Neuroendocrine Theory of Aging Chapter 2
Adaptive Homeostat Dysfunction
By Ward Dean, M.D.
In Part I of the Neuroendocrine Theory of Aging we 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 hypothalamic sensitivity to inhibition by hormones and other signaling substances. This loss of hypothalamic sensitivity results in a progressive shifting of homeostasis in the body and altered metabolic 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 intervention approaches to delay and even reverse aging become obvious. All of these areas will be discussed at greater length in forthcoming issues of VRP News.
The Adaptive Homeostat
The Adaptive Homeostat consists of the hypothalamo-pituitary-adrenal axis (Figure 1). In order to fully appreciate the significance of Dilman’s work and his sometimes-unfamiliar terminology, we should review some basic endocrinology.
Stressors normally excite the hypothalamus to produce corticotrophin releasing factor (CRF). CRF in turn causes the pituitary to produce adrenocorticotropic hormone (ACTH), which induces the adrenal cortex to secrete glucocorticoids (principally cortisol) and DHEA.
If cortisol levels drop, the hypothalamus senses that more cortisol is needed. The hypothalamus responds by releasing corticotropin-releasing hormone (CRH), the substance which causes the pituitary to release adrenocorticotropic hormone (ACTH). ACTH, in turn, stimulates the adrenals to release even more cortisol. When cortisol levels rise to the degree necessary to deal with the stress, the stimulus for production of more cortisol is inhibited, and the system returns to normal.
However, with age, the hypothalamus becomes less sensitive to the inhibitory effects of cortisol, requiring higher and higher levels of cortisol to have the same effect of shutting down the stimulus for
increased cortisol production that we had when we were younger. The adverse effects of aging on the adaptive homeostat were demonstrated in a study by one of Dilman’s colleagues (Ostroumova, 1991), in which cortisol levels were measured in surgical patients of various ages. The study revealed clearly that the stress response is greater and of longer duration as age increases (Fig. 2).
Effects of Cortisol
Cortisol is a 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 lysozomes.
However, 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 hypertension, reduced glucose tolerance (development of diabetes), loss of even more hypothalamic glucocorticoid (cortisol) receptors (creating a vicious cycle), and increased neuronal cell death in the brain. This subject has been reviewed in depth by USC’s Professor Robert Sapolsky (1992).
Hyperadaptosis
After age 40, the appearance of many people undergoes a characteristic change with age. Their faces become moon-like, and fat accumulates around their waist. There is usually a relative loss of fat and muscle on the arms and legs. When these changes are severe, they cause the person to resemble someone with Cushing’s Disease. Cushing’s Disease results from excessive release of cortisol by the adrenal glands (Fig. 3).
In many ways, the age-related metabolic and physiologic changes in the adaptive homeostat that are caused by aging are similar to the body’s response to chronic stress. Thus, Dilman coined the term, hyperadaptosis, to describe this state, as he believed that aging is a chronic stressor. Hyperadaptosis, then – characterized by prolonged exposure to excess cortisol levels – is caused by the loss of hypothalamic sensitivity to the inhibitory effects of cortisol.
Therapeutic Approaches/Intervention Based on the Neuroendocrine Theory
Among the approaches Dilman proposed to delay (and even reverse) the aging process and ameliorate the diseases of aging are: (1) Restore hypothalamic sensitivity; and (2) Restore hormone levels to more youthful values by implementing hormone replacement therapy (Dilman and Dean, 1992). Although much remains to be learned, we now have enough knowledge to begin employing elements of these approaches in our personal anti-aging/life extension programs.
With regard to the adaptive homeostat, there are a number of approaches that can be beneficially used. For example, when possible, deal with or eliminate as many stressors as possible. There are also many non-nutritional/non-pharmacological approaches that can be used to reduce the adverse effects of stress such as exercise, relaxation techniques, or music. Not to be overlooked are stress-reducing dietary supplements like Kava Kava and GHB (as well as GHB precursors like butanediol [BD] and butyrolactone [GBL]).
The most innovative approach, however, is to use dietary supplements and pharmaceutical substances to restore hypothalamic sensitivity. Restoring hypothalamic sensitivity results in increased effectiveness of various hormones, neurotransmitters, and cell signalling substances, which increases their effect in lower doses, and thereby reduces any potential adverse effects.
I. Hypothalamic Resensitizers
With regard to the adaptive homeostat, hypothalamic resensitizers that seem to be most effective include: (1) combinations of adaptogenic herbs like Siberian ginseng (eleutherococcus), Manchurian thorn tree extract, Hawthorn extract, Echinopanax elatum, Schisandra, Rhaponticum carthinoides, and Adjuga turkistanica; (2) phosphatidylserine (100-300 mg per day); and (3) the prescription drug Metformin (Glucophage) (available from International Anti-Aging Systems - from North America, call 011-44-870-151-4144, from Europe or Japan, call 00-44-870-151-4144. See my article, Metformin – An effective and underappreciated life extension drug, Vitamin Research News, November, 1998)
II. Hormone Replacement Therapy
Blood levels of three hormones which drop dramatically with age that are integrally related to the adaptive homeostat are (1) melatonin, (2) DHEA and (3) pregnenolone. I recommend that replacement of these three dietary supplements should be considered 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. Melatonin dosages generally recommended range from 750 mcg to 6 mg per day, at bedtime.
DHEA, the most abundant steroid in the body except for cholesterol, and produced by the adrenals, drops precipitously with age. Dosages of DHEA found to be effective usually range from 12.5 to 50 mg per day.
Replacement dosages of pregnenolone — which is believed to decrease as profoundly as DHEA — range from 10 to 100 mg/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. For example, (1) when allergies strike, (2) the adrenals are exhausted due to chronic stress, or (3) an additional stressor is experienced which exceeds the body’s ability to adapt, it is sometimes necessary to augment the body’s own cortisol production.
A safe, natural way to supplement the body’s endogenous cortisol production, and to give the adrenals a rest, is to use an extract from licorice known as glycerrhizin. Glycerrhizin mimics many of the actions of cortisol. In doses of 25 to 100 mg per day, glycerrhizin 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. Glycerrhizin should not be used for more than several weeks at a time to prevent the adverse effects of excess cortisol.
Next Issue: Energy Homeostat Dysfunction
References
Dilman, Vladimir. The Law of Deviation of Homeostasis and Diseases of Aging, John Wright.PSG, 1981).
Dilman, Vladimir, and Dean, Ward. The Neuroendocrine Theory of Aging, The Center for Bio-Gerontology, Pensacola, 1992.
Sapolsky, Robert. Stress, The Aging Brain, and the Mechanisms of Neuron Death. MIT Press, Cambridge, Massachusetts, 1992.
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