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    <h1>Tryptophan, serotonin, and aging</h1>
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<p>From the <a href="https://raypeat.com/articles/aging/tryptophan-serotonin-aging.shtml" target="_blank">original article</a> in 2006. Author: <a href="https://raypeat.com/" target="_blank">Ray Peat</a>.</p>
<p>Beginning with the industrial production 
of glutamic acid (sold as MSG, monosodium glutamate), the public has 
been systematically misinformed about the effects of amino acids in 
the diet. The FDA has been industry&#39;s powerful ally in misleading the 
public. Despite research that clearly showed that adults assimilate 
whole proteins more effectively than free amino acids, much of the public 
has been led to believe that “predigested” hydrolized protein and 
manufactured free amino acids are more easily assimilated than real 
proteins, and that they are not toxic. Even if free amino acids could 
be produced industrially without introducing toxins and allergens, they 
wouldn&#39;t be appropriate for nutritional use. </p>
<p>Although some research shows that babies 
up to the age of 18 months can assimilate free amino acids, a baby formula 
containing hydrolyzed protein was associated with decreased serum albumin, 
which suggests that it interfered with protein synthesis.</p>
<p>The myth that free amino acids are 
“natural nutritional substances” has been used to promote the use 
of many products besides MSG, including aspartame, chelated minerals, 
and tryptophan.</p>
<p>Although several amino acids can be 
acutely or chronically toxic, even lethal, when too much is eaten, tryptophan 
is the only amino acid that is also carcinogenic. (It can also produce 
a variety of toxic metabolites, and it is very susceptible to damage 
by radiation.) Since tryptophan is the precursor of serotonin, the amount 
of tryptophan in the diet can have important effects on the way the 
organism responds to stress, and the way it develops, adapts, and ages.</p>
<p>When an inflammatory disease (eosinophilia-myalgia 
syndrome) was noticed in people using tryptophan tablets (1989-90), 
there was an intense campaign to exonerate the tryptophan itself by 
blaming the reaction on an impurity in one company&#39;s product. But the 
syndrome didn&#39;t occur only in the people who used that company&#39;s product, 
and similar changes can be produced by a high-tryptophan diet (Gross, 
et al., 1999).</p>
<p>There are people who advocate the use 
of tryptophan supplementation or other means to increase serotonin in 
the tissues as a treatment for the fibromyalgia syndrome, but the evidence 
increasingly suggests that excessive serotonin, interfering with muscle 
mitochondria, is a major factor in the development of that syndrome.</p>
<p>In 1965, Hans Selye showed that the 
injection of serotonin caused muscular dystrophy. Subsequent studies 
suggest that serotonin excess is involved in both muscular and nervous 
dystrophy or degeneration. (O&#39;Steen, 1967; Narukami, et al., 1991; Hanna 
and Peat, 1989.)</p>
<p>The fatigue produced by “over-training” 
is probably produced by a tryptophan and serotonin overload, resulting 
from catabolism of muscle proteins and stress-induced increases in serotonin. 
Muscle catabolism also releases a large amount of cysteine, and cysteine, 
methionine, and tryptophan suppress thyroid function (Carvalho, et al., 
2000). Stress also liberates free fatty acids from storage, and these 
fatty acids increase the uptake of tryptophan into the brain, increasing 
the formation of serotonin. Since serotonin increases ACTH and cortisol 
secretion, the catabolic state tends to be self-perpetuating. This process 
is probably a factor influencing the rate of aging, and contributing 
to the physiological peculiarities of aging and depression.</p>
<p>Malnutrition, and specifically protein 
deficiency, produces an inflammatory state that involves extreme serotonin 
dominance. Stress or malnutrition prenatally or in infancy leads to 
extreme serotonin dominance in adulthood. Other functions of tryptophan 
are reduced, as more of it is turned into serotonin.</p>
<p>Decreasing tryptophan or decreasing 
serotonin improves learning and alertness, while increased serotonin 
impairs learning.</p>
<p>Tryptophan is an essential amino acid 
for reproduction and growth of the young animal. Most research on the 
nutritional requirements for amino acids has been done on farm animals, 
because of the economic incentive to find the cheapest way to produce 
the fastest growth. Farmers aren&#39;t interested in the nutritional factors 
that would produce the longest-lived pigs. Some research has been done 
on the amino acid requirements of rats over a significant part of their 
short lifespans. In rats and farm animals, the amount of tryptophan 
required decreases with time as the rate of growth slows.</p>
<p>In some ways, rats never really mature, 
since they keep growing for nearly their whole lifespan. Their growth 
stops just a short time before they die, which is usually around the 
age of two or three years. (At this age, rats&#39; cells still retain approximately 
the same high water content seen in the cells of a two year-old child.) 
They usually become infertile about half-way through their lifespan. 
If we try to draw conclusions about amino acid requirements from the 
rat studies, I think we would want to extrapolate the curve for the 
decreasing need for tryptophan, far beyond the point seen during the 
rat&#39;s short life. And those “requirements” were determined according 
to the amounts that produced a maximum rate of growth, using the index 
of the pig farmers, as if the rats were being studied for possible use 
as meat.</p>
<p>When rats were fed a diet completely 
lacking tryptophan for a short period, or a diet containing only one 
fourth of the “normal” amount for a more prolonged period, the results 
were surprising<strong>:</strong> They kept the ability to reproduce up to the 
age of 36 months (versus 17 months for the rats on the usual diet), 
and both their average longevity and their maximum longevity increased 
significantly. They looked and acted like younger rats. (A methionine-poor 
diet also has dramatic longevity-increasing effects.)</p>
<p>On the tryptophan-poor diet, the amount 
of serotonin in the brain decreased. When brain serotonin decreases, 
the level of testosterone in male animals increases. More than 20 years 
ago, a chemical (p-chlorophenylalanine) that inhibits serotonin synthesis 
was found to tremendously increase libido.</p>
<p>In old age, the amount of serotonin 
in the brain increases. This undoubtedly is closely related to the relative 
inability to turn off cortisol production that is characteristic of 
old age (Sapolsky and Donnelly, 1985). Hypothyroidism increases the 
formation of serotonin, as does cortisol (Henley, et al., 1997, 1998; 
Neckers and Sze, 1976).</p>
<p>In white hair, the amount of tryptophan 
is higher than in hair of any other color. Although serotonin and tryptophan 
are very important during rapid growth, their presence in senile tissues 
is probably closely associated with the processes of decline. The hair 
loss that occurs in hypothyroidism, postpartum syndrome, and with the 
use of drugs such as St. John&#39;s wort (which can also cause the “serotonin 
syndrome”) could be another effect of excess serotonin.</p>
<p>Serotonin stimulates cell division 
and tends to increase the formation of connective tissue, so its formation 
should be closely regulated once full growth is achieved. It contributes 
to the age- or stress-related thickening of blood vessels, and other 
fibrotic processes that impair organ function.</p>
<p>The metabolic rate (eating more without 
gaining extra weight) and ability to regulate body temperature are increased 
by early tryptophan deprivation. (Ashley and Curzon, 1981; Segall and 
Timiras, 1975.) The ability to oxidize sugar is impaired by serotonin, 
and several drugs with antiserotonin actions are being used to treat 
diabetes and its complications, such as hypertension, obesity, and foot 
ulcers. </p>
<p>An excess of tryptophan early in life, 
stress, or malnutrition, activates the system for converting tryptophan 
into serotonin, and that tendency persists into adulthood, modifying 
pituitary function, and increasing the incidence of pituitary and other 
cancers. </p>
<p>Serotonin&#39;s contribution to high blood 
pressure is well established. It activates the adrenal cortex both directly 
and through activation of the pituitary. It stimulates the production 
of both cortisol and aldosterone. It also activates aldosterone secretion 
by way of the renin-angiotensin system. Angiotensin is an important 
promoter of inflammation, and contributes to the degeneration of blood 
vessels with aging and stress.<strong> It can also promote estrogen production.</strong></p>
<p>In the traditional diet, rather than 
just eating muscle meats, all the animal parts were used. Since collagen 
makes up about 50% of the protein in an animal, and is free of tryptophan, 
this means that people were getting about half as much tryptophan in 
proportion to other amino acids when they used foods such as “head 
cheese,” ox-tails, and chicken feet.</p>
<p>While some of the toxic effects of 
an excess of individual amino acids have been investigated, and some 
of the protective or harmful interactions resulting from changing the 
ratios of the amino acids have been observed, the fact that there are 
about 20 amino acids in our normal diet means that there is an enormous 
number of possibilities for harmful or beneficial interactions. </p>
<p>The optimal quantity of protein in 
the diet has traditionally been treated as if it were a matter that 
could be resolved just by observing the rate of growth when a certain 
protein is given in certain quantities, along with “standard amounts” 
of calories and other nutrients. This kind of research has been useful 
to farmers who want to find the cheapest foods that will produce the 
biggest animals in the shortest time. But that kind of research climate 
has spread a degraded concept of nutrition into the culture at large, 
influencing medical ideas of nutrition, the attitudes of consumers, 
and the policies of governmental regulatory agencies.</p>
<p>When synthetic amino acids are used 
to supplement natural proteins, they are usually chosen according to 
irrelevant models of the “ideal protein&#39;s” composition, and many 
toxic contaminants are invariably present in the synthetic free amino 
acids. </p>
<p>For the present, the important thing 
is to avoid the use of the least appropriate food products, while choosing 
natural foods that have historical, epidemiological, and biochemical 
justification. </p>
<p>Whey has been promoted as a protein 
supplement, but it contains a slightly higher proportion of tryptophan 
than milk does. Cheese (milk with the whey removed) contains less tryptophan. 
Some people have been encouraged to eat only the whites of eggs, “to 
avoid cholesterol,” but the egg albumin is rich in tryptophan.</p>
<p>The expensive tender cuts of meat contain 
excessive amounts of cysteine and tryptophan, but bone broth (gelatin) 
and the tougher cuts of meat contain more gelatin, which lacks those 
amino acids. Many fruits are deficient in tryptophan, yet have very 
significant quantities of the other amino acids. They also contain some 
of the “carbon skeleton” (keto-acid) equivalents of the essential 
amino acids, which can be converted to protein in the body.</p>
<p>Serotonin excess produces a broad range 
of harmful effects<strong>:</strong> Cancer, inflammation, fibrosis, neurological 
damage, shock, bronchoconstriction, and hypertension, for example. Increased 
serotonin impairs learning, serotonin antagonists improve it.</p>
<p>The simplest, nonessential, amino acid, 
glycine, has been found to protect against carcinogenesis, inflammation, 
fibrosis, neurological damage, shock, asthma, and hypertension. Increased 
glycine improves learning (Handlemann, et al., 1989; File, et al., 1999), 
glycine antagonists usually impair it. Its antitoxic and cytoprotective 
actions are remarkable. Collagen, besides being free of tryptophan, 
contains a large amount of glycine--32% of its amino acid units, 22% 
of its weight. </p>
<p>The varied antiinflammatory and protective 
effects of glycine can be thought of as an antiserotonin action. For 
example, serotonin increases the formation of TNF (tumor necrosis factor, 
also called cachectin), glycine inhibits it. In some situations, glycine 
is known to suppress the formation of serotonin.<strong> Antagonists of serotonin 
can potentiate glycine&#39;s effects</strong> (Chesnoy-Marchais, et al., 2000). 
People who ate traditional diets, besides getting a lower concentration 
of tryptophan, were getting a large amount of glycine in their gelatin-rich 
diet.</p>
<p>Gelatin, besides being a good source 
of glycine, also contains a large amount of proline, which has some 
antiexcitatory properties similar to glycine.</p>
<p>If a half-pound of steak is eaten, 
it would probably be reasonable to have about 20 grams of gelatin at 
approximately the same time. Even a higher ratio of gelatin to muscle 
meat might be preferable.</p>
<p>Carbon dioxide, high altitude, thyroid, 
progesterone, caffeine, aspirin, and decreased tryptophan consumption 
protect against excessive serotonin release. When sodium intake is restricted, 
there is a sharp increase in serotonin secretion. This accounts for 
some of the antiinflammatory and diuretic effects of increased sodium 
consumption--increasing sodium lowers both serotonin and adrenalin.</p>
<p>The polyunsaturated oils interact closely 
with serotonin and tryptophan, and the short and medium chain saturated 
fatty acids have antihistamine and antiserotonin actions. Serotonin 
liberates free fatty acids from the tissues, especially the polyunsaturated 
fats, and these in turn liberate serotonin from cells such as the platelets, 
and liberate tryptophan from serum albumin, increasing its uptake and 
the formation of serotonin in the brain. Saturated fats don&#39;t liberate 
serotonin, and some of them, such as capric acid found in coconut oil, 
relax blood vessels, while linoleic acid constricts blood vessels and 
promotes hypertension. Stress, exercise, and darkness, increase the 
release of free fatty acids, and so promote the liberation of tryptophan 
and formation of serotonin. Increased serum linoleic acid is specifically 
associated with serotonin-dependent disorders such as migraine.</p>
<p>Coconut oil, because of its saturated 
fatty acids of varied chain length, and its low linoleic acid content, 
should be considered as part of a protective diet.</p>
<p>In the collagen theory of aging, it 
is argued that changes in the extracellular matrix are responsible for 
isolating cells from their environment, reducing the availability of 
nutrients and oxygen, and reducing their ability to send and receive 
the chemical signals that are needed for correct adaptive functioning. </p>
<p>In diabetes, basement membranes are 
thickened, and in a given volume of tissue there are fewer capillaries. 
This effect probably involves excessive serotonin<em> </em>
(Kasho, et al., 1998). Old animals contain a higher proportion of collagen. 
Old tendons (or tendons that have been exposed to excessive estrogen, 
which stimulates the formation of collagen) are more rigid, and behave 
almost as if they have been partly cooked. In diseases such as carcinoid, 
in which very large amounts of serotonin are released systemically, 
fibrosis is exaggerated, and may be the direct cause of death. Radiation 
and oxygen deprivation also lead to increased tissue fibrosis.</p>
<p>In specific fibrotic conditions, such 
as cirrhosis of the liver, it is known that glycine and saturated fats 
can reverse the fibrosis. In fibrosis of the heart, thyroid hormone 
is sometimes able to reverse the condition. </p>
<p>I think these facts imply that excessive 
tryptophan, estrogen, and polyunsaturated fats contribute significantly, 
maybe decisively, to the degenerative changes that occur in aging. Experiments 
have separately shown that reducing dietary tryptophan or unsaturated 
fats can extend the healthy lifespan, and several antiestrogenic interventions 
(removal of the pituitary, or supplementing with progesterone) can slow 
age-related changes and delay degenerative diseases. Since these factors 
interact, each tending to promote the others, and also interact with 
exogenous toxins, excess iron accumulation, and other stressors, it 
would be reasonable to expect greater results when several of the problems 
are corrected at the same time. </p>
<h2>References</h2>
<small>
<p>Toxicol Pathol 1998 May-Jun;26(3):395-402. <strong>
Glycine modulates the toxicity of benzyl acetate in F344 rats.</strong> Abdo 
KM, Wenk ML, Harry GJ, Mahler J, Goehl TJ, Irwin RD. “These results 
suggest that the neurodegeneration induced by BA is mediated by a depletion 
of the glycine pool and the subsequent excitotoxicity.”</p>
<p>Res Clin Stud Headache 1978;6:110-6.<strong> 
Role of individual free fatty acids in migraine. </strong>
Anthony M “Total plasma free fatty acids, platelet serotonin content 
and plasma stearic, palmitic, oleic and linoleic acids were estimated 
in 10 migraine patients before, during and after a migraine attack. 
Total and individual plasma free fatty acid levels rose and platelet 
serotonin content fell in most patients. <strong>The highest rise was observed 
in linoleic acid, which is known to be a potent liberator of platelet 
serotonin in vitro</strong> and is the only precursor of all prostaglandins 
in the body. It is suggested that the rise in plasma levels of<strong> linoleic 
acid in migraine could be responsible for the platelet serotonin release 
observed during the attack.”</strong></p>
<p>Clin Exp Neurol 1978;15:190-6.<strong> Individual 
free fatty acids and migraine.</strong> Anthony M Total plasma free fatty 
acids (FFAs), platelet serotonin content and plasma stearic, palmitic, 
oleic and linoleic acids were estimated in 10 migrainous patients before, 
during and after a migraine attack. Total and individual plasma FFA 
levels rose and platelet serotonin fell in most patients. Comparison 
of the pre-headache and headache mean values showed that of the FFAs 
linoleic acid rises most during headache. <strong>10 non-migrainous controls 
had platelet serotonin content estimated before and after the ingestion 
of 20g linoleic acid. All showed a significant fall in platelet serotonin 
in the post-ingestion period. It is shown that linoleic acid releases 
platelet serotonin in vitro, and this study suggests that it has the 
same action in vivo.</strong> Further, it is the precursor of all prostaglandins 
in the body and its marked elevation during migraine may serve as a 
source of increased prostaglandin E1 (PGE1) synthesis. It is<strong> suggested 
that linoleic acid plays an important role in the biochemical process 
of the migraine attack, acting both as a serotonin releasing factor 
and a source</strong> of PGF1, the vasodilating action of which can aggravate 
the clinical symptoms of migraine.</p>
<p>J Appl Physiol 1993 Jun;74(6):3006-12. <strong>
Neuroendocrine and substrate responses to altered brain 5-HT activity 
during prolonged exercise to fatigue.</strong> Bailey SP, Davis JM, Ahlborn 
EN. “Pharmacological manipulation of brain serotonergic [5-hydroxytryptamine 
(5-HT)] activity affects run time to exhaustion in the rat. These effects 
may be mediated by neurochemical, hormonal, or substrate mechanisms. 
Groups of rats were decapitated during rest, after 1 h of treadmill 
running (20 m/min, 5% grade), and at exhaustion. Immediately before 
exercise rats were injected intraperitoneally with 1 mg/kg of quipazine 
dimaleate (QD; a 5-HT agonist), 1.5 mg/kg of LY 53857 (LY; a 5-HT antagonist), 
or the vehicle (V; 0.9% saline). LY increased and QD decreased time 
to exhaustion (approximately 28 and 32%, respectively; P &lt; 0.05).” 
“Brain 5-HT and 5-hydroxyindole-3-acetic acid<strong> concentrations were 
higher at 1 h of exercise than at rest (P &lt; 0.05), and the latter 
increased even further at fatigue in the midbrain and striatum (P &lt;</strong> 
0.05).”</p>
<p>Neurochem Int 1993 Sep;23(3):269-83. <strong>
Glutamate, GABA, glycine and taurine modulate serotonin synthesis and 
release in rostral and caudal rhombencephalic raphe cells in primary 
cultures.</strong> Becquet D, Hery M, Francois-Bellan AM, Giraud P, Deprez 
P, Faudon M, Fache MP, Hery F.</p>
<p>Acta Physiol Scand 2001 Oct;173(2):223-30. <strong>
Exercise-induced changes in brain glucose and serotonin revealed by 
microdialysis in rat hippocampus: effect of glucose supplementation.</strong> 
Bequet F, Gomez-Merino D, Berthelot M, Guezennec CY.</p>
<p>Amino Acids 2001;20(1):25-34. <strong>Amino 
acids and central fatigue.</strong> Blomstrand E. “There is an increasing 
interest in the mechanisms behind central fatigue, particularly in relation 
to changes in brain monoamine metabolism and the influence of specific 
amino acids on fatigue.” <strong>“When the 5-HT level was elevated in 
this way the performance was impaired in both rats and human subjects, 
and in accordance with this a decrease in the 5-HT level caused an improvement 
in running performance in rats. The precursor of 5-HT is the amino acid 
tryptophan and the synthesis of 5-HT in the brain is thought to be regulated 
by the blood</strong> supply of free tryptophan in relation to other large 
neutral amino acids (including the branched-chain amino acids, BCAA) 
since these compete with tryptophan for transport into the brain.”</p>
<p>J Neurol Sci 1988 Apr;84(2-3):239-46. <strong>
Increased platelet aggregation and release reaction in myotonic dystrophy.</strong> 
Bornstein NM, Zahavi M, Korczyn AD, Zahavi J.</p>
<p>Curr Med Chem 2001 Sep;8(11):1257-74. <strong>
The inhibitory neural circuitry as target of antiepileptic drugs.</strong> 
Bohme I, Luddens H. “Impairments and defects in the inhibitory neurotransmission 
in the CNS can contribute to various seizure disorders, i.e., gamma-aminobutyric 
acid (GABA) and glycine as the main inhibitory neurotransmitters in 
the brain play a crucial role in some forms of epilepsy.” </p>
<p>Braz J Med Biol Res 2000 Mar;33(3):355-61. <strong>
Thyroid peroxidase activity is inhibited by amino acids.</strong> Carvalho 
DP, Ferreira AC, Coelho SM, Moraes JM, Camacho MA, Rosenthal D</p>
<p>Q J Exp Psychol B 2000 Aug;53(3):225-38. <strong>
Rapid visual learning in the rat: effects at the 5-HT1a receptor subtype.</strong> 
Cassaday HJ, Simpson EL, Gaffan EA. “<strong>The 5-hydroxytryptamine1a 
(5-HT1a) receptor agonist 8-hydroxy-2-(di-n-propylamino) tetralin (8-OH-DPAT; 
0.15 mg/kg) impaired rats&#39; rapid visual learning on a computerized maze. 
This treatment also increased decision time (DT) but the learning impairment 
was not necessarily a side-effect of slower responding because, in this 
task, responses made at long DT are more accurate than those at short 
DT.</strong>” “Its reversal with WAY-100635 offers support to the hypothesis 
that 5-HT1a receptor antagonists could improve cognitive function, under 
conditions of pre-existing impairment due to overactive serotonergic 
inhibition, as is thought to occur in Alzheimer&#39;s disease.”</p>
<p>Med Sci Sports Exerc 1997 Jan;29(1):58-62. <strong>
Effects of acute physical exercise on central serotonergic systems.</strong> 
“This paper reviews data concerning the effects of acute physical 
exercise (treadmill running) in trained rats. Works from the 1980&#39;s 
have established that<strong> acute running increases brain serotonin (5-hydroxytryptamine: 
5-HT) synthesis in two ways. Lipolysis-elicited release of free fatty 
acids in the blood compartment displaces the binding of the essential 
amino acid tryptophan to albumin, thereby increasing the concentration 
of the so-called &quot;free tryptophan&quot; portion, and because exercise 
increases the ratio of circulating free tryptophan to the sum of the 
concentrations of the amino acids that compete with tryptophan</strong> for 
uptake at the blood-brain barrier level, tryptophan enters markedly 
in the brain compartment. However, this marked increase in central tryptophan 
levels increases only to a low extent brain 5-HT synthesis, as assessed 
by the analysis of 5-hydroxyindoleacetic acid levels, thereby suggesting 
that exercise promotes feedback regulatory mechanisms. Indirect indices 
of 5-HT functions open the<strong> possibility that acute exercise-induced 
increases in 5-HT biosynthesis are associated with (or lead to) increases 
in 5-HT release.”</strong></p>
<p>Int J Dev Neurosci 1997 Apr;15(2):257-63. <strong>
Postnatal changes of brain monoamine levels in prenatally malnourished 
and control rats.</strong> Chen JC, Turiak G, Galler J, Volicer L.</p>
<p>Eur J Pharmacol 2000 Aug 25;402(3):205-13.<strong> 
Glycinergic potentiation by some 5-HT(3) receptor antagonists: insight 
into</strong> <strong>selectivity.</strong> Chesnoy-Marchais D, Levi S, Acher F.</p>
<p>Mech Ageing Dev 1986 Oct;36(2):161-71. <strong>
Influence of low tryptophan diet on survival and organ growth in mice.</strong> 
De Marte ML, Enesco HE. Greater survival and reduced growth were found 
to characterize mice on a tryptophan deficient diet as compared to fully 
fed control mice. The 50% survival point was reached by the tryptophan 
restricted group at 683 days, and by the control group at 616 days. 
Measurements of body weight, organ weight, and DNA level were made at 
8, 12, 24, 36, 52 and 78 weeks of age. Both whole body weight and organ 
weight of liver, kidney, heart and spleen were about 30% lower in the 
tryptophan restricted group as compared to the controls, so that the 
ratio of organ weight to body weight remained at a constant value for 
both groups. There was no significant change in cell number as determined 
by DNA measurements, as a result of the tryptophan restriction.</p>
<p>J Clin Psychopharmacol 1999 Dec;19(6):506-12. <strong>
Beneficial effects of glycine (bioglycin) on memory and attention in 
young and middle-aged adults.</strong> File SE, Fluck E, Fernandes C. .”The 
effects of Bioglycin(Konapharma, Pratteln, Switzerland), a biologically 
active form of the amino acid glycine, were . . . studied in healthy 
students (mean age, 20.7 years) and middle-aged men (mean age, 58.9 
years) with tests that measured attention, memory and mood, using a 
double-blind, randomized, crossover design. Compared with the young 
group, the middle-aged group had significantly poorer verbal episodic 
memory, focused, divided, and sustained attention; they also differed 
in their subjective responses at the end of testing. Bioglycin significantly 
improved retrieval from episodic memory in both the young and the middle-aged 
groups, but it did not affect focused or divided attention. However, 
the middle-aged men significantly benefited from Bioglycin in the sustained-attention 
task. The effects of Bioglycin differed from those of other cognitive 
enhancers in that it was without stimulant properties or significant 
effects on mood, and it primarily improved memory rather than attention. 
It is likely to be of benefit in young or older people in situations 
where high retrieval of information is needed or when performance is 
impaired by jet lag, shift work, or disrupted sleep. It may also benefit 
the impaired retrieval shown in patients with schizophrenia, Parkinson&#39;s 
disease, and Huntington&#39;s disease.</p>
<p>Brain Res 1997 Sep 12;768(1-2):43-8.<strong> 
Mobilization of arachidonate and docosahexaenoate by stimulation of 
the 5-HT2A receptor in rat C6 glioma cells.</strong> Garcia MC, Kim HY Laboratory 
of Membrane Biochemistry and Biophysics, National Institute on Alcohol 
Abuse and Alcoholism, National Institutes of Health, Rockville, MD 20852, 
USA.<strong> “In this study, we demonstrate that astroglial 5-HT2A receptors 
are linked to the mobilization of polyunsaturated fatty acids (PUFA). 
Stimulation of C6 glioma</strong> cells, prelabeled with [3H]arachidonate 
(AA, 20:4n6) and [14C]docosahexaenoate (DHA, 22:6n3), with serotonin 
and the 5-HT(2A/2C) receptor agonist (+/-)-2,5-dimethoxy-4-iodoamphetamine 
hydrochloride (DOI) resulted in the mobilization of both [3H] and [14C] 
into the supernatant of the cell monolayers. The increased radioactivity 
in the supernatant was mainly associated with free fatty acids.” “These 
results indicate that the 5-HT2A receptor is coupled to the mobilization 
of PUFA.”</p>
<p>Neurosci Lett 1995 May 5;190(2):143-5.<strong> 
Serotonin involvement in the spontaneous alternation ability: a behavioral 
study in tryptophan-restricted rats.</strong> Gonzalez-Burgos I, Olvera-Cortes 
E, Del Angel-Meza AR, Feria-Velasco A. Laboratorio de Psicobiologia, 
Centro de Investigacion Biomedica de Occidente, IMSS, Guadalajara, Jal., 
Mexico. Spontaneous alternation (SA) is controlled by septal cholinergic 
terminals in the hippocampus. Serotoninergic terminals end on cholinergic 
nerve endings in the hippocampus, and their possible role in SA was 
investigated in rats fed with a tryptophan-deficient diet, from weaning 
to 60 days of age. <strong>A T-maze was used for the test. At the age of 
40 days, an increase in SA occurred in the tryptophan deficient rats, </strong>
although this effect disappeared by 60 days of age. A modulatory role 
of serotonin in the psychoneural control of SA is suggested, and it 
may be through presynaptic inhibition of hippocampal cholinergic terminals.</p>
<p>Physiol Behav 1998 Jan;63(2):165-9.<strong> 
Effect of tryptophan restriction on short-term memory.</strong> Gonzalez-Burgos 
I, Perez-Vega MI, Del Angel-Meza<strong> </strong>
AR, Feria-Velasco A. Centro de Investigacion Biomedica de Michoacan, 
Instituto Mexicano del Seguro Social, Morelia. Several brain regions 
are involved in the learning process that is integrated from sensorial 
inputs. It is thereafter consolidated in short- (STM) or long-term memory. 
Serotonin is strongly related to both types of memory, and particularly, 
to STM, however, its regulatory role is still unclear. In this study, 
the effects of tryptophan (TRY) restriction on learning and STM were 
evaluated. Ten Sprague-Dawley female rats were fed with a TRY-restricted 
diet (0.15g/100g) starting from postnatal Day 21. At 21, 40, and 60 
days of age, 5 trials per animal were carried out in a &quot;hard-floor&quot;-Biel 
maze, after 24 h of water abstinence. The number of errors per trial 
were registered before reaching<strong> </strong>
the goal.<strong> At both 40 and 60 days, experimental rats committed less 
errors than controls. Likewise, the TRY-restricted group learned the 
task from the second trial on, whereas controls did not solve it until 
the third trial. </strong>TRY restriction, and therefore brain serotonin 
reduction, could impair normal cholinergic activity in some areas such 
as the hippocampus and the cerebral cortex, where involvement in learning 
and memory is well documented. Morphological and neurochemical plastic 
events could also be related to the more efficient performance of the 
task by the TRY-restricted rats.</p>
<p>Am J Physiol 1997 Jul;273(1 Pt 2):R324-30. <strong>
Mechanisms in the pressor effects of hepatic portal venous fatty acid 
infusion.</strong> Grekin RJ, Dumont CJ, Vollmer AP, Watts SW, Webb RC Portal 
venous infusion of oleate solution has pressor effects. We have examined 
efferent mechanisms, measured the response to sustained infusion, and 
determined the effect of linoleate. Eight conscious animals received 
concurrent infusions of prazosin or vehicle with portal venous infusion 
of oleate. Oleate alone<strong> increased mean arterial pressure from 109.0 
+/- 4.1 to 123.0 +/- 5.8 mmHg (P = 0.02), whereas no increase in blood 
pressure occurred when oleate was infused</strong> with prazosin. In 10 rats, 
concurrent infusion of losartan had no effect on the pressor activity 
of portal oleate infusion. Twenty-two animals received portal oleate 
or vehicle as a continuous infusion for 7 days. Mean arterial pressure 
(126.1 +/- 2.0 vs. 107.8 +/- 2.6 mmHg, P &lt; 0.001) and heart rate 
(383 +/- 5 vs. 366 +/- 5, P = 0.0257) were increased in oleate-infused 
animals. No differences in plasma fatty acids, glucose, insulin, pressor 
hormones, liver enzymes, or in vitro arterial pressor responsiveness 
were observed. “Portal venous infusion of<strong> linoleate increased arterial 
pressure by 12.2 +/- 3.2 mmHg (P = 0.033). These results indicate that 
alpha-adrenergic activity is necessary for the acute pressor effects 
of portal oleate, that sustained portal oleate infusion results in persistent 
blood pressure elevation, and that other long-chain fatty acids besides 
oleate have pressor effects.”</strong></p>
<p>Adv Exp Med Biol 1999;467:507-16. <strong>
Tryptophan toxicity--time and dose response in rats.</strong> Gross B, Ronen 
N, Honigman S, Livne E. “During the past decade L-tryptophan (Trp) 
ingestion have been associated with a multisystemic syndrome, known 
as eosinophilia myalgia syndrome (EMS). Even though an epidemic studies 
indicated that a contaminant, 1,1&#39;-ethylidene-bis-L-tryptophan was involved 
in EMS, <strong>abnormalities in metabolism of Trp have been reported in 
other similar clinical syndromes such as carcinoid syndrome, scleroderma 
or eosinophilic fasciitis.”</strong> <strong>“Increased amounts of connective 
tissue</strong> <strong>and induction of inflammatory cell proliferation were 
observed in lung, spleen and in gastrocnemia muscle of rats treated 
with higher dose of Trp for longer period.</strong> Induction of kynurenine 
pathway by injection of p-CPA caused more tissue damage. It is concluded 
that excessive Trp or elevation of its metabolites could play a role 
in amplifying some of pathological features of EMS. This pathological 
damage is further augmented by metabolites of the kynurenine pathway.”</p>
<p>Zh Nevrol Psikhiatr Im S S Korsakova 
1999;99(2):12-20. <strong>[Neuroprotective effects of glycine in the acute 
period of ischemic stroke.]</strong> [Article in Russian] Gusev EI, Skvortsova 
VI, Komissarova IA, Dambinova SA, Raevskii KS, Alekseev AA, Bashkatova 
VG, Kovalenko AV, Kudrin VS, Iakovleva EV.</p>
<p>Pharmacol Biochem Behav 1989 Dec;34(4):823-8. <strong>
Milacemide, a glycine prodrug, enhances performance of learning tasks 
in normal and amnestic rodents.</strong> Handelmann GE, Nevins ME, Mueller 
LL, Arnolde SM, Cordi AA. “Increasing glycine concentrations in the 
brain by administration of a glycine prodrug, milacemide, is shown here 
to enhance performance of a shock-motivated passive avoidance task in 
rats, and to reverse drug-induced amnesia in a spontaneous alternation 
paradigm in mice.” “These studies indicate a role of glycinergic 
neurotransmission in memory processes, and support the therapeutic potential 
of glycinergic drugs in memory impairment.”</p>
<p>Pain 1989 Aug;38(2):145-50.<strong> Ketanserin 
in reflex sympathetic dystrophy. A double-blind placebo controlled cross-over 
trial. </strong>Hanna MH, Peat SJ.</p>
<p>Synapse 1997 Sep;27(1):36-44. <strong>Thyroid 
hormones and the treatment of depression: an examination of basic hormonal 
actions in the mature mammalian brain. </strong>
Henley WN, Koehnle TJ. “The lack of mechanistic insight reflects, 
in large part,<strong> a longstanding bias that the mature mammalian central 
nervous system is not an important target site for thyroid hormones.”</strong></p>
<p>Am J Physiol 1997 Feb;272(2 Pt 2):H894-903. <strong>
Hypothyroid-induced changes in autonomic control have a central serotonergic 
component. </strong>Henley WN, Vladic F. Three experiments were conducted 
in unanesthetized rats made hypothyroid (Hypo) or maintained as euthyroid 
controls (Eu) to examine general cardiovascular responsiveness [experiment 
I (Exp I)]; responsiveness to a serotonin (5-HT2) agonist, dl-2,5-dimethoxy-4-iodoamphetamine 
[DOI intracerebroventricularly; experiment II (Exp II)]; or responsiveness 
to a 5-HT(1A) agonist dl-8-hydroxydipropyl-aminotetralin hydrobromide 
[8-OH-DPAT intracerebroventricularly; experiment III (Exp III)]. In 
Exp I, intravenous infusions of phenylephrine and nitroprusside provided 
little evidence that findings in Exp II and III were caused by generalized 
impairment in cardiovascular responsiveness in Hypo. In Exp II and III, 
Eu and Hypo were given either intra-arterial atropine or vehicle. Atropine 
significantly elevated heart rate (Exp II and III) and mean arterial 
pressure (Exp II) in Eu only. When compared with Eu, Hypo had a reduced 
pressor response (5.2 vs. 20.1%), an attenuated pulse pressure response 
(19.3 vs. 35.4%), and a more robust bradycardia (-17.7 vs. -7.0%) in 
response to DOI. These differences were atropine sensitive. In Exp III, 
Hypo had larger decrements in mean arterial pressure (-9.0 vs. -5.1%), 
heart rate ( -13.9 vs. - 7.7%), and body temperature (-4.5 vs. -2.7%) 
in response to 8-OH-DPAT in comparison to Eu. Parasympathetic involvement 
in the differential responses to 8-OH-DPAT was less clear than with 
DOI. Deranged autonomic control in hypothyroidism may be caused, in 
part, by changes in central serotonergic activity.</p>
<p>Brain Res 1986 Mar;390(2):221-6. <strong>
Brain serotonin synthesis and Na+,K+-ATPase activity are increased postnatally 
after prenatal administration of L-tryptophan.</strong> Hernandez-Rodriguez 
J, Chagoya G. The effect of prenatal L-tryptophan supplementation on 
the serotonin (5-HT) synthesis and the activity of Na+,K+-ATPase in 
the cerebral cortex was studied during postnatal development, from birth 
up to day 30. A parallel and<strong> significant elevation of the serotonin 
content and the activity of tryptophan-5-hydroxylase was observed in 
the brain of infant rats born to mothers treated with L-tryptophan, 
as related to non-treated controls. The</strong> activity of Na+,K+-ATPase 
was also significantly elevated at the different ages studied throughout 
the developmental period, as related to controls. These results suggest 
an important role of L-tryptophan in the early regulation of the<strong> 
serotonin-synthesizing machinery, which lasts postnatally. Elevation 
of ATPase activity seems to be associated to the elevation in the activity 
of the 5-HT system.</strong></p>
<p>Brain Res 1977 Mar 4;123(1):137-45. <strong>
Daily variations of various parameters of serotonin metabolism in the 
rat brain. II. Circadian variations in serum and cerebral tryptophan 
levels: lack of correlation with 5-HT turnover.</strong> Hery F, Chouvet 
G, Kan JP, Pujol JF, Glowinski J “Significant circadian variations 
in 5-HT and 5-HIAA levels were found in cerebral tissues.” “Important 
significant circadian variations in free and total serum tryptophan 
levels were also observed. In both cases, the maximal levels were found 
during the middle of the dark phase after the peak of 5-HIAA levels.” 
“The diurnal changes in tryptophan content in cerebral tissues seemed 
thus related to those found in serum.”</p>
<p>Kidney Int 1998 Oct;54(4):1083-92. <strong>
Serotonin enhances the production of type IV collagen by human mesangial 
cells.</strong> Kasho M, Sakai M, Sasahara T, Anami Y, Matsumura T, Takemura 
T, Matsuda H, Kobori S, Shichiri M.</p>
<p>Pharmacol Biochem Behav 1977 Sep;7(3):245-52. <strong>
Fatty acid and tryptophan changes on disturbing groups of rats and caging 
them singly.</strong> Knott PJ, Hutson PH, Curzon G The effects of disturbing 
groups of 24 hr fasted rats on plasma unesterified fatty acid (UFA) 
and tryptophan concentrations and brain tryptophan concentrations were 
investigated. Removing rats from cages rapidly increased plasma UFA 
and corticosterone and decreased plasma and whole blood tryptophan of 
cage mates. The disturbance also appeared to influence biochemical values 
of rats in other cages within the same chamber. Effects specific to 
individual cages were also suggested. In subsequent experiments 24 fasting 
rats caged together were rapidly transferred to 24 separate cages and 
killed at intervals. Plasma UFA rose to a maximum by 12 min and then 
fell toward initial values. Plasma total tryptophan concurrently fell 
then rose. Its percentage in the free (ultrafilterable) state, and in 
some experiments the absolute values of free tryptophan rose then fell. 
When the latter rise was marked <strong>then brain tryptophan and the 5-HT 
metabolite 5-hydroxyindoleacetic acid rose.</strong> Tyrosine changes were 
negligible. Thus altered brain tryptophan level and 5-HT metabolism 
may be associated with plasma tryptophan changes caused by brief environmental 
disturbance.</p>
<p>J Insect Physiol 2000 May 1;46(5):793-801. <strong>
Effect of an amino acid on feeding preferences and learning behavior 
in the honey bee, Apis mellifera.</strong> Kim YS, Smith BH. <strong>“Subjects 
preferred to feed on a sucrose stimulus that contained glycine, and 
the highest relative preference was recorded for the highest concentration 
of glycine.”</strong> “<strong>All concentrations of glycine enhanced the 
rate and magnitude of a conditioned response to an odor . . . .”</strong></p>
<p>Eur J Pharmacol 1981 May 22;71(4):495-8. <strong>
Antagonism of L-glycine to seizures induced by L-kynurenine, quinolinic 
acid and strychnine in mice.</strong> Lapin IP.</p>
<p>Int J Circumpolar Health 1998;57 Suppl 
1:386-8. <strong>Seasonal variation of the amino acid, L-tryptophan, in interior 
Alaska.</strong> Levine ME, Duffy LK. “The seasonal pattern of L-tryptophan 
was studied in a Fairbanks, Alaska, population that was unadapted to 
the extreme light variations of the North. Previously, this population 
was shown to exhibit seasonal behavior effects such as increases in 
fatigue and sleep duration, as well as endocrine effects such as increases 
in melatonin levels and phase shifting.” “Prominent results included 
finding increased levels in the winter at several different diurnal 
time points. These findings support hypotheses which relate underlying 
physiological adaptations to the North to the increased incidence of 
behavioral disorders such as depression and alcoholism.”</p>
<p>Infect Immun 2001 Sep;69(9):5883-91. <strong>
Dietary glycine prevents peptidoglycan polysaccharide-induced reactive 
arthritis in the rat: role for glycine-gated chloride channel.</strong> Li 
X, Bradford BU, Wheeler MD, Stimpson SA, Pink HM, Brodie TA, Schwab 
JH, Thurman RG.</p>
<p>J Neurol Sci 1989 Jan;89(1):27-35. <strong>
Polyamine biosynthetic decarboxylases in muscles of rats with different 
experimental myopathies.</strong> Lorenzini EC, Colombo B, Ferioli ME, Scalabrino 
G, Canal N.</p>
<p>Int J Dev Neurosci 1996 Aug;14(5):641-8. <strong>
Nutritional recovery does not reverse the activation of brain serotonin 
synthesis in the ontogenetically malnourished rat.</strong> Manjarrez GG, 
Magdaleno VM, Chagoya G, Hernandez J Coordinacion de Investigacion Biomedica 
del Centro Medico Nacional, I.M.S.S. Mexico, D.F. In the present work 
we confirm that gestational malnutrition effects body and brain composition 
and results in an activation of the synthesis of the brain neurotransmitter 
5-hydroxytryptamine. These results also demonstrate more activity of 
the rate-limiting enzyme tryptophan hydroxylase in the malnourished 
fetal and postnatal brain. However, the activity of this enzyme remains 
increased in the brain of nutritionally recovered animals accompanied 
by an increase in the synthesis of 5-hydroxytryptamine. We therefore 
suggest that, in the nutritionally recovered animal, the mechanism of 
activation of this biosynthetic path in the brain may be not dependent 
on the increased<strong> availability of free L-tryptophan observed in malnourished 
animals, but might be due to a specific change in the enzyme complex 
itself. This hypothesis is</strong> supported by the fact that plasma free 
and brain L-tryptophan return to normal in the recovered animal.</p>
<p>Brain Res 1997 Nov 7;774(1-2):265-8. <strong>
Tryptophan ingestion by gestant mothers alters prolactin and luteinizing 
hormone release in the adult male offspring.</strong> Martin L, Rodriguez 
Diaz M, Santana-Herrera C, Milena A, Santana C.</p>
<p>Rev Esp Fisiol 1984 Jun;40(2):213-9.<strong> 
[Lipolytic effect of serotonin in vitro].</strong> [Article in Spanish] Martinez-Conde 
A, Mayor de la Torre P, Tamarit-Torres J The lipolytic action of serotonin 
on isolated adipocytes from the adipose tissue of rats has been studied. 
The adipocytes were incubated in serotonin 10(-6) M. Changes both in 
concentration and composition of the free intra and extracellular fatty 
acids as well as diacylglycerides through liquid gas chromatography 
were evaluated at different intervals. A lower concentration of<strong> free 
fatty acids and diacylglycerides is produced during the first minutes 
of incubation as well as a subsequent increase in the concentration 
of both, which becomes greatest after 20-30 minutes. The composition 
of both lipidic fractions</strong> (FFA and DAG) into fatty acids at 5, 10, 
20 and 30 minutes, is related to the composition of the triacylglycerides 
(TAG), since during the esterification<strong> process a decline in the DAG 
of linoleic and palmitoleic acid is observed, both acids arranging themselves 
preferably in the TAG 2 position. Whereas the inverse process occurs 
during lipolysis; i.e. an increase in the proportion of the acids</strong> 
in the 2 position. In the FFA fraction, a higher proportion of fatty 
acids, preferential by arranged in positions 1 + 3 of the TAG&#39;s is observed. 
Similarly a decrease is observed in the extracellular concentration 
of FFA in the presence of serotonin with respect to the controls, a 
fact which has been described by other authors. An analysis of the present 
data leads us to revise the possible<strong> role of &quot;Cahill&#39;s cycle&quot; 
(simultaneous activation of the DAG-acyl-transferase and the HSL-TAG-lipase) 
in the action of serotonin and other hormones.</strong></p>
<p>Nahrung 1991;35(9):961-7. <strong>[The effect 
of different protein diets on longevity and various biochemical parameters 
of aged rats].</strong> Medovar BJa, Petzke KJ, Semesko TG, Albrecht V, Grigorov 
JuG Institut fur Gerontologie, AMW, UdSSR, Kiev. In this work 23 month 
old rats were fed for 200 days with different protein diets (NT-diet: 
19% protein, 72% of animal origin and LP-diet: 8.8% protein exclusively 
of vegetable origin). Some metabolic parameters and lifespan (on the 
base of a 50% death-rate) were determined. The relations of the liver 
free amino<strong> acids glycine + alanine and tyrosine + phenylalanine + 
branched chain amino acids and the ratio of phenylalanine/tyrosine were 
determined to be higher in the LP-group.</strong> Phenylalanine in liver 
and urea concentrations in liver and serum were lower in the LP-group. 
Furthermore the dopamine or serotonin levels were significantly lower 
in lateral and medial or lateral regions of the hypothalamus respectively 
in LP-diet fed rats. The norepinephrine content was not modified by<strong> 
the diets. The median lifespan of 23 month old rats was higher by 24% 
following LP-treatment. These results suggest that the protein component 
(amino acids) of</strong> different diets may modify metabolic parameters 
and lifespan of animals by mechanisms in which the central regulation 
may be involved.</p>
<p>J Neurol Sci 1976 May;28(1):41-56. <strong>
Skeletal muscle necrosis following membrane-active drugs plus serotonin.</strong> 
Meltzer HY.</p>
<p>Brain Res Bull 1977 Sep-Oct;2(5):347-53.<strong> 
Effects of developmental protein malnutrition on tryptophan utilization 
in brain and peripheral tissues.</strong> Miller M, Leahy JP, McConville 
F, Morgane PJ, Resnick O.</p>
<p>Exp Neurol 1977 Oct;57(1):142-57. <strong>
Tryptophan availability: relation to elevated brain serotonin in developmentally 
protein-malnourished rats.</strong> Miller M, Leahy JP, Stern WC, Morgane 
PJ, Resnick O.</p>
<p>Synapse 1990;6(4):338-43. <strong>Age-related 
changes of strychnine-insensitive glycine receptors in rat brain as 
studied by in vitro autoradiography</strong>. Miyoshi R, Kito S, Doudou N, 
Nomoto T. “3H-glycine binding sites were most concentrated in the 
hippocampus, cerebral cortex, and olfactory tubercle, and moderate densities 
of binding sites were located in the striatum, nucleus accumbens, amygdala, 
and certain thalamic nuclei.” <strong>“In aged animals, severe decline 
of 3H-glycine binding sites was observed in the telencephalic regions 
including the hippocampus and cerebral cortex.” “These results suggest 
that the decrease of glycine receptors in particular brain regions has 
some relation with changes of neuronal functions associated with aging 
process in these areas.</strong>”</p>
<p>Enzyme 1976;21(6):481-7. <strong>Inhibition 
of actomyosin ATPase by high concentrations of 5-hydroxytryptamine. 
Possible basis of lesion in 5HT-induced experimental myopathy.</strong> Mothersill 
C, Heffron JJ, McLoughlin JV.</p>
<p>Brain Res 1975 Jul 25;93(1):123-32. <strong>
Regulation of 5-hydroxytryptamine metabolism in mouse brain by adrenal 
glucocorticoids.</strong> Neckers L, Sze PY “A single injection of<strong> hydrocortisone 
acetate (HCA; 20 mg/kg, i.p.) accelerated the accumulation of 5-HT in 
whole brain after inhibition of monoamine oxidase activity by paragyline. 
The hormone did not appear to change brain tryptophan hydroxylase or 
5-hydroxytryptophan decarboxylase activity. However, tryptophan levels 
in brain were elevated by 50% within 1 h after treatment with HCA.”</strong></p>
<p>Proc Soc Exp Biol Med 1967 Nov;126(2):579-83. <strong>
Serotonin antagonist increases longevity in mice with hereditary muscular 
dystrophy.</strong> O&#39;Steen WK.</p>
<p>Mech Ageing Dev 1988 Apr;43(1):79-98. <strong>
Histology and survival in age-delayed low-tryptophan-fed rats. Ooka 
H, Segall PE, Timiras PS.</strong> Diets containing tryptophan in concentrations 
30 and 40 percent of those fed to controls from weaning to 24-30 months 
or more, can delay aging in Long-Evans female rats. Mortality among 
low-tryptophan-fed rats was greater in the juvenile period, but substantially 
less than controls at late ages. Histological biomarkers of aging were 
also delayed after tryptophan restriction in some organs (liver, heart, 
uterus, ovary, adrenal and spleen) but not in others (kidney, lung, 
aorta). Brain serotonin levels were low in tryptophan-deficient rats 
but showed remarkable capacity for rehabilitation. Effects on early 
and late mortality and brain levels of serotonin were proportional to 
the severity of the restriction.</p>
<p>Age Ageing 1985 Mar;14(2):71-5. <strong>
Plasma tryptophan, age and depression.</strong> Phipps DA, Powell C. Plasma, 
obtained from 131 nondepressed, otherwise healthy subjects aged from 
17 to 102 years, and 22 depressed subjects aged over 70 years, was analysed 
for total and free tryptophan. Variation with age was found in total 
tryptophan.<strong> This association has not been described hitherto. There 
was a significant increase in total tryptophan and a non-significant 
increase in free tryptophan with depression. This is in contrast to 
some studies in younger people showing a decline in plasma tryptophan 
in depressed subjects.</strong></p>
<p>Bratisl Lek Listy 1975 Jul;64(1):58-63. <strong>
[The effect of serotonin on the release of free fatty acids from human 
and rat adipose tissue (author&#39;s transl)].</strong> [Article in Czech] Rath 
R, Kujalova V.</p>
<p>Adv Exp Med Biol 1999;467:497-505. <strong>
Oxidative damage in rat tissue following excessive L-tryptophan and 
atherogenic diets.</strong> Ronen N, Livne E, Gross B.</p>
<p>FASEB J 1994 Dec;8(15):1302-7.<strong> Methionine 
restriction increases blood glutathione and longevity in F344 rats.</strong> 
Richie JP Jr, Leutzinger Y, Parthasarathy S, Malloy V, Orentreich N, 
Zimmerman JA “Met restriction resulted in a 42% increase in mean and 
44% increase in maximum life span, and in 43% lower body weight compared 
to controls (P &lt; 0.001). Increases in blood GSH levels of 81% and 
164% were observed in mature and old Met-restricted animals, respectively 
(P &lt; 0.001).” </p>
<p>Carcinogenesis 1999 Nov;20(11):2075-81. <strong>
Dietary glycine prevents the development of liver tumors caused by the 
peroxisome proliferator WY-14,643.</strong> Rose ML, Cattley RC, Dunn C, 
Wong V, Li X, Thurman RG.</p>
<p>Mech Ageing Dev 1983 Nov-Dec; 23(3-4):245-52. <strong>
Low tryptophan diets delay reproductive aging.</strong> Segall PE, Timiras 
PS, Walton JR. Newly weaned female rats fed diets severely deficient 
in the essential amino acid tryptophan show marked delays in reproductive 
aging, with conception and delivery occurring as late as 36 months. 
The rate of aging in these rats seems inversely related to both their 
early growth rates and the accessibility of brain tryptophan. The subsequent 
age retardation may depend on a reduction in both early cell loss and 
rate of brain maturation.</p>
<p>Mech Ageing Dev 1978 Jan;7(1):1-17. <strong>
Neural and endocrine development after chronic tryptophan deficiency 
in rats: I. Brain monoamine and pituitary responses.</strong> Segall PE, 
Ooka H, Rose K, Timiras PS. “Caloric restriction and tryptophan deficient 
diets have been shown to delay aging in the immature laboratory rat.” 
“Another group of animals, in which growth and maturation was delayed 
by feeding d,1-parachlorophenylalanine (PCPA) showed decreases in serotonin, 
norepinephrine and dopamine concentrations in all brain regions investigated. 
All treatments employed to arrest growth and maturation resulted in 
pituitary alterations manifested by gross, histological and ultrastructural 
changes. It is postulated that there maturation- and age-retarding treatments 
delay the development of the central nervous system resulting in postponed 
maturation of the neuroendocrine axis, with consequent hypoactivity 
of certain pituitary functions and a resultant delay in the onset of 
maturation and senescence.”</p>
<p>Aktuelle Gerontol 1977 Oct;7(10):535-8.<strong> 
Long-term tryptophan restriction and aging in the rat.</strong> Segall P. 
Growth-retarded rats fed a tryptophan deficient diet at 21 days for 
periods of<strong> 6-22 months were shown to reach normal body weight when 
subsequently fed Purina Rat Chow. They demonstrated an increased ability 
over similar aged controls to recover from hypothermia induced by 3-minute 
whole-body ice water immersion,</strong> were able to bear litters at 17--28 
months of age, showed a delay in the age of onset of visible tumors, 
and indicated an increase in their average lifespan at<strong> late ages. 
Animals fed on this diet from 3 months of age revealed a similar ability 
to reproduce at advanced ages, but not as marked as those placed on 
the diet earlier. The average lifespan (in months +/- the standard error 
of the mean) of the rats recovering from the long-term tryptophan-deficient 
diets was 36.31 +/- 2.26 while the control rats survived an average 
of 30.5 +/- 1.90</strong> months. The last of 8 rats surviving the period 
of tryptophan-deficiency died at<strong> 45.50 months (1387 days) while the 
last of 14 control rats died at 41.75 months (1266 days). It is hypothesized 
that some kind of subtle mechanism exerts its</strong> influence on the rats 
during the period of tryptophan deficiency which caused an accelerated 
morbidity and mortality as they approached senescence approximately<strong> 
1 to 2 years after refeeding. </strong>This is parallel to the situation 
with immature<strong> animals subjected to long-term caloric restriction 
and then fed on normal diets.</strong></p>
<p>Mech Ageing Dev 1976 Mar-Apr;5(2):109-24. <strong>
Patho-physiologic findings after chronic tryptophan deficiency in rats: 
a model for delayed growth and aging.</strong> Segall PE, Timiras PS. Long-Evans 
female rats three weeks, three months and 13-14 months of age were placed 
on tryptophan-deficient diets for periods ranging from a few months 
to nearly two years. Growth was interupted during the period of tryptophan-deficiency, 
but when the animals were returned to a complete diet, they gained weight 
and grew to normal size. Ability to reproduce, as indicated<strong> by litter 
production, was present at 17-28 months of age in rats which had been 
deprived of tryptophan, whereas no controls over 17 months of age produced 
any offspring. Other signs of delayed aging in the experimental group 
included, at advanced ages, greater longevity, as well as later onset 
in the appearance of obvious tumors, and better coat condition and hair 
regrowth. Many of these effects were also seen in pair-fed controls 
(fed a diet equal in amount to that</strong> eaten by the tryptophan-deprived 
rats, but with 1-tryptophan added). It is hypothesized that tryptophan 
deficiency delays growth, development and maturation of the central 
nervous system (CNS), in particular, by decreasing the levels of the 
neurotransmitter serotonin, for which tryptophan is the necessary precursor. 
In a parallel experiment, chronic treatment with d, 1-parachlorophenylalanine, 
an inhibitor of brain serotonin synthesis, from weaning until adulthood, 
also inhibited growth (body weight) and delayed sexual maturation (age 
of vaginal opening). These observations suggest that diets deficient 
in tryptophan or restricted in calories can affect maturation and aging 
by interfering with CNS protein synthesis, or neurotransmitter metabolism, 
or both.</p>
<p>Naturwissenschaften 1965 Sep;52(18):519. <strong>
[Serotonin-caused muscular dystrophy].</strong> [Article in German] Selye 
H.</p>
<p>Toxicology 1999 Feb 15;132(2-3):139-46. <strong>
Protection against chronic cadmium toxicity by glycine.</strong> Shaikh ZA, 
Tang W</p>
<p>Biosci Biotechnol Biochem 1998 Mar;62(3):580-3. <strong>
Increased conversion ratio of tryptophan to niacin in severe food restriction.</strong> 
Shibata K, Kondo T, Miki A.</p>
<p>Monogr Neural Sci 1976;3:94-101.<strong> 
Sex, migraine and serotonin interrelationships.</strong> Sicuteri F, Del 
Bene E, Fonda C. “Sexual deficiency or frank impotence in man could 
be due to an imbalance of monoamines, particularly 5-HT, at the mating 
center level. An absolute or<strong> relative excess of 5-HT seems to antagonize 
testosterone at the level of the mating center receptors in the brain. 
Plasma testosterone levels in so-called psychological impotence are 
normal. When the 5-HT concentration in sexually deficient men is sufficiently 
decreased with parachlorophenylalanine (PCPA)</strong> treatment and testosterone 
levels increased following its administration, a vivid sexual stimulation 
appears in about half of the untractable cases.” “Yet the PCPA-MAOI 
treatment avoids the prostate carcinogenic risk of testosterone administration 
in aging males, and seems to have euphorizing effects stronger than 
those expected only from MAOI therapy. Because of the several side effects 
of PCPA-MAOI testosterone, the present experiments should be interpreted 
very cautiously.”</p>
<p>Hepatology 1999 Mar;29(3):737-45.<strong> 
Glycine and uridine prevent D-galactosamine hepatotoxicity in the rat: 
role of Kupffer cells.</strong> Stachlewitz RF, Seabra V, Bradford B, Bradham 
CA, Rusyn I, Germolec D, Thurman RG.</p>
<p>Eur J Appl Physiol Occup Physiol 1999 
Mar;79(4):318-24. <strong>Effect of acute and chronic exercise on plasma 
amino acids and prolactin concentrations and on [3H]ketanserin binding 
to serotonin2A receptors on human platelets.</strong> Struder HK, Hollmann 
W, Platen P, Wostmann R, Weicker H, Molderings GJ.<strong> “The neurotransmitter 
serotonin (5-hydroxytryptamine, 5-HT) has been shown to modulate various 
physiological and psychological functions such as fatigue.</strong> Altered 
regulation of the serotonergic system has been suggested to play a role 
in response to exercise stress.” “The present results support the 
hypothesis that acute endurance exercise may increase 5-HT availability.<strong> 
This was reflected in the periphery by increased concentration of the 
5-HT precursor free TRP, by increased plasma PRL concentration, and 
by a reduction of</strong> 5-HT2A receptors on platelets.” </p>
<p>Epilepsy Res 1999 Jan;33(1):11-21.<strong> 
Pharmacokinetic analysis and anticonvulsant activity of glycine and 
glycinamide derivatives.</strong> Sussan S, Dagan A, Bialer M.</p>
<p>Adv Biochem Psychopharmacol 1976; 15:251-65. <strong>
Glucocorticoid regulation of the serotonergic system of the brain.</strong> 
Sze PY. “Glucorticoids at concentrations above 10(-7) M stimulate 
the uptake of tryptophan by brain synaptosomes.”</p>
<p>Neurobiol Aging 1984 Fall;5(3):235-42. <strong>
Lifetime brain serotonin: regional effects of age and precursor availability.</strong> 
Timiras PS, Hudson DB, Segall PE.<strong> “In the rat, regional brain serotonin 
levels which do not change from 2-30 months of age are increased at 
36 months.” </strong>“Impaired brain serotonin levels recover moderately 
but remain lower than controls as late as 36 months, growth is never 
completely compensated, and norepinephrine levels show a rebound increase.”</p>
<p>Kidney Int 1996 Feb;49(2):449-60. <strong>
Cytoprotection of kidney epithelial cells by compounds that target amino 
acid gated chloride channels.</strong> Venkatachalam MA, Weinberg JM, Patel 
Y, Saikumar P, Dong Z</p>
<p>Am J Physiol Lung Cell Mol Physiol 
2000 Aug;279(2):L390-8<strong>. Dietary glycine blunts lung inflammatory 
cell influx following acute endotoxin.</strong> Wheeler MD, Rose ML, Yamashima 
S, Enomoto N, Seabra V, Madren J, Thurman RG.</p>
<p>Am J Physiol 1999 Nov;277(5 Pt 1):L952-9.<strong> 
Production of superoxide and TNF-alpha from alveolar macrophages is 
blunted by glycine.</strong> Wheeler MD, Thurman RG.</p>
<p>Stroke 1991 Apr;22(4):469-76. <strong>Identification 
of capric acid as a potent vasorelaxant of human basilar arteries.</strong> 
White RP, Ricca GF, el-Bauomy AM, Robertson JT<strong> “To determine whether 
naturally occurring fatty acids, especially saturated ones, might act 
directly as vasodilators, segments of human basilar arteries and umbilical 
arteries were precontracted submaximally with prostaglandin F2 alpha 
and then exposed to different saturated fatty acids (C4 through C16) 
or</strong> unsaturated fatty acids (C14:1, C18:1, C18:2, and C18:3) at concentrations 
from 4 microM to 4 mM. The results showed caprate (C10) to be the most 
potent vasorelaxant and basilar arteries to be more responsive (EC50 
= 63 microM) than umbilical arteries (EC50 = 780 microM). <strong>Caprate 
also inhibited contractions elicited by KCl, serotonin, and the thromboxane 
analogue U46619.</strong>”</p>
<p>Neurochem Res 1978 Jun;3(3):295-311. <strong>
Adaptive changes induced by high altitude in the development of brain 
monoamine enzymes.</strong> Vaccari A, Brotman S, Cimino J, Timiras PS.</p>
<p>Growth Dev Aging 1991 Winter; 55(4):275-83. <strong>
Effect of aging and diet restriction on monoamines and amino acids in 
cerebral cortex of Fischer-344 rats.</strong> Yeung JM, Friedman E.</p>
<p>Proc Natl Acad Sci U S A 1992 Jul 15;89(14):6443-6. <strong>
Platelet activation by simultaneous actions of diacylglycerol and unsaturated 
fatty acids.</strong> Yoshida K, Asaoka Y, Nishizuka Y “Several cis-unsaturated 
fatty acids such as oleic, linoleic, linolenic, eicosapentaenoic, and 
docosahexaenoic acids added directly to intact human platelets greatly 
enhance protein kinase C activation as judged by the phosphorylation 
of its specific endogenous substrate, a 47-kDa protein.” “I<strong>n 
the presence of ionomycin and either 1,2-dioctanoylglycerol or phorbol 
12-myristate 13-acetate, the release of serotonin from the platelets 
is also remarkably increased by cis-unsaturated fatty acids. The effect 
of these fatty acids is observed at concentrations less than 50 microM. 
Saturated fatty acids and trans-unsaturated fatty acids are inactive.”</strong> 
“. . . cis-unsaturated fatty acids increase an apparent sensitivity 
of the platelet response to Ca2+. The results suggest that cis-unsaturated 
fatty acids, which are presumably produced from phosphatidylcholine 
by signal-dependent activation of phospholipase A2, may take part directly 
in cell signaling through the protein kinase C pathway.”</p>
<p>Jpn J Physiol 1969 Apr 15;19(2):176-86. <strong>
Lipolytic action of serotonin in brown adipose tissue in vitro.</strong> 
Yoshimura K, Hiroshige T, Itoh S</p>
<p>Hepatology 2000 Sep;32(3):542-6. <strong>
Glycine prevents apoptosis of rat sinusoidal endothelial cells caused 
by deprivation of vascular endothelial growth factor.</strong> Zhang Y, Ikejima 
K, Honda H, Kitamura T, Takei Y, Sato N</p>
<p>Mol Pharmacol 1999 Sep;56(3):455-63. <strong>
Dietary glycine and renal denervation prevents cyclosporin A-induced 
hydroxyl radical production in rat kidney.</strong> Zhong Z, Connor HD, Yin 
M, Moss N, Mason RP, Bunzendahl H, Forman DT, Thurman RG </p>
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