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July 2004

By Dave Tuttle

Cortisol is an essential hormone that plays many vital roles, including helping the human body adapt to stress. Yet this naturally occurring hormone is one of the few whose levels in the body increase with age, with potentially damaging consequences that have been linked to depression, Alzheimer's disease, and other maladies.

The good news is, new research on nutrients such as phosphatidylserine, DHEA, and ginkgo biloba offers valuable insights on how to control cortisol levels to promote optimal health.

Declining hormone levels are a hallmark of the aging process. The body's production of DHEA, pregnenolone, and testosterone drops significantly as we age, and these changes in hormone levels can have dramatic effects on our health.

But not all hormones follow this pattern. One major exception is cortisol, a hormone released in response to stress. While cortisol plays vital roles in the body, excessive secretions of this hormone can have serious health implications, including loss of mental function, depression, and a reduction in lean tissue. Extreme overproduction of cortisol, as occurs in Cushing's syndrome, results in increased body fat, decreased bone density, and severe muscle weakness. Thus it is critical to maintain cortisol levels within a healthy range. Fortunately, scientists have discovered that phosphatidylserine, DHEA, and ginkgo biloba can reduce cortisol levels, helping to keep this catabolic hormone from damaging your body.

Cortisol's Many Roles
Cortisol is one of several hormones in the hypothalamic-pituitary-adrenal axis. This auto-regulating system maintains a tight integration of the endocrine, nervous, and immune systems, constantly reacting to a variety of internal and external stimuli.1 This allows the body to adapt to a broad range of changing circumstances, promoting survival and longevity. When this axis is partially inactivated or functions improperly, the body may be exposed to excessive amounts of neural, endocrine, and immune stress, resulting in pathological consequences.

When the body experiences stress, the hypothalamus sends corticotropin-releasing hormone to the pituitary gland through a specialized circulation system called the hypophyseal portal duct. This stimulates the anterior lobe of the pituitary gland to secrete larger amounts of a hormone known as adrenocorticotropin, or ACTH. This hormone regulates the activities of the outer portion of the adrenal gland known as the adrenal cortex, where cortisol is produced.

An enhanced secretion of ACTH triggers increased production of cortisol and other related glucocorticoids in the adrenal cortex. Cortisol, also called hydrocortisone, is responsible for about 95% of the body's glucocorticoid activity. It has several important metabolic and non-metabolic effects in the body.2 Cortisol increases the mobilization of free fatty acids, making them more available as an energy source. It decreases glucose use, sparing it for essential brain functions. Cortisol also stimulates protein catabolism (breakdown) so that amino acids can be released for use in repair, enzyme synthesis, and energy production, while stimulating gluconeogenesis, the process by which protein or fat is converted into glucose. Cortisol even serves as an insulin antagonist by inhibiting glucose uptake and oxidation. The principal non-metabolic activities of cortisol include restraining the immune system's production of inflammatory cytokines, increasing catecholamine release to improve blood flow and distribution, and enhancing mental acuity.

Cortisol has short-term anti-inflammatory properties, which is why it was used to treat arthritis when first made available as a drug in the 1950s. Unfortunately, cortisol also depresses immune reactions, and as a result produces serious negative effects when administered for prolonged periods. Once considered wonder drugs, cortisol-based drugs are now used only as a last resort, and even then only for short periods. High levels of cortisol in the body also have been shown to produce hypertension, poor wound healing, bone loss, muscle wasting, thin skin, increased abdominal fat, insulin resistance, and sleep fragmentation, all of which are common in older individuals.

Clearly, cortisol is a double-edged sword. We cannot live without it, nor would we want to, as it helps the body adapt to stressful situations, such as illness or a deadline at work. Yet for reasons that remain unknown, the body's cortisol-regulation system can spin out of control as we age, especially in the frail, sending cortisol production soaring to damaging levels. A recent German study found that daily cortisol production increased by 54% from a group of 21- to 30-year-old men to a group of men over 70, all of whom were otherwise healthy.3 This excess cortisol has been implicated in numerous diseases of aging, making proper regulation of cortisol levels a vital necessity.


Major Life Stressors (chronic)
• Divorce
• Death of a family member
• Prolonged illness
• Poverty
• Unhappiness in the workplace

Daily Life Stressors (acute)
• Traffic jams
• Bill-paying
• Family tension
• Noise
• Crowds
• Sleep disturbance
• Isolation
• Hunger
• Danger

Implicated in Depression and Alzheimer's
Cortisol levels increase as much as fivefold even in healthy individuals when they are confronted with stressful events. Everyday hassles and the distress and agitation that accompany them are associated with greater cortisol production in all of us. But when someone has a depressive disorder, cortisol levels increase even more; in fact, considerable evidence suggests that hypercortisolemia secondary to increased corticotropin release is involved in the pathogenesis of depressive disorders.4 Minor stressful events can lead to increased adrenocortical activity and depression in vulnerable individuals, and the elevated cortisol levels associated with these stressful events can in turn worsen the condition of the depressed patients. The number of secretory pulses increases in these individuals, as reflected in their high daily rates of cortisol production.

Researchers have found that cortisol can affect mood and behavior, and disrupt memory and recall.5 Administering cortisol to healthy volunteers has been shown to alter processes associated with prefrontal cortex functions, such as inhibitory control, attention regulation, and planning. Cortisol has significant interactions with the neurotransmitters, neuropeptides, and brain circuits that are associated with depressive symptoms. Because elevated cortisol levels also can affect the endocrine, metabolic, pro-inflammatory, and hemostatic factors that increase vulnerability to cardiovascular disease and other medical conditions, it is not surprising that depression is an independent risk factor for coronary artery disease. Even worse, recurring depressive symptoms result in cumulative injury to the hippocampus, which can further impair the feedback pathways for the hypothalamic-pituitary-adrenal axis and send already depressed individuals into even deeper depression.

Cortisol also plays a role in the progression of Alzheimer's disease. The hippocampus is closely associated with the acquisition, retrieval, and consolidation of new memories. Excessive cortisol levels have neurotoxic effects on the hippocampus, resulting in atrophy and memory impairment.6 A study conducted at the University of Genova, Italy, found that cortisol levels are directly related to the degree of cognitive impairment in people with Alzheimer's disease.7 These patients also had much lower levels of DHEA sulfate (DHEA-S), and therefore a dramatically higher cortisol:DHEA-S ratio than individuals without Alzheimer's. This suggests that a reduction in cortisol levels could help treat people with Alzheimer's, particularly when linked to DHEA supplementation.

The negative effects of cortisol on memory and cognitive decline are not limited to people with Alzheimer's. A four-year longitudinal study found a significant relationship between increasing cortisol levels and the impairment of explicit memory and selective attention performance in otherwise healthy individuals.8 This long-term rise in cortisol production is even more problematic in light of declining levels of DHEA and other neuroprotective hormones. In fact, some scientists now believe that brain aging depends on cumulative exposure to increasing cortisol levels throughout life, particularly when this occurs along with reduced secretions of the protective androgen hormones. Cortisol also enhances the expression of the 5-lipoxygenase (5-LOX) enzyme, which is the central enzyme responsible for synthesis of the inflammatory leukotrienes involved in neurodegeneration. These interrelationships underscore the importance of controlling cortisol production.

Phosphatidylserine Reduces Cortisol
Phosphatidylserine is an essential nutrient for cells, and one of a number of phospholipids that help hold together the large molecules that make up the cell membrane. Phosphatidylserine is particularly plentiful in nerve cells. Studies have shown that phosphatidylserine helps these cells communicate with other cells by promoting the accumulation, storage, and release of neurotransmitters such as dopamine.9 Phosphatidylserine also is important in supporting homeostasis in each cell.

Phosphatidylserine assists the proteins that manage membrane functions, apparently anchoring many of these proteins in the matrix of the membrane, permitting them to operate at peak efficiency. Functions facilitated by phosphatidylserine include entry of nutrients into the cell and exit of waste products from the cell, movement of charged atoms (ions) into and out of the cell, transmission of molecular messages, changes in cell movement and shape, and cell-to-cell communication.