Helena Pike

Good Proteins, Bad Proteins: The Amino Acids in Health and Disease

A few months ago, an interesting Danish study was published, showing that a “high-fat/high-sugar” diet would cause obesity to mice consuming chicken, cod, or crab as their main protein source. However, the group of mice eating scallop protein didn’t develop these problems at all. The researchers performed some statistical analyses, and suggested that the particularly high glycine and taurine content of scallop protein might explain some of these effects.

The scientific literature also includes several reports of anti-inflammatory and hypocholesterolemic effects of fish protein in humans and rodents. Some of the researchers explain these effects by the high content of arginine, glycine, and taurine in seafood.[2]

Lately, I have spent a lot of time thinking about the metabolic effects of various amino acids. It seems that not all protein is created equal, and the effects are largely mediated by their amino acid content (yet there are other factors as well).


2.   Metabolic Effects of Amino Acids: Glycine

When I started reading protein research, one of the first things I noticed was the fact that many of the healthy protein sources contain a fair amount of glycine.
Since there are numerous studies showing that this simple amino acid protects from inflammation, metabolic syndrome, cancer, diabetes, animal protein, endotoxin, hypoxia, hemorrhagic shock, lead and cadmium toxicity, dental caries, intestinal damage and many other things, I started to consider that altering amino acid composition of diet might have very far-reaching health effects. In one study, a high-glycine diet was also associated with 28% increased median lifespan of rats.[3]

A Mexican research group has also shown that in rats, 1.5% glycine (added in drinking water) can reverse the metabolic syndrome caused by a high-sugar diet. The same research group has also shown that glycine can prevent most of the harm caused by high ethanol consumption in rats.[4] In my previous article, I wrote about their study as follows:

This research group did something quite nasty to their rats. They added 30% sucrose to their water for 20 weeks. Consequently, the rats got a huge amount of calories from their drinking water and thus their food intake decreased by more than fifty percent. That equals a huge decrease in protein, mineral, and vitamin intake as well.

The rats developed full-blown metabolic syndrome in 20 weeks. But after that, the researchers also added 1% glycine to the drinking water. In 4 weeks, the sugar-fed rats became almost as healthy as the control group. With glycine, the rats’ blood pressure, fat cells, blood markers and many other things quickly became normalized despite the continued sugar feeding and low nutrient intake.

The blood pressure was decreased after the addition of 1% glycine to the drinking water. The adipocyte size was also normalized in the group receiving glycine in addition to their high-sucrose diet. (El Hafidi et al. 2004)

In humans, two studies examining the effects of glycine on metabolic syndrome have been published (15 grams a day for 3 months). The noted effects aren’t nearly as remarkable as in rodent studies, but the changes in some markers related to oxidative stress still appear quite beneficial.[5] “A1C levels of patients given glycine were significantly lower after 3 months of treatment than those of the placebo group.” (Cruz et al. 2008)
“A significant reduction in TNF-receptor I levels was observed in patients given glycine compared with placebo.” (Cruz et al. 2008)
“Individuals treated with glycine showed a 25% decrease in TBARS compared with the placebo-treated group. Furthermore, there was a 20% reduction in SOD-specific activity in the glycine-treated group, which correlated with SOD2 expression. G6PD activity and SNO-Hb levels increased in the glycine-treated male group.” (Díaz-Flores et al. 2013)

“Systolic blood pressure (SBP) also showed a significant decrease in the glycine-treated men (p = 0.043).” (Díaz-Flores et al. 2013)
A research group from Houston has also shown that high doses of glycine and N-acetyl-cysteine (NAC) had very quick beneficial effects in diabetic patients, HIV patients, and healthy elderly people.

In their studies, the subjects received approximately 100mg/kg/d of both amino acids for two weeks. If we look at the study of healthy elderly subjects, for example, we can see that the treatment improved the subjects’ energy-metabolism, insulin sensitivity, and oxidative stress to the levels of healthy young persons. Based on these results, it seems possible that the combination of glycine and cysteine has beneficial effects that cannot be achieved with glycine alone.[6]


3. Metabolic Effects of Amino Acids: Glycine:Methionine Ratio and The “Animal vs. Plant Protein” (Paleo vs. Vegan) Controversy

When thinking about glycine, it might be also wise to consider the effects of another amino acid, methionine. According to animal studies, high amounts of methionine might predispose to the metabolic syndrome. In some animal studies methionine restriction has been shown to protect against obesity, and to prolong lifespan.[7]

In many studies, the restriction has been quite large (80%), which isn’t very easy to achieve in real life. However, some researchers have reported beneficial effects even with a moderate methionine restriction (40%).[7]

It has also been suggested that some of the harmful effects of methionine might be caused by glycine depletion, because glycine is needed in the clearance of excess methionine. Animal studies have shown that glycine can protect from the harmful effects of methionine, e.g. by dramatically decreasing homocysteine levels.[7]

Some scientists have been explaining some of the possible benefits of vegetarianism or plant protein by their low methionine content or high ratio of glycine to methionine. For example, potatoes, soy, rice, almonds, lentils, and beans have quite a high glycine:methionine ratio while meat, milk, and eggs usually contain much more metionine and less glycine.[7]

Amino acid profiles of casein, soybean, potato and rice proteins. Milk protein (casein) contains more methionine and less glycine than most plant proteins. (Morita et al. 1997)

Rice protein has been studied in animals, and it has been reported to have a positive impact on metabolism (fat mass, cholesterol, inflammation). Rice protein has twice as much glycine and a little bit less methionine than casein, and it is possible that this is an important factor causing these beneficial effects. According to some studies, the ratio of lysine to arginine might also affect some health variables (especially cholesterol levels).[8]

Here in Finland, some researchers at my university have been studying the health effects of whey proteins. Whey seems to protect mice from obesity, and the main anti-obesity factor seems to be the alpha-lactalbumin (ALA) protein. It has also been shown that ALA has an aspirin-like effect on inflammation, thus protecting mice from colon cancer and probably other diseases as well.[8]

A study showed that the effects of ALA are mainly mediated by its amino acid composition, which has much higher glycine:methionine ratio than casein or the predominant whey protein, beta-lactoglobulin (Shi et al. 2011). High content of cysteine and/or tryptophan might also mediate these beneficial effects.[8]

Collagen is the most abundant protein in mammals, and accounts for 25-30% for the total body protein in humans. Biologist Ray Peat talks about proportion of 50%, but I don’t know to which animal he is referring to. However, collagen is an important source of glycine, containing 22% glycine by weight.
In the Western culture, few people eat the collagen-containing parts of the animal (skin, bones, cartilage), and thus, the low intake of collagen usually leads to a low glycine:methionine ratio of the Western diet. I think that the unbalanced way of eating animal protein (eg. eating only the muscles) might be one reason why in some studies, “animal protein” is associated with degenerative diseases.

This is an example of the graphs that the Vegan/ChinaStudy/ForksOverKnives folks often like to show us.

(Source: http://joshmitteldorf.scienceblog.com/2013/02/12/china-study-a-voice-for-veganism/ )


4. Metabolic Effects of Amino Acids: Taurine and GABA

Taurine and GABA have also been shown to protect humans and rodents against the harmful effects of junk food.
In animal studies, taurine has been shown to be beneficial in the prevention of metabolic syndrome, liver injury, brain damage and several other conditions. Epidemiological studies also support the idea of its important effects for health. One Japanese research group went as far as to suggest that taurine is “the nutritional factor for the longevity of the Japanese“.

In clinical human studies, taurine (1.5-6.0 grams a day) has been useful for metabolic syndrome, heart failure, liver diseases, and the alleviation of the side effects of chemotherapy. While the results are promising, the quality of the these studies isn’t very high.[9]

GABA seems to protect rodents from the metabolic syndrome, and some special protective effects have been noted in the islet cells of the pancreas. A moderate protective effect on mice can be observed even with a very small dose (0.06% GABA added to drinking water).[9]

In humans, the effects of GABA haven’t really been studied. Some papers seem to show that it might alleviate high blood pressure, but we have no information about other possible beneficial effects.[9]

Fish and shellfish are a decent source of taurine. (Yamori et al. 2010, Fig. 12)


5. Metabolic Effects of Amino Acids: Histidine (and Carnosine)

Histidine and the histidine-containing dipeptides (carnosine/anserine) protect humans and rodents from metabolic syndrome and some other problems associated with inflammation. In mice, even the addition of 0.1% histidine or carnosine to the drinking water has a strong protective effect against the many harms caused by a high-fat diet.[10] These excellent results have also been reproduced in humans. In a recent 3-month study, the daily use of histidine was associated with a 30% decrease in inflammatory markers (TNF-alpha, IL-6, CRP) and a 2.7kg fat loss (5 pounds). The dose was 4 grams a day, which is 2-3 times the average amount of histidine obtained from food (1.5 grams).[10]

In the histidine group, the treatment effects were surprisingly good: fat mass decreased (FM), chronic inflammation decreased (TNF-α, IL-6), oxidative stress decreased (SOD, GSH-Px), insulin sensitivity improved (HOMA-IR), free fatty acid level decreased (NEFA). (Feng et al. 2013)


6. The Mechanisms of Amino Acids: Chloride Channels, Endotoxemia, Inflammation, Bile Acids, Antioxidant Effects

In my earlier article (Thyroid, Inflammation, and Metabolic Syndrome: The Surprising Power of Context), I wrote that metabolic syndrome isn’t necessarily caused by sugar, alcohol, or fat itself, but generally, junk foods allow the entry of bacterial endotoxin (LPS) into the bloodstream. This activates the immune system, and the subsequent inflammation is the real reason behind metabolic syndrome and many other issues.

If amino acids have a protective effect against metabolic syndrome, it is likely that they affect some part of this chain of events. And it seems that inflammation is the part in question.

The most important effects of glycine, taurine, and GABA are probably related to their inhibitory effects via chloride channels (glycine and GABA receptor). Glycine hyperpolarizes macrophage cells and endothelial cells, thus limiting the secretion of cytokines and growth factors stimulated by endotoxins and other harmful things. This anti-inflammatory action is the main reason why glycine has a strong protective effect against almost every kind of physical illness.[11] Some of the effects of glycine and taurine are also related to their effects on the conjugation of bile acids. Bile acids protect intestines against bacterial overgrowth and endotoxemia, and they can also activate intracellular thyroid hormone metabolism.[12] Different animal species conjugate bile acids in different ways. Mice conjugate bile acids mainly with taurine. Rats conjugate them with glycine and taurine, but mostly with taurine. Humans conjugate them with glycine and taurine, but mostly with glycine. These differences might explain some of the varying results between different animal models.[12]

Taurine also activates glycine receptors, and it has some similar effects as glycine.[11] Histidine and carnosine appear to have anti-inflammatory, antioxidant, anti-nitrosative and metal-chelating effects. Some of their effects seem to be related to histamine metabolism, but there is also some evidence of anti-histamine effects. It’s unfortunate that these compounds have strong effects but the mechanisms seem to be partially unknown.[13]


7. What Else Besides The Amino Acid Composition Matters? (Intact Protein vs. Hydrolyzed Protein)

In addition to its amino acid profile, some other properties such as structure and fat-absorptive effects also mediate the health effects of proteins.
If milk protein (casein) is given to mice in the pre-digested (hydrolyzed) form, the fat mass of mice is dramatically reduced by 70%.[14]

The fat mass of mice eating hydrolyzed casein was only one-third of the fat mass of mice eating intact casein. [I-16 = intact casein (16E%) // H-16 = hydrolyzed casein (16%) // eWAT = epididymal white adipose tissue // iWAT = inguinal white adipose tissue] (Lillefosse et al. 2013)
These effects might be mediated by gut hormones such as cholecystokinin (CCK) or glucagon-like peptide (GLP-1), but so far, very little research on this topic has been conducted.

Casein also seems to decrease fat absorption in the intestines a little bit. This might lead to a slight or moderate anti-obesity effect.[14]


8.   Conclusions

– In health blogs and nutrition discussions, the health effects of carbohydrates and fats are often emphasized. However, it also seems that carefully choosing your proteins might also have important effects.
– The health effects of different proteins are largely mediated by their amino acid profiles. Some amino acids such as glycine and histidine might decrease low-grade inflammation, while high intake of methionine might be harmful. These effects have been mostly studied in rodents, and currently there seems to be quite little human research on the subject.
– Examples of protein sources with a good glycine:methionine ratio would include: gelatin, scallop, fish, potatoes, lentils and beans. Many popular animal foods such as milk, eggs and meat tend to have quite a poor ratio of these amino acids. The amino acid profiles of plant proteins might explain some of the beneficial effects of vegetarian diets.
– Amino acids are not the only factor affecting the biological effects of dietary protein. In some cases, hydrolyzed protein (peptide) might be more suitable for weight control than intact protein, and the effect might be mediated by gastrointestinal hormones. Casein might decrease the harmful effects of a high-fat diet by decreasing fat absorption in the intestines.
– Some studies have been showing that individuals with insulin resistance might have lower plasma levels of glycine, histidine, and taurine than healthy people. Because this “deficiency” of anti-inflammatory amino acids might lead to more inflammation, it is possible that people with insulin resistance would benefit most from the amino acid supplementation.[15]

About the Author
Vladimir Heiskanen of Finland has been researching and writing about health for several years. Currently a dental student at the University of Helsinki and a blogger since 2010, he has a keen interest in human biology, and has studied scores of books, reports, and cutting-edge health websites, especially the work of Chris Masterjohn, Steven Hamley, Ray Peat, and Matt Stone. You can read all of his fascinating articles published at 180D

Appendix: Further Reading
180DegreeHealth – Thyroid, Inflammation, and Metabolic Syndrome: The Surprising Power of Context (by Vladimir Heiskanen)
180DegreeHealth – Fibromyalgia: A Disease of Low Metabolism (by Vladimir Heiskanen)
180DegreeHealth – Diet and Inflammation, part I (by Joel Brind)
180DegreeHealth – Diet and Inflammation, part II (by Joel Brind)
180DegreeHealth – Diet and Inflammation, part III (by Joel Brind)
180DegreeHealth – Diet and Inflammation, part IV (by Joel Brind
180DegreeHealth – Glycine and Cancer (by Joel Brind)
180DegreeHealth – Glutathione: Is More Better? (by Joel Brind)
Valtsu’s – Health Benefits of Glycine