Neuroendocrine Theory of Aging: Chapter 2

Adaptive Homeostat Dysfunction

Ward Dean, MD

Part I of the Neuroendocrine Theory of Aging introduced Professor Vladimir Dilman’s revolutionary theory of the causes of aging, as well as potential therapeutic approaches.

The central thesis of the Neuroendocrine Theory is that the aging process is caused by an age-related loss of central (hypothalamic) and peripheral receptor sensitivity to inhibition by hormones and other signaling substances.

This loss of hypothalamic sensitivity results in a progressive shifting of homeostasis—the body’s regulatory system for maintaining internal balance—and altered levels of hormones, neurotransmitters, and cell signalers. These metabolic shifts are believed to cause aging and the diseases of aging.

With this new understanding, novel therapeutic approaches to delay and even reverse aging become obvious. All of these areas will be discussed at greater length in forthcoming chapters.

Stress and Its Relation to Diseases and Aging

Professor Hans Selye defined stress as the nonspecific response of the body to any demand made upon it.(1) Stress-producing factors, or stressors, can be physical (work and exercise), biological (viral, bacterial and fungal), environmental (heat and cold), and situational (job, family, etc).

And while there are numerous stressors, the responses they elicit from the body are very similar. Reactions to stress are totally nonspecific, and common to all types of stressors. Emotional stimuli are probably the most common stressors that most of us encounter in our daily lives—but they elicit the same physiological response that an encounter with a saber-tooth tiger did for our cave-man ancestors.

While excess stress can adversely affect human health, certain types of stress are actually good for us and can benefit our health. For example, most people today recognize the multiple physical and emotional benefits to be gained from physical exercise.

Physicians once treated heart attacks with enforced inactivity. Now, we know that early resumption of physical activity (stress) is often the key to a successful recovery. According to Selye, stress is “the spice of life.” Certainly a life free of stress and devoid of challenges would be filled with boredom and hardly worth living. The most memorable events in life tend to be those that are the most stressful—situations that require us to rise to a challenge and push past our normal limits. Selye asks, “Who would enjoy a life of no runs, no hits, no errors?” When stress becomes excessive, is damaging or unpleasant, we then properly refer to it as “distress.”

Consequently, when we say someone is “under stress,” we usually mean excessive stress, or distress. Clearly, an issue for those looking to survive (and enjoy) the best in life is not how to avoid stress, but how to best manage stress.

How the Body Reacts to Stress

1. General Adaptation Syndrome (GAS)

The General Adaptation Syndrome (GAS) was first described by Professor Selye in 1936 (Fig. 1). The GAS involves three progressive stages. The first stage is the alarm reaction, characterized by surprise and anxiety when confronted with a new situation. During the alarm reaction, the adrenal medulla produces epinephrine and norepinephrine—the “flight or fight” hormones. Additionally, the adrenal cortex is stimulated to produce additional cortisol and related hormones.

The second stage is that of resistance, where we learn to efficiently cope with the stressor (adaptation). An ideal situation is one in which adaptation occurs and continues until the stressful situation resolves, with a rapid return to the resting state. If the stage of resistance is prolonged, or the response is excessive, hyperadaptosis can occur.(2,3) While everyone’s adaptational capacity (i.e., tolerance to stress) is different— what may “charge one person’s batteries” may totally devastate someone else— ultimately our capacity for adaptation is limited.

Consequently, the third stage of the GAS is that of exhaustion, involving a depletion of our energy reserves and loss of adaptational ability, leading to fatigue, or other symptoms or diseases. Just as a chain breaks at its weakest link, exhaustion of our adaptive capacity results in stress-induced disease.

2. Neuroendocrine Adaptation Mechanisms—the Adaptive Homeostat

Dilman described the system that enables the body to deal with stress as the adaptive homeostat. The adaptive homeostat consists of the hypothalamus-pituitary-adrenal axis (Fig. 2). In order to fully appreciate the significance of Dilman’s work and his sometimes-unfamiliar terminology, a review of basic endocrinology may be helpful.

Stressors normally excite the hypothalamus to produce corticotropin releasing hormone (CRH). CRH in turn causes the pituitary to produce adrenocorticotropic hormone (ACTH), which induces the adrenal cortex to secrete glucocorticoids (principally cortisol) and DHEA.

ACTH also stimulates the adrenal medulla to secrete the “flight or fight” hormones, epinephrine and norepinephrine. As cortisol levels rise they have an inhibitory effect on the hypothalamus and pituitary, which in turn decrease CRH and ACTH production, respectively. Conversely, when blood cortisol levels decrease, hypothalamic activity increases, releasing CRH.

This increases pituitary ACTH output, which stimulates the adrenal cortex to increase blood cortisol levels. In this cyclic manner, equilibrium is maintained in the system.

Cortisol concentrations in the blood undergo cyclic, diurnal (circadian) changes—higher in the morning, and lower in the afternoon and evening. These changes are due to variations in CRH and ACTH output, as well as to changes in hypothalamic and CNS sensitivity to cortisol (these changes in hypothalamic sensitivity are very important). With normal diurnal rhythm, blood ACTH levels rise between 3 and 6 a.m., causing increases in blood cortisol. These peak levels gradually decrease, dropping to minimal levels by night. Under normal conditions, basal morning cortisol concentrations are twice those at night.

Effects of Cortisol

Cortisol is an anti-inflammatory, catabolic hormone, which is essential to life. Release of high amounts of cortisol for short periods enables the body to deal with stress. Cortisol elevates blood glucose, decreases protein synthesis, and promotes fatty acid mobilization, making these substances available for energy and for synthesis of other compounds needed by different tissues of the body. Cortisol also helps to control allergies and inflammation by stabilizing lysosomes. Cortisol has been described by Dr. William Jefferies, author of Safe Uses of Cortisone, as “the hormone of life,” as without it we would be unable to adapt to the various stressors of life.(4) However, when cortisol is produced in excess over a prolonged period, it can have a number of adverse, damaging effects.


Prolonged periods of exposure to elevated levels of cortisol (such as occurs during chronic stress) cause a number of adverse effects in the body. These include elevation of blood sugar (diabetes), sodium retention (resulting in hypertension), suppression of immunity, gastric ulcers, headaches, loss of bone density (osteoporosis), heart attacks, loss of even more hypothalamic glucocorticoid (cortisol) receptors (creating a “vicious cycle”), and increased neuronal cell death in the brain.(5)

Dilman theorized that with increased age the hypothalamus becomes less sensitive to the inhibitory effects of cortisol. Thus, increasingly higher levels of cortisol are required to inhibit cortisol production and restore balance. Dilman conclusively demonstrated the adverse effects of aging on the adaptive homeostat in women by measuring cortisol levels in surgical patients of various ages before and after surgery.(6)

His study revealed that while there were no differences in basal cortisol levels in women of different ages, in older women cortisol levels rose faster, went higher, and remained elevated longer following surgery. This confirmed that the stress response is more intense and of longer duration with increased age (Fig. 3). Indeed, after age 40 many people undergo a characteristic change of appearance with age, as faces become moon-like and fat accumulates around the waist.

These changes are usually accompanied by a relative loss of fat and muscle on the arms and legs. When severe, these changes cause the person to resemble someone with Cushing’s Syndrome. Cushing’s Syndrome results from chronic excessive exposure to cortisol (Fig. 4).

In many ways, age-related metabolic and physiologic changes in the adaptive homeostat resemble the body’s response to chronic stress and prolonged exposure to excess cortisol. Dilman coined the term hyperadaptosis to describe this state. He believed that aging itself is a chronic stressor, and that everybody suffers, to a greater or lesser degree, from hyperadaptosis.


Diagnosis of hyperadaptosis is usually based on a spectrum of signs and/or symptoms listed in Table 1. These signs and symptoms are similar to those found in persons who suffer from hypoglycemia, hypothyroidism, chronic fatigue, and fibromyalgia—all of which may be related to hyperadaptosis.

Often, treatment is initiated on an empirical basis (i.e., “educated guesswork”), with no further testing, since treatment is relatively benign and the likelihood of improvement so high.

There are a number of tests that may contribute to the diagnosis, including blood or salivary tests of a.m./p.m. cortisol levels, and the DHEA-S/cortisol ratio. The low-dose dexamethasone-suppression test (used by many psychiatrists to evaluate depression) is considered the “gold standard.” These tests provide objective information on which to base the optimal therapeutic program.

Prevention and Treatment of Hyperadaptosis

Therapeutic Approaches / Intervention Based on the Neuroendocrine Theory

Dilman proposed that the most effective approaches to delay (and even reverse) the aging process and ameliorate the diseases of aging were to:

  1. Restore hypothalamic (and peripheral) receptor sensitivity;
  2. Restore hormone levels to more youthful values by hormone replacement therapy;
  3. Prevent damaging effects of the hormones(3);
  4. Restore intracellular bioenergetics.

1. Restore Receptor Sensitivity

With regard to the adaptive homeostat, hypothalamic resensitizers that seem to be most effective include combinations of adaptogenic herbs such as: Siberian ginseng (Eleutherococcus senticosus), Manchurian thorn tree extract, Hawthorn extract, Echinopanax elatum, Schisandra, Rhapon-ticum carthinoides, Adjuga turkistanica; Aralia mundshurica, Rhodiola rosea Myricetin, Magnolia officinalis, Phelloden-dron amurense, and Ashwagandha (Withania somnifera). These are all contained in VRP’s premier line of adaptogenic formulas—AdaptaPhase® I and II, and Cortisol Control.

Other substances that restore cortisol receptor sensitivity include phosphatidylserine (100 to 300 mg per day); the anti-diabetic drug, Metformin (Glucophage) (500 mg two to three times per day), and the anti-epileptic drug, Dilantin® (100 mg twice per day).

All of the above-mentioned substances have been documented to enhance the body’s response to cortisol—essentially restoring the adaptive homeostat to a more youthful state.

2. Hormone Replacement Therapy

The three hormones which drop most dramatically with age are: 1) DHEA(8) (Fig. 5), 2) melatonin(9) (Fig. 6), and 3) pregnenolone. These are all integrally related to the adaptive homeostat. I recommend that these three hormone/dietary supplements be considered by virtually everyone after age 35.

Melatonin, produced by the pineal gland, has been called “the anti-stress hormone,” due in large part to its ability to regulate rhythms of other hormones, and to its ability to blunt the negative effects of cortisol.(10) Melatonin dosages generally range from 750 mcg to 6 mg per day, at bedtime.

DHEA, the most abundant steroid in the body after cholesterol, is produced by the adrenals. Dosages of DHEA found to be effective usually range from 12.5 to 50 mg per day (lower doses for women, higher doses for men). Pregnenolone is an anti-inflammatory neurosteroid that is also produced by the adrenal glands. Levels of pregnenolone are believed to decrease as profoundly as DHEA. Replacement dosages range from 10 to 100 mg per day.

In order to mimic the body’s own hormonal cycles (DHEA and pregnenolone levels are highest in the morning, and lowest in the late afternoon and evening), I recommend that these hormones be taken first thing in the morning. Restoration and maintenance of melatonin, DHEA and pregnenolone to youthful levels can play a tremendous role in enhancing quality of life and preventing age-related degenerative diseases.

Although chronically elevated levels of cortisol are generally harmful, and relative hypercortisolemia occurs with age, there are times when additional cortisol is beneficial and necessary, such as when 1) an additional stressor is experienced that exceeds the body’s ability to adapt; or 2) the adrenals are exhausted due to overwhelming acute or chronic stress.

Adrenal support may be accomplished by the use of 1) low-dose hydrocortisone treatment (as outlined in Dr. William Jefferies’ book, Safe Uses of Cortisone), or 2) intravenous adrenal cortical extract (available from many physicians who administer chelation therapy). Nutritional supplementation with adrenal glandular supplements and/or glycyrrhizin may also be used.

Glycyrrhizin is a nutritional supplement extracted from licorice. By mimicking the effects of cortisol, glycyrrhizin offers users a safe and natural method for supplementing the body’s endogenous cortisol production to “give the adrenals a rest.” In doses of 25 to 100 mg per day, glycyrrhizin has been demonstrated to be of benefit in a wide range of conditions, including colds and flu, asthma, allergies, chronic fatigue, hypoglycemia and other acute stressful conditions.

Glycyrrhizin, and its “cousin,” cortisol, however, are like two-edged swords. In small to moderate doses, usually for short periods, they can be very beneficial. In excess, they can cause a number of adverse side effects. Consequently, it is very important to use the minimum effective dosage of glycyrrhizin, and to use it intermittently as needed (usually, for no more than one to two weeks at a time).

Periods of glycyrrhizin use should be interrupted by two to three weeks of non-use. Many people find that taking 25 to 100 mg per day of glycyrrhizin provides significant relief of symptoms of chronic fatigue, fibromyalgia, and other conditions that are related to “adrenal exhaustion.”

In order to mimic the body’s normal rhythm of cortisol, I recommend that glycyrrhizin be taken first thing in the morning, approximately 30 minutes before breakfast, and another (usually smaller) dose (if needed) before lunch. With glycyrrhizin, as with many supplements—more is not necessarily better. Only the minimum dose that produces the desired effect should be taken.

Whenever cortisone or glycyrrhizin support is used, I recommend that it be combined with one or more of the adaptogenic substances mentioned above to maximize the effectiveness and minimize the dosage and side effects of the supporting substance.


1. Selye Hans. Stress Without Distress. Signet, New York, 1974.
2. Dilman Vladimir. The Law of Deviation of Homeostasis and Diseases of Aging, John Wright. PSG, 1981.
3. Dilman Vladimir, Dean Ward. The Neuroendocrine Theory of Aging, The Center for Bio-Gerontology, Pensacola, 1992.
4. Jefferies William McK. Safe Uses of Cortisone, Charles C. Thomas, Springfield, Illinois, 1981.
5. Sapolsky Robert. Stress, The Aging Brain, and the Mechanisms of Neuron Death. MIT Press, Cambridge, Massachusetts, 1992.
6. Dilman Vladimir. Pathogenetic approaches to prevention of age-associated increase of cancer incidence, in: Physiological Senescence and its Postponement—Theoretical Approaches and Rational Interventions, Ann NY Acad Sci Vol 621, by Walter Pierpaoli and Nicola Fabris (eds), NYAS, New York, 1991, 385-400.
7. Tintera John W. The hypoadrenal state and its management. New York State Journal of Medicine, 55:13, July 1, 1955, 1-35.
8. Nair NPV, Hariharasubramanian N, Pilapil C, Isaac I, Thavundayil JX. Plasma melatonin—An index of brain aging in humans? Biol Psychiatry 1986 21:141-150.
9. Finch CE, Mobbs, CV. Nonlethal measurements involving steroids and neurotransmitters as reflections of physiological aging, in: Biological Markers of Aging, by Reff, M.E., and Schneider, E.L. (eds) 1982, Baltimore, USDHHS, NIHPublication No., 82-2221, pp. 30-41.
10. Pierpaoli Walter, Releson William. The Melatonin Miracle—Nature’s Age-Reversing, Disease-Fighting, Sex-Enhancing Hormone, Simon and Schuster, New York, 1995.