Comprehensive Review of the Neuroendocrine Theory of Aging, Part 2
Ward Dean, MD
Part I of our review of the Neuroendocrine Theory of Aging focused on the role of noted Russian scientist Vladimir Dilman, who theorized that aging is caused by the inexorable and gradual loss of hypothalamic sensitivity to feedback signals, leading to the progressive shifting of homeostasis, or balance of physiological processes.
In Part II we continue our review of the body’s homeostats and their role in good health and aging.
Hypothalamus and Homeostasis
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 stimulate the pituitary to release 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).
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 that bring about the adjustment.
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. Jet travelers commonly experience this — particularly when traveling in an easterly direction. However, jet lag can also be caused by sleep dysregulation 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 (Fig. 7).
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.
Hypothalamic-Pituitary Axes, or “Homeostats”
Dilman viewed the endocrine system as a classic cybernetic system, with feedback through various levels. He also theorized that the central regulator — the hypothalamus — was responsible for the shifting of homeostasis. Today, articles about receptor up-regulation and receptor down-regulation are not hard to find. However, Dilman figured this out even before anyone even knew there were receptors.
Dilman reasoned that all living organisms have four capabilities essential for life: (1) reproduction, (2) adaptation, (3) energy production, and (4) protection. He thus theorized the existence of four separate “hemostats” — reproductive, adaptive, energy, and immune — which controlled these functions.
He proposed that a progressive loss of sensitivity in these homeostatic systems not only enables us to grow and develop, but is the cause of the increased incidence of chronic degenerative diseases as we grow older, including aging and death. The Neuroendocrine Theory explains the cause of the major diseases of aging that contribute to over 85 percent 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 so strange.
The central part of the reproductive homeostat is the hypothalamus, the central organ in the brain. The hypothalamus produces releasing factors that stimulate the pituitary, which then releases the tropic hormones — follicle stimulating hormone (FSH) and luteinizing hormone (LH) — which then stimulate the testes in men and the ovaries in women to produce estrogen, testosterone, and progesterone (Fig. 8 and 9).
If we were truly homeostatic beings, the small amounts of estrogen and progesterone that are produced even in infants would be adequate through feedback inhibition to shut down the production of releasing hormones by the hypothalamus and gonadotropins by the pituitary. Dilman theorized that the only way to produce the higher amounts of estrogen and testosterone necessary to trigger the maturation of the reproductive axis would be through a loss of sensitivity of the hypothalamus to negative feedback inhibition.
As a woman ages, FSH and LH progressively increase, resulting in an increase in the release of estrogen until, at some point during menopause, even extremely high amounts of FSH and LH can no longer stimulate the ovaries to produce more estrogen, resulting in ovarian failure (Fig. 10). Ovarian failure is likely due to the ovaries having been “pummeled” for many years by progressively higher and higher amounts of FSH and LH, as well as by the toxic effects of estrogen itself. Following ovarian failure, as menstruation stops, there is virtually no output of progesterone. Thus, as a woman ages, she begins to become more and more estrogen-dominant postmenopausally, making the toxic effects of estrogen even more pronounced.
Similar changes occur in men, although the changes are not quite so abrupt and as dramatic as in women (Fig. 11). As with women, FSH and LH continue to overwhelm the testicles in order to induce higher and higher amounts of testosterone, until at some point the testes fail. Note also that estrogen levels in men continue to rise, facilitated by the actions of the enzyme aromatase — which converts higher amounts of whatever testosterone is produced into estrogen.
The adaptive homeostat consists of the hypothalamus, the pituitary gland, and the adrenal glands. In the adaptive homeostat we see a similar mechanism as in the reproductive homeostat (Fig 12). The hypothalamus produces corticotropin releasing hormone, which stimulates the anterior pituitary to produce adrenocorticotropic hormone (ACTH), which in turn causes the adrenal cortex to produce cortisol. Cortisol — the body’s primary adaptive hormone — is produced in high amounts during stress. Cortisol is essential for life — without cortisol, we could not survive. But cortisol — like estrogen and insulin — is an essential toxin. We need it, but we need it in small amounts. High amounts over a prolonged period of time have very damaging effects. Dilman showed that both time and aging are natural stressors that promote elevated production of cortisol.
Dilman performed a unique study with a group of women who were undergoing surgery for breast cancer (Fig. 13). He found that the youngest group, those under 46 years of age, produced less cortisol in response to the surgical stress, and they more rapidly returned to lower baseline levels. As the age of the women increased, Dilman found that cortisol levels rose progressively higher, as did its attendant damaging effects. Dilman referred to this progressive worsening of the cortisol response with age as hyperadaptosis. Hyperadaptosis causes many of the symptoms seen in Cushing’s disease, including “moon face,” red cheeks, central obesity, thin skin, easy bruisability, bulging abdomen, poor wound healing, and poor muscle development (Fig. 14). These are all characteristics of excess exposure to cortisol.
Some of the known effects of hyperadrenocorticism include immunosuppression, osteoporosis, atherosclerosis, diabetes, impaired blood sugar regulation, and death of brain cells. These are all effects of chronic stress. Dilman believes that everybody suffers to a greater or lesser degree from hyperadaptosis.