yet we don’t want too much inflammation in our system causing damage to our arteries” and other harm’.
The prevailing dogma, unfortunately, does not really distinguish the separate roles of immune defense and tissue repair.
To take a simple example, say you sprain your ankle. It gets all swollen and painful and immobilized from what process? Inflammation. In fact, everyone knows that the immediate treatment of choice is to put ice on it. To do what? To suppress inflammation!
Why? Because the inflammation prevents healing from taking place.
OK, so why does inflammation happen at all when you sprain your ankle? Because, it is generally believed, inflammation is the body’s natural response to tissue injury; to distress signals released from damaged cells and tissues. But why? If you sprain your ankle, where is the route of infection? There are no invading microbes to destroy, and if inflammation happens anyway and does more harm than good, why does your body do it? Why do you have to interfere with your body’s natural response to the blunt injury, for optimal healing to occur?
The answer is quite simple: Your body is not acting appropriately, because it is laboring under a nutritional imbalance. Actually, the typical Western diet tends to be deficient and/or imbalancedin 3 key nutrients: salicylic acid, omega-3 fatty acids (vs. omega 6), and glycine (vs. methionine). The third is the most important and the least well known (although Vladimir Heiskanen’s excellent recent post on this blog gives a pretty good introduction). I’ll get to the specifics of how all this works—down to the cellular and molecular level–in my next post.

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Diet and Inflammation Part 2
Diet and Inflammation
Aug 11, 2014

My last post—part 1 of Diet and Inflammation—left off with my conclusion that the answer to the widespread prevalence of chronic inflammation was a nutritional imbalance incurred by the typical Western diet, specifically deficiencies or imbalances in 3 key nutrients: omega-3 (v. omega 6) fatty acids, salicylic acid and glycine (v. methionine).
What exactly happens in inflammation? Inflammation is the basic action of the innate immune system to destroy potentially pathogenic microbes that get into the internal body tissues. It is a non-specific aggressive action by amoeba-like cells called macrophages (derived from the Greek and meaning “big eaters”), the immune system’s first responders, which can literally gobble up bacteria and other microbes. Several types of these cells—called granulocytes—have long been recognized as circulating in the blood as a type of white blood cell. More recently, macrophages have been recognized as populating all sorts of organs and tissues.
But all these diverse types of macrophages are immune system cells, and all of them originate in the bone marrow. If there is tissue injury, injured cells and cell debris will be gobbled up by these macrophages. But if there is infection—the recognition of the generic signature of bacteria, for example—these macrophages get activated, producing toxins such as hydrogen peroxide in order to kill the bacteria. In order to amplify the reaction, these macrophages release chemical signals called prostaglandins to recruit and activate other macrophages, the purpose being to destroy the infecting microbes before they can destroy the host. Of course, like other first responders, the macrophages will put down the infection just like the firemen will put out the fire, but they will also do lots of damage to normal tissues.
Unfortunately, there is still lots of confusion out there about the role of inflammation and innate immunity; most medical authorities believing that inflammation is part of the healing response and a normal response to tissue injury. Why? Because it always seems to happen with tissue injury. You sprain your ankle, and it gets swollen and painful and immobilized; i.e., inflamed. But why should this happen if there is no route of infection? There are no microbes to kill. And we all know that, contrary to healing, the inflammation inhibits healing, which is why we have to put ice on the injury, to suppress inflammation. So why does your body do it?
Here’s where nutrition comes in. The activation of macrophages is affected by an electrochemical switch mechanism on the cell surface membrane. When these cells are at rest, they are, so to speak, switched off, there is a resting voltage between the outside and the inside of the cell (positive outside; negative inside). Just like a light switch on your wall, when it is off, there is a resting voltage (120 volts in the US) between the hot wire attached to the switch and the light fixture. When the light is switched on, the voltage drops as the energetic electrons flow through the switch and activate the fixture. The electrochemical switches in cells are channels in the membrane which allow positively charged ions (calcium or sodium ions) to flow across the membrane. The voltage drops when these channels open up momentarily, activating the cell. That’s how nerve impulses (called action potentials) activate muscles, for example. But it’s also how macrophages get activated.
However, the cell surface membrane is a very dynamic envelope, like a constantly moving, constantly changing, highly sophisticated soap bubble. In the course of ordinary activity, lots of leakage of ions occurs, and there are specialized channels in the membrane that let negatively charged chloride ions in to maintain the resting voltage of 0.07 volts. A substantial proportion of these chloride channels are operated—i.e., maintained in an open position—by the amino acid glycine. Glycine is ordinarily present in body fluids at high concentrations. But if they are not high enough, the glycine-gated chloride channels (aka glycine receptors) are not open enough to allow adequate chloride entry. Thus, the voltage between the outside and inside of the cell deteriorates and the cell is too easily activated, like when there is tissue injury but no infection. Once a macrophage is activated, the extent to which it recruits and activates other macrophages to the site of inflammation is related to the levels of the two other key nutrients: salicylic acid and omega-3 v. omega-6 fatty acids.
How the balance—or imbalance—in the intake of these types of polyunsaturated fatty acids (PUFAs) will be the subject of Part 3 in this series.

Ray Peat states this about this very topic…

A generous supply of glycine/gelatin, against a balanced background of amino acids, has a great variety of anti-stress actions. Glycine is recognized as an “inhibitory” neurotransmitter, and promotes natural sleep. Used as a supplement, it has helped to promote recovery from strokes and seizures, and to improve learning and memory. But in every type of cell, it apparently has the same kind of quieting, protective anti-stress action. The range of injuries produced by an excess of tryptophan and serotonin seems to be prevented or corrected by a generous supply of glycine. Fibrosis, free radical damage, inflammation, cell death from ATP depletion or calcium overload, mitochondrial damage, diabetes, etc., can be prevented or alleviated by glycine.

Some types of cell damage are prevented almost as well by alanine and proline as by glycine, so the use of gelatin, rather than glycine, is preferable, especially when the gelatin is associated with its normal biochemicals. For example, skin is a rich source of steroid hormones, and cartilage contains “Mead acid,” which is itself antiinflammatory.

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Diet and Inflammation Part 3
diet and inflammation
Aug 25, 2014

In my last post—Part 2 of this diet and inflammation series—I discussed the cells—called macrophages—which actually affect the inflammatory response, and how the amino acid glycine is crucial in regulating the activation of the macrophages at the level of the cell surface membrane. In the present installment, I’ll be discussing the propagation and amplification of the inflammatory response, and the key roles played by two other nutrients: salicylic acid and omega-3 (v. omega-6) fatty acids.
The cell membrane itself is made up mainly of molecules called phospholipids; natural soap-like molecules which each contain two fatty acids. Upon cellular activation, some of these phospholipid molecules are broken down such that one of the fatty acids is enzymatically converted to a messenger molecule—a prostaglandin—which diffuses away to activate—or inhibit the activation of—other cells it reaches (Such local messenger molecules are known as paracrine factors.) The enzyme that catalyzes the key step in the process is called a cyclooxygenase 2 (COX2). Salicylic acid inhibits the activity of COX2. (The synthetic drug aspirin, or acetylsalicylic acid, is a much more potent COX2 inhibitor; more on this later.)
The type of prostaglandin molecule released reflects the composition of the type of fatty acids that make up the membrane, which in turn reflects the fatty acid composition of the diet. The prostaglandins that amplify the inflammatory activation are made from the omega-6 fatty acid, arachidonic acid (AA); whereas prostaglandins that inhibit this activation are made from the omega-3 fatty acid, eicosapentaenoic acid (EPA).
Hence, the greater the preponderance of omega-6 fatty acids in the diet (largely from seed oils, e.g., corn, soybean, sunflower, peanut) as opposed to omega-3 (fish or krill oil, flaxseed oil), the greater the amplification of the pro-inflammatory prostaglandin signal. (The optimal dietary ratio of omega-6 to omega-3 is about 3 or 4 to one; although whether either type of these polyunsaturated fatty acid types—”PUFAs”—are even essential to the human diet is still debated. Oils that seem to have a perfect balance of fatty acid types include walnut and olive oils [Hemp Seed Oil ~JP].) Since the mass campaign to replace saturated fats with PUFAs over the latter half of the 20th century was largely successful in saturating the Western diet (and that of its livestock) with omega-6 PUFAs, it has clearly contributed to the high prevalence of chronic inflammation.
Meanwhile, the extent of COX2 activity is largely controlled by the concentration of salicylic acid. For some reason, salicylic acid is often viewed as a “nutraceutical”, rather than an everyday nutrient. In fact, it is often not viewed as a nutrient at all, although aspirin is viewed as something middle-aged and older individual are encouraged to take daily to prevent thrombotic events such as heart attacks and strokes. Aspirin, however, is a potent synthetic drug. Although it acts like salicylic acid (as well as increasing the actual salicylic acid content of the blood), it has potentially dangerous side-effects, like excess bleeding. Meanwhile, salicylic acid itself is a widespread botanical compound, particularly high in berry fruits, grapes and kiwis, and also present in significant amounts in nuts like almonds and walnuts. (It is also a key component of EVOO that is removed when olive oil is refined.)
It is my belief that it is salicylic acid, rather than the much touted polyphenols in fruits and nuts which are key to “anti-inflammatory diets”, and which lower risk of cardiovascular disease, for example. These polyphenols (e.g., resveratrol, quercetin) are great anti-oxidants, but the value of anti-oxidants is largely to mitigate the effects of inflammation. I think it’s better to stop inappropriate inflammation from getting started. I also believe, for example, that the “French paradox”—why French people eat such a high-fat diet but suffer a low rate of heart disease—is not due to the polyphenols in the wine they drink daily, but from the high salicylic acid content of grapes, and therefore, wine.
So it’s pretty clear how the typical Western diet that is low in fruits and vegetables, and low in omega-3—but high in omega-6 fats—contributes to excess inflammation, by helping to amplify—and therefore exaggerate—the inflammatory response. But getting back to the initiation of inflammation in the first place, why should glycine levels be low in the first place, and allow inflammation to develop inappropriately? After all, glycine is a non-essential amino acid, so you really should not have to eat any of it, right? And if the diet is rich in high-protein foods (meat, fish, poultry, eggs, dairy), we are also eating plenty of it.
The answer turns out to be quite simple: Although we discovered a century ago that we need to eat whole grains to avoid devastating deficiency diseases like pellagra, we never thought that we also need to eat whole cows, pigs, chickens and fish! But it turns out that the key to a healthy omnivorous diet is to balance the content of essential amino acid methionine that predominates in muscle with the glycine that predominates in the bones and connective tissues, the parts we usually throw away.
The specifics of the biochemistry—the metabolic interactions of glycine and methionine and key intermediate metabolites and cofactors—are now understood, and present a fascinating picture of how our bodies’ metabolic machinery works as best it can with what we feed it to keep us alive and healthy. That will be the focus of my next post.

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Diet and Inflammation Part 4
Diet and Inflammation Part 4 - 180 Degree Health
Sep 20, 2014

My last post focused on the propagation of the inflammatory signal, and how nutrients such as omega-6 PUFAs and the lack of salicylic acid results in amplification of that signal, thus contributing to the overall increase in inflammation-related disease we currently experience.

Collagen

But what about the initiation of the inflammatory signal in the first place? That often turns out to be due to a widespread deficiency in the amino acid glycine, which I described in an earlier post. Glycine acts as a sort of “cellular voltage regulator”, preventing the inappropriate initiation of inflammation in response to cellular injury. (Inflammation is really only appropriate when there is infection taking place.)

But if glycine is the most abundant amino acid in the body, and it is nonessential—i.e., the human body can make it from scratch—why should anyone be deficient, especially nowadays, when the dietary intake of protein is usually so high?

As Matt Stone often says, it is really a matter of context; a matter of balance, rather than a matter of absolutes. Glycine is so abundant that it comprises about 22% by weight of the most abundant protein in the body. That protein would be collagen, the tough, extracellular fibrous protein that makes up the bones, cartilage and all the connective tissues. Hence, the collagen—and therefore most of the glycine—is the part of the meat, fish and poultry that we usually throw away. Bone broth is one way to recover it in the diet, and when the collagen is boiled out of the bones and purified, it is called gelatin.

But even though we discard most of the glycine from our animal flesh foods, we are still taking some in with our muscle meats, so that still doesn’t explain a widespread glycine deficiency. But in fact, the consumption of muscle meats actually exacerbates the deficiency because of the amino acid content of the muscle meats. Specifically, muscle meats are very rich in the essential amino acid methionine, and it is an understanding of the intimate relationship between methionine and glycine that provides the answer to this question of balance.

A problem with traditional nutritional thinking on amino acids is the rigid classification of those which are essential, as opposed to those which are non-essential; in particular, a disproportionate interest in the former v. the latter. Methionine, in particular, has long been known to play key roles in metabolism independent of its role as a constituent of proteins. Specifically, methionine—when activated to form S-adenosylmethionine (SAMe), is the universal methyl group donor, which adds a one-carbon methyl group (CH3 group) to a variety of important metabolic intermediates, including DNA bases and neurotransmitters.

So fundamental is this role of methylation, that the body (essentially, the liver) has numerous pathways of conserving, recycling, and salvaging methionine, so that it can withstand long periods of reduced methionine intake. So intense has been the emphasis on the essentiality of methionine, that methionine deficiencies have been hypothesized to underlie a number of pathologies, including cancer. But nothing could be further from the truth. In fact, typical Westerners consume about 10 times more methionine than is needed to support good health. (We really only need about 300 – 500 mg per day of methionine: more like the daily requirement for a B vitamin than a bulk nutrient!) Over 20 years’ worth of animal research has shown that laboratory animals (rats and mice) live substantially longer and healthier lives if their normal methionine intake is reduced by 80%. Moreover, it is now understood that metabolically, far from salvaging, recycling and regenerating methionine, the body switches gears and gets rid of most of the methionine absorbed from a typical high-protein meal.

What’s that got to do with glycine? The answer is remarkably simple: There is only one metabolic pathway that exists in the human body to get rid of excess methionine. That pathway—via the enzyme glycine-N-methyltransferase (GNMT)—uses up glycine in the process.

In Figure “a” below, we see a typical description of what is called the methionine cycle. It is my own version (I originally published these diagrams at the Annual Meeting of the Federation of American Societies for Experimental Biology [FASEB] in 2011.), but it typically shows how methionine is recycled, in order to conserve it maximally. I say typical, because this is the only metabolic picture generally shown in textbook descriptions of the methionine cycle. And it is accurate insofar as it applies when methionine levels are low, like when there is no methionine coming in from the diet, so methionine needs to be conserved.



In this metabolic diagram, the green arrows refer to active metabolic pathways, and the dotted black arrows refer to inactive or minimally active pathways; the red, upper case abbreviations stand for enzymes (e.g., GNMT), whereas the names and abbreviations in black are metabolic intermediates (e.g., SAMe). The heavy red dotted line shows a metabolic brake or inhibition (i.e., an “off switch”) of GNMT by an intermediate called MeTHF. MeTHF is a form of folic acid which recharges the intermediate amino acid homocysteine (Hcy) by adding a methyl group to it, thus regenerating methionine. The presence of MeTHF is a signal that methionine is being regenerated because it is scarce, and it specifically turns off GNMT so that methionine is not wasted in this time of need. The SAMe that is generated is available for essential processes, such as the methylation of DNA bases, as shown by the green arrow across the top of the diagram.

But what is not generally appreciated by biochemists and nutritionists is that when methionine is abundant, especially when methionine is being absorbed after a high-protein meal, the liver’s metabolic machinery switches gears (like it does in the transition after a high carb meal, when it switches from regenerating glucose to getting rid of glucose), working maximally to get rid of the excess methionine.

This situation is illustrated in Figure “b” below. In this diagram are also shown the two metabolic “on switches” (Solid yellow arrows with star points) for enzymes. Specifically, the high concentration of methionine itself cranks up the activity of MAT, which turns methionine into SAMe at a much higher rate. Most of this SAMe is not needed for essential methylation reactions, such as making DNA bases, but is instead deliberately wasted by GNMT, which has been turned on by the release of the braking action of MeTHF (shown in figure “a”). That’s because MeTHF is no longer being made, because SAMe itself shuts off MTHFR, the enzyme that makes MeTHF. Meanwhile, SAMe also turns on the enzyme CBS, which diverts homocysteine (“used” methionine) into the production of downstream sulfur-containing compounds (a pathway called “transulfuration”), including cysteine and glutathione, now that the remethylation (regeneration) of methionine has been turned off.



Note especially that in this high-methionine condition, glycine is required both for the action of GNMT (a pathway called “transmethylation”) and for the transsulfuration pathway, to make glutathione. In this mode, glycine can be made both from serine and from scratch (i.e., from CO2 and ammonia), through the operation of a glycine-serine cycle. However, the liver cannot keep up with the need for glycine when methionine intake is too high relative to glycine intake (i.e., when we eat lots of muscle meat without the accompanying collagen from the bones and connective tissues), and glycine levels end up being inadequate to properly regulate the immune system. The result: chronic inappropriate and/or excessive inflammation. The antidote: Eat enough glycine to balance the high intake of methionine. 8 grams per day is about right for the typical omnivorous diet.

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Glycine Methionine Balance Revisited: A Matter of Timing
Glycine Methionine Balance
Apr 23, 2015

In one of my earlier posts on this blog, I discussed the largely reciprocal nature of the amino acids glycine and methionine. Specifically, too much dietary methionine depletes glycine, because your body uses up glycine in order to get rid of the excess methionine. This is a common condition these days, because the typical diet is high in methionine-rich muscle meats, but low in glycine-rich bone and connective tissue. Many are waking up to the benefits of getting more glycine by eating more wholesome meats by supplementing with bone broths, or gelatin (collagen) products. (I take the easy way out, by simply supplementing with the glycine product “sweetamine” which I formulated and sell myself.)

The key to understanding the complex relationship between glycine and methionine is to be aware that, in addition to the role of both of them in serving as protein building blocks, they also both have many critical metabolic and other roles as free amino acids. As free amino acids—which are small, water soluble molecules—both glycine and methionine cycle very quickly through the body in a matter of hours, compared to the weeks-to-months turnover time of protein molecules.

The key difference between glycine and methionine which has been the traditional focus of nutritional and metabolic research, is the fact that methionine is essential, i.e., you’ll eventually die if you don’t get adequate dietary intake, because your body cannot make it from simpler materials; but glycine is non-essential, i.e., your body can make it from simpler compounds. Hence, the importance of glycine in the diet has been largely ignored.

Methionine—when activated to form S-adenosylmethionine, or SAMe—is the universal methyl donor. As such, it performs the critical function of adding one-carbon methyl groups, an operation necessary to form and modify DNA bases, detoxify drugs, and make certain key molecules like the hormone adrenalin, to name a few examples. Since methionine is so important, the body—mainly the liver—has a number of pathways to reuse, regenerate and recycle methionine. Best known is the methionine cycle, whereby the methyl group—once donated by SAMe—gets added back to the “spent” SAMe (the amino acid homocysteine) to reform methionine. The result of all these pathways is to render the minimal methionine daily dietary requirement very small, i.e., a few hundred milligrams; more like a vitamin than a protein amino acid.

But the dark side of methionine—long ignored—is that too much is toxic, so that after eating that methionine-rich steak, your liver is not operating the methionine cycle to conserve methionine, but rather, getting rid of it as fast as it can. To do that, the liver needs to use up glycine. Therefore, the more methionine in the diet, the more glycine is needed to help get rid of it.

Although glycine is non-essential, your liver can’t make an unlimited amount, and the typical diet usually comes up short 8-10 grams of glycine per day. Meanwhile, glycine has critical functions in the body only recently discovered. Most relevant to human diet and health is the fact that glycine is the most important endogenous regulator of inflammation. In fact, I’m convinced that glycine deficiency lies at the core of most conditions that make people sick and die these days, from diabetes and arthritis to heart disease and cancer. That’s because they’re all traceable to chronic excess inflammation. If you are glycine-deficient, it will show up as chronic inflammation sooner or later, one way or another.

So that’s why I have been quick to say that most people eat too much methionine, and really should avoid supplements such as SAMe, TMG, etc, which boost methylating power. But in one of the comments after one of my posts on this site a few months ago, the suggestion that some people are “under-methylators” prompted me to have another look at what is going on. After all, it is well known that mutations of the gene for the enzyme MTHFR—which is critical for the regeneration of methionine from homocysteine—are quite common in all human populations (between 10 and 20%). People with defective forms of MTHFR do not regenerate methionine efficiently. Consequently, during periods of fasting (or even shorter periods of say, 4-6 hours between meals), they may actually be somewhat methionine-deficient, precisely because excess methionine is so efficiently removed after absorbing a meal’s worth of high protein.

Therefore, such people may endure chronic health problems by being both glycine AND methionine-deficient! So as a simple, harmless experiment, I suggested that one could eat a rich natural source of methionine for a snack between meals. Brazil nuts are the perfect such snack, comprised of 1% methionine by weight. That means a snack of 3 Brazil nuts provides about 100mg of methionine.

Then I looked further into the topic of “under-methylation” and realized that one of my own daughters fit the profile perfectly: prone to hypoglycemia between meals and always needing a high-protein snack to tide her over, and more seriously, suffering from recurrent bronchitis—a borderline asthmatic since childhood. Of course, being my kid, she’s been taking her sweetamine glycine supplement for a couple of years now, and although feeling somewhat better, the respiratory problems persisted.

So I suggested she try a few Brazil nuts as a snack between meals. The first sign that this suggestion was on the right track was the fact that she has always loved Brazil nuts (Talk about intuitive eating!), but had avoided them because they are relatively expensive compared to other high protein snacks (peanuts, string cheese, etc.).

But the most encouraging sign of spring (literally), is that for the first time I can remember, my daughter has gotten through a northeast winter (and this year was the worst in a long time) without a single major respiratory infection!

So at this point, my working hypothesis seems to be gathering some evidence for the advantage —at least for undermethylators—of supplementing with both glycine and methionine, starting the day with the former and taking Brazil nut snacks for methionine in between meals. [: idi] (And btw, Brazil nuts are also a rich source of usable selenium, in the form of the rare but also essential amino acid, selenocysteine. Selenocysteine is essential for the formation of glutathione reductase, the enzyme which regenerates the key anti-oxidant glutathione.)

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About the Author: Joel Brind, Ph.D. has been a Professor of Biology and Endocrinology at Baruch College of the City University of New York for 28 years and a medical research biochemist since 1981. Long specializing in steroid biosynthesis and metabolism and endocrine-related cancers, he has specialized in amino acid metabolism in recent years, particularly in relation to glycine and one-carbon metabolism. In 2010 he founded Natural Food Science, LLC to make and market glycine supplement products via Sweetamine"

- glycine and cancer
- Glutathione: Is More Better? - 180 Degree Health
- http://180degreehealth.com/amino-acids-metabolic-syndrome/

Very interesting. Thank you.

 

[ecstatichamster]

I had missed this. Quite good. I find collagen very helpful.

 

[danishispsychic]

super interesting- i finally switched to Mag Glycinate after wasting my time on all the other Mags and of course course course Ray Peat is correct once again. It is really healing and helping my whole intestinal thingy. thank you for this post. !

 

[Fractality]

I also highly recommend against storing extra already cooked gelatin in the fridge since it can easily get eaten up by bacteria yet still appear solid. One test would be just to leave it covered and out of the fridge. If it turns to liquid that ***t is contaminated as ****. 100% do not eat that. You will get super sick guaranteed.

Do you think this applies to homemade gelatinous broth? I've stored excess broth in the fridge and had it the next day without issues. This is not commercialized gelatin.

 

[TreasureVibe]

Gelatine, hydrolyzed or not, is full of endotoxin and probably other dangerous junk. I wouldn't buy any product and go with oxtail, etc instead

So Ray Peat is wrong on gelatin? Gelatin is bad for you?

 

[Fractality]

So Ray Peat is wrong on gelatin? Gelatin is bad for you?

No, but perhaps he might agree that homemade gelatin is preferable to commercial gelatin. I feel better on homemade gelatin broth compared to hydrolyzed great lakes gelatin. There are some posts on the forum about high levels of endotoxin in the animal skin they use to make gelatin.

 

[X3CyO]

Do you think this applies to homemade gelatinous broth? I've stored excess broth in the fridge and had it the next day without issues. This is not commercialized gelatin.

Yeah, that should be fine. Its just the easiest medium to contaminate up there with soup when itʻs warm. The less it stays warm, the less stuff will grow on it. Ive recooked things up to two times in broth and not had it go bad. Just something to keep an eye on.

 

[Amazoniac]

- Glycine Metabolism and Its Alterations in Obesity and Metabolic Diseases

 

[GorillaHead]

Any new endotoxin. Tlrf4 antagonists. Blockers etc?