Life Extension Magazine April 2008
Why Aging People Become Depressed, Fatigued, and Overweight
By William Faloon
Serotonin is a compound in the brain that promotes feelings of personal security, relaxation, and confidence. A serotonin deficiency can result in sleep disturbance, anxiety, depression, and a propensity to overeat, particularly carbohydrates like simple sugars.
Startling research reveals that serotonin levels decline as we age!1-3 These findings provide a biochemical rationale to explain common age-related disorders such as depressed mood and sleep difficulties. Based on these discoveries, aging people may appreciably improve their health by restoring serotonin to youthful levels.
The amino acid tryptophan is needed to produce serotonin in the brain.4 While the amount of tryptophan in a typical diet meets basic metabolic requirements, it often fails to provide optimal brain serotonin levels.
Ever since the FDA restricted the importation of tryptophan for use in dietary supplements, there has been an upsurge in the percentage of overweight and obese Americans.
One could argue that a widespread serotonin deficiency is at least partially responsible for the record numbers of depressed, sleep-deprived, and overweight individuals.
Why Dietary Tryptophan Is Inadequate
Tryptophan is one of the eight essential amino acids found in the human diet. Essential amino acids are defined as those that cannot be made in the body and therefore must be obtained from food or supplements. (A ninth amino acid, histidine, is sometimes considered essential for children.)
Our bodies do need additional amino acids, but these other amino acids are made from the eight essential amino acids when we are in optimal health.
In any normal diet, be it omnivorous or vegetarian, tryptophan is the least plentiful of all amino acids. A typical diet provides only 1,000 to 1,500 mg/day of tryptophan, yet there is much competition in the body for this scarce tryptophan.
Tryptophan is used to make various protein structures of the body. In people with low-to-moderate intakes of vitamin B3(niacin), tryptophan may be used to make B3 in the liver at the astounding ratio of 60 mg tryptophan to make just 1 mg of vitamin B3.5
Yet even maintaining a minute amount of tryptophan provides little benefit in boosting serotonin in the brain due to competition with other amino acids for transport through the blood-brain barrier. Nutrients must be taken up through the blood-brain barrier by transport molecules. Tryptophan competes for these transport molecules with other amino acids.
As one can see, diet-derived tryptophan contributes very little actual tryptophan to the brain. As you will soon read, even eating tryptophan-containing foods like turkey may not always provide the body with enough of this essential amino acid. One reason is that aging people make enzymes that rapidly degrade tryptophan in the body.
Remember, tryptophan is the only normal dietary raw material for serotonin synthesis in the brain. Given all we now know about the difficulty in maintaining adequate tryptophan status, is it any wonder that so many aging humans suffer from disorders such as depression, insomnia, and excess weight gain associated with a serotonin deficiency?
How Tryptophan Functions in the Body
L-tryptophan converts into serotonin, primarily in the brain. Since serotonin is a neurotransmitter involved in controlling moods and appetite, tryptophan supplementation has been recommended for individuals suffering from a variety of conditions associated with decreased serotonin levels, including sleep disorders, depression and fibromyalgia, and eating disorders.6-8
It has been shown in human clinical studies that low levels of tryptophan contribute to insomnia.9 Increasing tryptophan may help to normalize sleep patterns.10-12 It is known that raising tryptophan levels in the body may decrease cravings and binge eating—especially for carbohydrates—and help people lose weight.13,14
L-tryptophan serves as a precursor not only to serotonin, but also melatonin and niacin. Serotonin is a major neurotransmitter involved in many somatic and behavioral functions including mood, appetite and eating behavior, sleep, anxiety, and endocrine regulation.6,15-17
There are two possible sources for L-tryptophan: diet and tissue proteins, from which L-tryptophan has been recycled during protein turnover. Aging, chronic inflammatory diseases, and HIV infection are associated with tryptophan depletion, even in the absence of dietary tryptophan deficiency.
An adult male needs 250 mg a day of tryptophan just to maintain nitrogen balance.18 While a normal diet contains 1,000 to 1,500 mg of tryptophan per day,19 the enzymatic breakdown of tryptophan increases with age,20 and certain disease states can severely deplete tryptophan.
How Tryptophan is Metabolized in the Body
There are three potential fates for L-tryptophan once ingested:
For every nutrient absorbed into the body, there are specific enzymes that convert the nutrient into other substances. There are two specific enzymes that can deprive the body of sufficient amounts of tryptophan. These enzymes are called L-tryptophan 2,3-dioxygenase (TDO) and indoleamine 2,3-dioxygenase (IDO).
The liver enzyme TDO is induced when plasma concentrations of L-tryptophan exceed those needed for conversion into serotonin and/or protein. This enzyme oxidizes surplus L-tryptophan into carbon dioxide, water, and ATP.22,23
The other tryptophan-degrading enzyme IDO is more insidious because it can degrade L-tryptophan even when circulating levels of L-tryptophan are low.23,24
This enzyme has been found outside the liver on macrophages and dendritic cells and is increased in pro-inflammatory states, HIV infection, and normal aging.25-30
Once the TDO or IDO enzymes act on tryptophan, it is no longer available for conversion to serotonin or incorporation into protein. Consuming large amounts of oral L-tryptophan will not generate more serotonin because more TDO will be induced to deplete the tryptophan.
Tryptophan and its metabolite 5-hydroxytryptophan (5-HTP) are taken up into the brain across the blood-brain barrier by a transport system that is active towards all the large neutral amino acids.31 The affinity of the various amino acids for the carrier is such that there is competition between the large neutral amino acids for entry into brain. In fact, the best predictor of a given meal’s effect on brain tryptophan-serotonin levels is the serum ratio of tryptophan to the pool of large neutral amino acids.32
More clinically relevant, however, is that serotonin levels are enhanced by carbohydrate ingestion.33 The reason is that the high amount of insulin released in response to carbohydrate ingestion accelerates the serum removal of valine, leucine, and isoleucine that compete against tryptophan for transport into the brain. Similarly, a higher percentage of protein in the diet slows serotonin elevation (by providing competing amino acids for the blood-brain barrier).34,35
Giving tryptophan with an inhibitor of the TDO enzyme would enable lower doses of tryptophan to be used. In the rat, high doses of pyridoxine (vitamin B6) can inhibit tryptophan catabolism in the liver and increase uptake of tryptophan into the brain.36 While the effect of high doses of pyridoxine on plasma tryptophan has not been studied in humans, pyridoxine should be given with tryptophan for another reason. When tryptophan was given to normal subjects for a week, levels of tryptophan metabolites in the plasma increased indicating that tryptophan was being broken down. This effect could be attenuated by pyridoxine (pyridoxine assists the breakdown of the tryptophan metabolite kynurenine, which can compete with tryptophan for uptake into the brain), suggesting that chronic tryptophan treatment increases pyridoxine requirements.37
Clinical Implications: Sleep Disorders
Tryptophan has been researched for sleep disorders for 30 years. Improvement of sleep normalcy has been noted38 at doses as low as 1,000 mg.19 Increased stage 4 sleep has been noted at even lower doses—as low as 250 mg tryptophan.19 Significant improvement in obstructive sleep apnea, but not central sleep apnea, has been noted at doses of 2,500 mg at bedtime, with those experiencing the most severe apnea demonstrating the best response.39 While many sedative medications have opioid-like effects, L-tryptophan administration does not limit cognitive performance or inhibit arousal from sleep.40
L-tryptophan depletion negatively impacts sleep. A significant decrease in serum tryptophan levels after a tryptophan-free amino acid drink was associated with an adverse effect upon sleep parameters (stage 1 and stage 2 time, and rapid eye movement sleep time).9 L-tryptophan is not associated with tolerance or difficulty with morning wakening and has been shown to be efficacious for sleep in several clinical trials of various designs and L-tryptophan dosages.
As previously mentioned, L-tryptophan is essential for the brain to synthesize serotonin, a neurotransmitter that has been shown to affect mood. Several studies have shown that acute tryptophan depletion can cause a depressive state in humans, especially patients who are in remission from depression.41,42 In a study of the effects of acute tryptophan depletion on healthy women and patients with bulimia nervosa, both groups were given amino acid mixtures to consume to decrease their plasma tryptophan levels. In both groups an increase in depression occurred.43
Plasma L-tryptophan levels can be raised through dietary intake of L-tryptophan, which raises serotonin levels in the brain, and thereby lessens the depressive state.44 In a study involving recovering alcoholic patients, it was found that the participants had severely depleted L-tryptophan levels accompanied by a high level of depressive state. When the patients were given supplemental doses of L-tryptophan over a short period of time, their depressive state lessened significantly.45 The tryptophan metabolite, 5-hydroxytryptophan (5-HTP), has shown significant clinical response for depression in 2-4 weeks, at doses of 50-300 mg three times daily.46-48