Our dopamine, serotonin, and acetylcholine systems
decline over our lifetimes, unless we augment them with …

The Letters of Memory
The need to bolster the neurotransmitter precursors phenylalanine,
tryptophan, and choline (PT&C) is under-appreciated

By Will Block

The energy of the mind is the essence of life.
(Widely quoted, but without citation; probably a popular summary
of Aristotle’s philosophy, and not his actual statement in these words.)
Illustration courtesy of juanosborne.com

A s seen from the outside, an organism is a semi-closed chemical system. Even though such an entity is an individual unit of life, it is open to the environment around it and, in order to function properly, must constantly take in and release energy. Depending on their energy-producing technology, organisms are divided into two types: autotrophs, which produce usable energy in the form of organic compounds using light from the sun or inorganic compounds, and heterotrophs, which take in organic compounds from the environment. We humans are among the latter. But producing and utilizing energy is not an automatic function; it is dependent on the thought and work needed to identify and implement strategies that are conducive to health and wellbeing. And thought is a neurocognitive process.

These neurotransmitter messages
are the letters of memory and life.

The Messengers of Life

To appreciate the twists and turns of our development across a lifespan requires understanding the interactions between our individual neurobiological faculties (including our brain mechanisms) and the socio-economic skills (including educational and experiential achievements) that we develop for ourselves. To put this another way, our cognitive and behavioral development is adaptive to our neurocognitive embodiments—such as our in motor, sensory, and perceptual processes—and to our situational interactions—such as social and occupational relations. In other words, every thought, every feeling, every ambition, everything that goes on in your mind is built upon our neurocognitive processes, the efficacy of which is dependent on our various neurotransmitter systems, the messengers of life. We manufacture these messenger chemicals in our brains and, when released by neurons, they play important roles in regulating signal transmission between our brain’s cells and thus constitute the core mechanics of memory. These neurotransmitter messages are the letters of memory and of life.

Vital Aspects of Cognition

(click on thumbnail for full sized image)
Several transmitter systems, such as the catecholamines (dopamine, serotonin, and noradrenaline) and acetylcholine, broadly empower nerve energy to various neural circuitries throughout the brain. These in turn modulate vital aspects of cognition, including attention and memory, not to mention the reward-mediated motivational influences on our behavior. Contingent on demands arising from situational or task contexts—as well as the integrity of brain functions—neurotransmitters modulate circuits in our brains that enable us to adapt behavior, action, and goals. Consequently, as neurotransmitter systems age and senesce, our behavioral and cognitive finesse across our lifespan tends to degrade and run downhill.

The Dopamine System Declines with Age

There is consensus among gerontologists and allied specialists that the integrities of the dopamine, serotonin, and acetylcholine systems deteriorate during the course of aging.1 For example, cross-sectional estimates have shown that in various striatal regions, located inside the forebrain, the pre- and postsynaptic markers of the dopamine system decline no less than 10% per decade starting around the beginning of the third decade of life.

In one study, 27 healthy male subjects aged from 21 to 82 years were examined with positron emission tomography (PET) for a variety of markers that measured age-related decreases of a dopamine receptor (D2) binding in all measured extrastriatal regions.2 The decrease of D2 receptor binding was 13.8% per decade in frontal cortex, 12.0% in temporal cortex, 13.4% in parietal cortex, 12.4% in occipital cortex, 12.2% in hippocampus, and 4.8% in thalamus. These findings suggest that the amounts of D2 receptors decline in all brain regions as part of the normal aging process.

Indeed, movement disorders are prevalent in the elderly and may have both central and peripheral origins. A recent study undertook to describe the differences between age-related parkinsonism and normal Parkinson’s disease.3 What the researchers found was that age-related parkinsonism often results in movement disorders identical to some of the cardinal symptoms of typical Parkinson’s disease.

In various striatal regions,
the pre- and postsynaptic markers of
the dopamine system decline no less
than 10% per decade starting
around the beginning of
the third decade of life.

A variety of evidence, from empirical and computational studies, has associated aging-related declines in dopamine modulation to age-related deficits in processing speed, processing fluctuations, episodic memory, working memory, and cognitive control. Little is known about the maturation of neuromodulatory systems during child and adolescent development, principally due to researcher hesitancy in applying invasive methods, such as PET receptor imaging, in these age groups. So comparisons of dopamine functions across the human life span have, so far, come from postmortem studies. From these investigations, it has been found that, after birth, the dopamine level in the striatum increases two- to threefold through adolescence, after which the level decreases during aging in the ensuing years.4

Also, it has been found that the activity of COMT, an enzyme that regulates extracellular dopamine levels in the prefrontal cortex, doubles from neonate to adulthood, after which it declines gradually.5 Animal studies suggest that the efficacies of both the subcortical and cortical dopamine systems (e.g., the receptor densities of different receptor types) increase continuously and steadily during the postnatal period and childhood, after which they decline. Moreover, there is current agreement that while the subcortical dopamine system reaches its peak in adolescence, the development of the cortical system is slower and reaches its peak level only in early adulthood.6 The more protracted maturation of the cortical dopamine system may constrain the development of attention and other frontal executive functions during childhood and adolescence.7 As well, the discrepancy in the maturational trajectories of the subcortical and cortical dopamine systems in adolescence may make this life period particularly malleable by positive (e.g., social rewards) or negative (e.g., extreme stress or addiction) contextual influences.8

Serotonin Receptor Decline is Also Age-Related

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Similarly, cross-sectional estimates of aging-related declines in the availability of serotonin receptors in various brain regions also range from 3% to 10% per decade.9 In fact, age-related decline in postsynaptic serotonin receptors has been demonstrated in postmortem human studies and in vivo imaging studies.10 These phenomena are thought to involve changes in mental function in the normal aging process. In the above cited study,10 research­ers examined 28 healthy male volunteers between the ages of 20 and 79 years. The uptake of a selective ligand for serotonin transporter (5-HTT) was quantified in the thalamus and midbrain by graphical analysis using positron emission tomography (PET) scanning. The results indicated that there was a significant age-related decline in binding potential in the thalamus and midbrain. The decline in selective binding to 5-HTT was 9.6% per decade in the thalamus and 10.5% per decade in the midbrain.

The Cholinergic System Fades with Aging Too

And finally, we come to the cholinergic system, the decline of which is known to be implicated in the neurodegenerative processes associated with dementia and Alzheimer’s disease. The loss of cortical nicotinic acetylcholine receptors with high affinity for agonists in Alzheimer’s patients is a common finding.11 What about the loss of these receptors in the normal aging brain? A recent receptor imaging study showed that, on average, in normal healthy, non-smoking males, there is about 5% per decade decline of the nicotinic acetylcholine receptor in eight brain regions, including the frontal cortex and striatum.12

Lifespan Changes May Affect Neuromodulation

Molecular genetics has opened new avenues for investigating neuromodulation of behavioral and cognitive development.13 Changes in brain resources at the anatomical or neurochemical level during maturation or senescence may modulate genotype-phenotype relations in different life periods, as brain mechanisms are the “intermediate phenotypes” between genetic expressions in the central nervous system and behavioral phenotypes.14 Genes related to the neurotransmitter dopamine is a good example.

Estimates of aging-related declines in
the availability of serotonin receptors
in various brain regions also range
from 3% to 10% per decade.

Evidence from clinical and animal studies as well as neurocomputational simulations suggests that the relation between dopamine signaling and cognitive performance follows an inverted-U function. As an example, the relationship between changes in arousal and motivation is often expressed as such an inverted-U function. The basic concept is that, as arousal level increases, performance improves but only to a point. Beyond that point, increases in arousal lead to a deterioration in performance.

Following this, the inverted-U function relating dopamine modulation to cognitive performance predicts that genetic effects on cognition would be more apparent when dopamine signaling recedes from an optimal level, such as in childhood or old age or when the natural dopamine level is disturbed by excessive stress or stimulants that affect neuromodulation.1

What Can Be Done?

From all of the above, it becomes obvious that development across the lifespan is, at least in part, regulated by the maturation and senescence of the neuromodulatory functions. Is it currently possible to intervene in this seemingly hopeless situation, and enhance temperament and cognitive control, as well as emotional regulation, and working memory plasticity during adulthood, not to mention working memory deficit in old age?

In a new paper, researchers focusing on neuromodulation of visual attention and working memory, reviewed evidence for interactive cholinergic and dopaminergic modulation of these processes.15 In light of aging-related declines in these two transmitter systems, the authors considered the possibility of enhancing genetic effects on these processes in older adults. That’s nice, but where they miss the boat is in their failure to consider any other ways of slowing the receptor damage (or other mechanical apparatus of the neurotransmitter systems), let alone repairing it. They also fail to note that enhancement might be achievable by increasing the supply of the neurotransmitters to compensate for reduced efficacy, or by increasing the utility of the neurotransmitters in the synapses.

Increasing Noradrenaline Production

It is known that the catecholamines, including noradrenaline, dopamine, and serotonin are made in the body from the amino acids phenylalanine and tryptophan. When supplemented, these neurotransmitter precursors, combined with specific cofactors, can help insure the production of higher levels of neurotransmitters than would otherwise be produced in the body.

Noradrenaline is a “fight or flight” hormone released by the adrenal glands in response to stress. Catecholamines are part of the sympathetic nervous system. In addition, noradrenaline operates as a memory messenger. Altogether, it exerts an abundance of effects and mediates many functions in living organisms. Noradrenaline plays an essential role in the central nervous system (CNS).

The decline in selective binding to
5-HTT was 9.6% per decade in
the thalamus and 10.5%
per decade in the midbrain.

Noradrenaline affects behaviors, including a modulation of vigilance, arousal, attention, motivation, reward, and also learning and memory. In a recent review, accumulated findings about the anatomy and physiology of the noradrenergic system in the CNS are summarized, and the pharmacological effects on specific adrenoceptor types are discussed.16 Even though noradrenaline was discovered by the Swedish physiologist Ulf von Euler in the mid-1940s, much information has complied, but alas, it is rarely reviewed in an encompassing way. This paper is valuable because it also shows the importance of noradrenaline to maintain the cognitive processes such as attention, perception, and particularly memory consolidation and retrieval. When these processes are disrupted, the results may include neuropsychiatric diseases and neurodegeneration. The precursor amino acid phenylalanine, along with vitamin and mineral cofactors (vitamin B6, vitamin C, folic acid and copper), is necessary to make more noradrenaline more efficiently in your brain.

In a paper published in 1997, Japanese researchers examined urinary excretion of noradrenaline during difficult mental work.17 Especially as the day went on, in the afternoon, noradrenaline excretion was markedly elevated compared to that during the rest condition at the corresponding time on the control day. These findings suggest that prolonged exposure to mental work, but not short-term mental work, produces a marked increase in noradrenaline excretion in human subjects. This makes a strong case for supplementing with phenylalanine, especially when your mental load is high, and as your noradrenaline supplies run down.

On average, in normal healthy,
non-smoking males, there is about
5% per decade decline of
the nicotinic acetylcholine receptor in
eight brain regions, including
the frontal cortex and striatum.

Increasing Serotonin Production

The essential nutrient tryptophan is converted in your body to the natural, normal, and necessary neurotransmitter serotonin. Neurotransmitters transmit signals from one nerve to another across the synapses, the gaps between nerves. Without sufficient supplies of serotonin, it is far more difficult to remain calm under stress, and the risk of anxiety and depression increase dramatically. Studies have shown that people with impulse, anger, and rage management problems are likely to have a low-activity tryptophan hydroxylase, which prevents them from making normal amounts of serotonin from tryptophan. There is an alternative and that is the amino acid 5-hydroxytryptophan (aka 5-HTP). If you take 5-HTP, you entirely bypass the serotonin production bottleneck caused by a low-activity isoform of tryptophan hydroxylase. You are directly ingesting the compound that the enzyme should be making. 5-HTP is converted to serotonin by an enzyme called aromatic amino acid decarboxylase. This enzyme is dependent on both vitamin B6 and copper as essential nutrient cofactors.

While animal and human adult studies reveal that making more serotonin helps with behavior regulation, even among young boys, tryptophan supplementation has been shown to be beneficial. In a recent study, 23 boys (age 10 years) with a history of elevated physical aggression were given either a chocolate milkshake supplemented with 500 mg tryptophan (n=11) or a chocolate milkshake without tryptophan (n=12).18 Following this, they engaged in a competitive reaction-time game against a fictitious opponent, during which their assessed response to provocation, impulsivity, perspective taking, and sharing were measured.

It is known that the catecholamines,
including noradrenaline,
dopamine, and serotonin are made in
the body from the amino acids
phenylalanine and tryptophan.

All of the boys responded similarly to the high tension. However, boys in the tryptophan group adjusted their level of responses optimally as a function of the level of provocation, whereas boys in the control group significantly decreased their level of response towards the end of the competition. Boys in the tryptophan group tended to show greater perspective taking, tended to better distinguish facial expressions of fear and happiness, and tended to provide greater instrumental help to the experimenter.

Increasing Cholinergic Production

Choline is the nutrient precursor to the memory messenger molecule acetylcholine. Also known as a neurotransmitter, the production of acetylcholine in brain and body requires the cofactor vitamin B5 (pantothenic acid). In Alzheimer’s disease and other memory dysfunctions, the loss of cholinergic neurons is associated with impaired cognitive function, including memory loss. Also associated with impaired cognitive function and Alzheimer’s are brain atrophy and white-matter hyperintensity.

In a recent study, researchers set out to determine if a relation exists between dietary choline intake, cognitive function, and brain morphology (the brain’s form and structure) in a large community-based cohort without any signs of dementia.19

Altogether, there were 1391 subjects consisting of 744 women and 647 men. Their ages ranged from 36–83 years, with a mean standard deviation age of 60.9 ± 9.29 years. All the subjects were from the Framingham Offspring population and had completed a food-frequency questionnaire administered from 1991 to 1995 and another from 1998 to 2001.

Top memory performance is strongly
related to higher choline intake.

All of the participants were evaluated neuropsychologically, and given a magnetic resonance imaging (MRI) scan. MRIs use a magnetic field and pulses of radio wave energy to make pictures of organs and structures inside the body, in this instance the brain. While MRIs provide different information about the brain than can be seen with other scans and may show problems that cannot be seen with other imaging methods.

There were four neuropsychological measurements:

  1. Verbal memory
  2. Visual memory
  3. Verbal learning
  4. Executive function

Also included in the MRI scan measurements was white-matter hyperintensity volume.

The principal findings show that top memory performance is strongly related to higher choline intake (from 1998 to 2001), whereas remote choline intake (from 1991 to 1995) is associated with a significant inverse relation to larger white-matter hyperintensity in a large, nondemented, community-based population.

Choline intake at midlife may be
neuroprotective later in life.

Verbal memory and visual memory were found to be strongly associated with choline intake in both age- and sex-adjusted models as well as in final models. Executive function had no relation to choline intake, at least not at the levels reported. But further investigation of the individual cognitive tests for each factor considered confirmed a significant positive association between choline intake and both visual and verbal memory. Remember that memory impairment is a hallmark sign of Alzheimer’s disease and that preservation of the neurologic pathways associated with memory may be of principal importance in preventing changes in the brain that lead to Alzheimer’s.

White-matter hyperintensities are seen in up to 90% of persons with vascular dementia and Alzheimer’s, and other researchers have found that subjects with large white-matter hyperintensity volumes have significantly poorer cognitive function and brain atrophy. Accordingly, large amounts of white-matter hyperintensity are pathologic in nature and prevention is important. The researcher’s findings show that early higher choline intake is significantly related to smaller white-matter hyper­intensity volume, which suggests that choline intake at midlife may be neuro­protective later in life.

In this community-based population of nondemented individuals, higher concurrent choline intake was related to better cognitive performance, whereas higher remote choline intake was associated with little to no change in intake white-matter hyperintensity volume. The message to take home is … If you are serious about preserving memory function, higher choline intake is a must. And don’t forget about tryptophan (or 5-HTP) and phenylalanine supplementation!


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Will Block is the publisher and editorial director of Life Enhancement magazine.

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