Neuroendocrine Theory of Aging Chapter 1
By Ward Dean, M.D.
The modern neuroendocrine theory of aging was first conceived in 1954 by the noted Russian gerontologist, Professor Vladimir Dilman. Since his books were only available in Russian, little was known of Dilman’s theory outside of Eastern Europe. The recent translation of several of Dilman’s books into English have made this unique theory and innovative therapeutic regimen available to Western readers and scientists (Dilman, 1981; Dilman and Dean, 1992; Dilman, 1994). The 1992 book, the most readable, cohesive and comprehensive exposition of Dilman’s unique aging theory ever written, is unfortunately out of print. Over the next year we will be elaborating and updating elements of this theory in installments in Vitamin Research News.
Dilman’s theory, in essence, is that aging is caused by a progressive loss of sensitivity by the hypothalamus and related structures in the brain to negative feedback inhibition. This loss of sensitivity not only enables us to grow and develop, but is the cause of post-maturational diseases, aging and death. The neuroendocrine theory explains the cause of the major diseases of aging which contribute to over 85% of deaths of middle-aged and elderly individuals. These diseases include: (1) obesity, (2) atherosclerosis, (3) hypertension, (4) diabetes, (5) cancer, (6) autoimmune disorders, (7) metabolic immunodepression, and (8) hyperadaptosis. Two other diseases— depression and menopause—although not fatal, also occur regularly with age. Several of these diseases (hyperadaptosis, and metabolic immunodepression) have strange-sounding names, but as one gains an understanding of Dilman’s theory, these names will not seem as strange.
Endocrine System
To understand Dilman’s concepts, we must first gain a working knowledge of the endocrine system (Fig. 1). Although the pituitary gland in the brain directs the activities of the endocrine system, the pituitary is itself controlled by another structure in the brain, called the hypothalamus.
Substances known as releasing factors trickle down from the hypothalamus to the nearby pituitary and activate the release of one or more of its hormones. These hormones, in turn, stimulate the production of hormones in other glands (i.e., the thyroid, the adrenals, the testes, the ovaries and the thymus), or prevent the hormones from affecting the cells or organs they would normally act upon.
A basic principle in physiology is the concept of homeostasis. Homeostasis is the state of maintaining the body’s physiological, endocrinological, and biochemical parameters within a relatively narrow range, compatible with health and life. When any critical parameter is above or below normal (like blood pressure, blood sugar, or body temperature), it is considered a disease.
Everyday examples of a homeostatic system are the thermostats which control the temperature in our homes, or the floats which control the water level in a toilet tank. A finely-tuned thermostat can maintain your home at a narrowly-defined, comfortable temperature. However, as the thermostat wears out and loses sensitivity, the house temperature is more varied and uncomfortable since the thermostat does not kick on and off as it should. Likewise, a poorly functioning toilet tank float can result in either too little water in the tank to flush adequately, or the water may overflow or never stop running.
Hypothalamus and Homeostasis
The hypothalamus is the body’s primary organ of homeostasis. It maintains the equilibrium of most biological processes within a fairly narrow range. Releasing factors (small protein-like molecules) from the hypothalamus initiate hormonal changes in the pituitary (formerly considered the master gland). Hypothalamic secretions keep internal temperature, blood pressure, thirst, hunger, sexual appetites, chemical and water balances, menstrual cycles, and numerous other activities functioning normally. For the hypothalamus to do this, it must be sensitive to biochemical changes that signify slight deviations in these functions. Too much or too little of a particular hormone in the tissues influences the hypothalamus to secrete more or less specific releasing factors and inhibiting factors which bring about the adjustment.
Pineal Gland
Recent research indicates that the hypothalamus is itself influenced by another structure in the brain known as the pineal gland. The pineal gland controls the regular cyclical functioning of the entire neuroendocrine system, most notably our 24-hour sleep-wake cycle, as well as many other chronobiological functions. The condition known as jet lag can be attributed to pineal gland function. This is commonly experienced by jet travelers (particularly when traveling in an easterly direction), but can also be caused by sleep disregulation from performing shift work, or just staying out too late at night. As we grow older the symptoms of jet lag become progressively worse due to a decrease in the output of melatonin, the principle hormone of the pineal gland.
Many older people have difficulty sleeping at night, and, as a result, are fatigued during the day. Usually this is accompanied by a constellation of other symptoms, including memory loss, irritability, confusion, depression, or constipation. These symptoms are similar to those of jet lag. Consequently, I believe that many elderly people who suffer from these symptoms are actually suffering from chronic chronobiological desynchronization like jet lag caused by depressed levels of melatonin (Fig 2).
The hormones released from the hypothalamus in turn cause the pituitary gland to release stimulating hormones. These stimulating hormones cause the peripheral endocrine glands (thyroid, adrenals, ovaries and testes) to secrete their hormones (i.e. thyroxin, cortisone, estrogen, progesterone, and testosterone, to name a few). In this fashion, this system is controlled by negative feedback—i.e., as the blood level of a peripheral hormone (like thyroxin or testosterone) rises, it causes feedback to the hypothalamus and pituitary, signalling them to reduce their output of stimulatory releasing factors and hormones (Fig. 3).
Homeostasis and Aging
If our bodies were able to remain in perfect homeostasis from birth, further growth and development would not take place. Dilman believed that the shift of hypothalamic sensitivity to negative feedback is the mechanism which enables growth and development to occur. This is also a primary mechanism of aging and the diseases of aging. For example, in an infant, only minute amounts of testosterone are produced. If our bodies truly maintained a state of homeostasis, even these small amounts of hormone would be adequate to prevent the hypothalamus and pituitary from producing greater amounts of testosterone-stimulating releasing factors and hormones. If this were the case (not only with testosterone, but with all hormones), growth and development would never occur, and we would remain infants throughout our lives. Thus, throughout childhood and puberty, there is a constant shifting of homeostasis, resulting in growth and development.
The problem is that once we have reached adulthood, there is no mechanism to shut off this progressive loss of hypothalamic sensitivity to feedback inhibition. Thus, the homeostatic balance—which appears to reach its optimum at ages 20-25—continues to shift, resulting in less-than-optimum levels of many hormones, and ultimately, the exhaustion of the peripheral endocrine glands due to their prolonged efforts to overcome the loss of hypothalamic sensitivity.
Hypothalamic Threshold
The following factors cause the hypothalamic threshold to rise with age: (1) reduced hypothalamic neurotransmitter levels (catecholamines and serotonin, in particular); (2) reduced quantity of hypothalamic hormone receptors (which may be caused partially by the drop in biogenic amine concentrations); (3) decline in the secretion of pineal gland hormones (melatonin and pineal polypeptide hormones); (4) fat accumulation; (5) reduced glucose; (6) accumulation of neuronal lesions produced by chronically elevated levels of cortisol due to prolonged stress; and (7) accumulation of cholesterol in plasma membranes of neurons.
Homeostats and Growth
Dilman believed that the three homeostatic systems which are involved in growth and development are: the adaptive (hypothalamic-pituitary-adrenal axis), reproductive (hypothalamic-pituitary-gonadal axis), and energy (hypothalamic-pituitary-thyroid axis) homeostats.
I believe that another homeostat should be added to these three—the immune (pineal-hypothalamic-pituitary-thymus) homeostat. It is the breakdown or alteration in the functioning of these homeostats which causes the metabolic changes that characterize aging and the diseases of aging. Dilman intuitively determined that all of the diseases of aging are characterized by similar metabolic changes. The most prevalent of these changes include (1) reduction in glucose tolerance, (2) hyperinsulinemia, and (3) hyperlipidemia. Dilman’s theory provides a bold new theoretical foundation for the aging process itself, as well as concrete, clinically tested protocols for the treatment and prevention of the diseases of aging. A beauty of this theory is that it neither contradicts other more established theories of aging, nor is it mutually exclusive. Rather, it either incorporates or supplements other theories.