Comprehensive Review of the Neuroendocrine Theory of Aging, Part 1
Ward Dean, MD
When discussing anti-aging, we need to define “aging” so that we can understand what we are “anti.” A standard dictionary defines aging as the “adverse physiological and biochemical changes and increased likelihood of death associated with the passage of time.” Of course, one of the principal concepts of anti-aging medicine is that the aging process is not merely a collection of “adverse physiological changes,” but is, instead, a serious and deadly disease in its own right.
The same dictionary defines disease as “an alteration of a living body that impairs its function.” As we grow older virtually every important process involved in homeostasis and maintenance of health changes in an adverse direction over time (Fig. 1). Thus, it should be clear that aging certainly qualifies as a disease.
The Science of Gerontology
When the science of gerontology — the study of aging — first began, there was a great deal of discussion about when aging begins. Does it begin at birth, during puberty, during adulthood or later? Professor Bernie Strehler from USC described four criteria that are inherent in aging-related changes. It is clear from these criteria that aging does not begin at birth, but instead begins post-adulthood.
The first criteria is that aging changes are universal — i.e., they occur in everyone. Most diseases don’t affect everyone — for example, one person may have arthritis, another person may suffer from coronary artery disease, and yet another may get cancer. But aging is universal — every living organism ages.
The second criteria that characterizes aging is that it is intrinsic — i.e., aging is a byproduct of normal metabolism. Although we make lifestyle changes, exercise, and consume a proper diet in an attempt to slow the aging process and maintain health, aging occurs anyway.
Third, aging is progressive — it’s sort of like a one-way street — it doesn’t reverse. One of our goals in anti-aging medicine is to reverse some of these adverse changes that were once believed to be irreversible.
The fourth criteria, and, of course, the major reason that we are for “anti-aging” is that aging changes are deleterious. They reduce the likelihood of survival, and increase the likelihood of disease. As shown in Figure 1, virtually every physiological and biochemical change that is involved in our health and maintenance of homeostasis moves in an adverse direction. The one thing that does not decrease or change adversely is the incidence of just about every other disease (Fig. 2).
The standard medical model approaches each individual degenerative disease separately. Trying to achieve life extension or anti-aging and improved health only by the elimination of disease is an approach that I believe is doomed to failure.
Extending Human Lifespan
Even with the best advances in biomedical science, the maximum human lifespan has stayed constant throughout recorded history (Fig. 3). Rather than extending the span of human life, modern medical practice has increased the number of people who survive into old age. Scientists refer to this as “squaring the curve.”
Anti-aging medicine takes the approach of looking at the aging process itself as a disease. Instead of simply squaring the curve — which is an admirable goal — we want to extend the curve (Fig. 4), to extend not only the healthy years of our life but also the quantity of life itself.
Aging as Disease
Thus, I consider the aging process to be a disease — the one disease that every-body over the age of 35 has “caught.” For example, note the age-related record times in the New York City Marathon (Fig. 5). After age 30 — even though these are among the most fit athletes in the world — the times slow as the athletes get older. How many professional athletes can you think of who are over 35 years of age? At that relatively youthful age, when other professionals are just getting started in their careers, and despite probably 20 years of active participation in a sport with the finest coaching, the finest diet, the finest training regimens — by the time an athlete is 35 years old, it is time to go out and look for another job.
The Free Radical Theory of Aging
Professor Denham Harman sparked the modern anti-aging movement by publishing his Free Radical Theory of Aging in 1954. Unfortunately, for the next 25 years one could only read about free radicals and antioxidants in scientific journals. Another important milestone in anti-aging science occurred in 1980 when Durk Pearson and Sandy Shaw — a couple of hippie-type scientists — popularized the concept of life extension by educating the public about Dr. Harman’s ideas on national television. Pearson and Shaw were extremely popular guests on the Merv Griffin TV show, and following each appearance, were swamped with mail requests for more information on anti-aging therapies. Durk and Sandy proved so popular with the public that the Merv Griffin show reported receiving more mail for these two guests than any other guest at the time.
In 1983, Durk and Sandy responded to the growing demand for more information on anti-aging by publishing their best-selling book, Life Extension: A Practical, Scientific Approach. This block-buster — presenting 30 years worth of research compiled by Dr. Harman and his associates — went on to sell over 2.5 million copies, and today is regarded as a primary contributor to starting many then-students on their paths to become the anti-aging physicians and scientists of today.
About the same time that Durk and Sandy were popularizing Life Extension, John Mann — who actually lived across the street from Pearson and Shaw in Manhattan Beach, California, and did not know who they were—was working on his own book called “Secrets of Life Extension.” Mann’s book also focused primarily on the free radical theory of aging although he also addressed a number of other potential anti-aging therapies.
Vladimir Dilman and Homeostasis
Shortly after Pearson and Shaw’s book came out, I read another book with a mouthful of a title — “The Law of Deviation of Homeostasis and Diseases of Aging”— written by a Russian scientist I’d never heard of by the name of Vladimir Dilman. This book was extremely complex, and I had a hard time understanding it. However, after reading it about three times, I began to understand what Dilman was talking about.
I began corresponding with Dilman in 1985. In 1990, when a window of opportunity availed itself for him to leave Russia, he jumped at the chance, and arrived at my doorstep shortly thereafter. We collaborated on a new book in English that presented his concepts and theories in more understandable terms. Even then, it was a highly technical book.
Dilman first conceived his theory in 1954. However, since his articles and books were mostly printed in Russian, little was known of Dilman’s theory outside of Eastern Europe. Dilman’s theory, in essence, is that aging is caused by a progressive loss of sensitivity of the hypothalamus and related structures in the brain to negative feedback inhibition. To understand this concept I had to pull out my basic Endocrinology books and do some studying.
To understand Dilman’s concepts, it was necessary to gain a working knowledge of the endocrine system (Fig. 6). We all learned in high school that a basic principle in physiology is the concept of ‘homeostasis.’ Homeostasis is the condition in which physiological states required for life and good health must remain within a very stable, narrow optimal range. For example, when any critical parameter is above or below “normal” (like blood pressure, blood sugar, or body temperature), it is considered a disease.
We also were taught that homeostasis is a primary function of life — that we are homeostatic beings — and that it is essential to be in homeostasis.
Everyday examples of a homeostatic system are the thermostats that control the temperature in our homes, or the floats that 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. This is the concept of homeostasis — everything in balance.
But Dilman turned much of what we had learned upside down. He proposed that there is actually a progressive shifting of homeostasis throughout life. In fact, he pointed out that this shift is absolutely necessary, because if we were truly homeostatic beings we would never grow and we would never develop.
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 that enables growth and development to occur. This is also a primary mechanism that causes 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 to 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.
It is the breakdown or alteration in the functioning of these homeostats that 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 (Table I). 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. The 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. Dilman’s theory explains how aging and stress combine to accelerate changes in the “adaptive homeostat,” resulting in the age-related disease, hyperadaptosis.
Likewise, changes in the “energy homeostat” explain how dysfunction of the energy homeostat results in a decline in physical activity and metabolic rate, accompanied by feelings of reduced energy, and increased fatigue, followed by the age-related diseases of (1) diabetes, (2) obesity, (3) essential hypertension, (4) atherosclerosis, (5) depression (6) fatigue, (7) coronary artery disease, and (8) cancer.
Part II of Dr. Dean’s review of the Neuroendocrine Theory of Aging will continue with a discussion on the endocrine system, including the hypothalamus and pineal glands, as well as a discussion of the reproductive, adaptive, energy and immune homeostats.