Neuroendocrine Theory of Aging Chapter 3, Part 1

Energy Homeostat Dysfunction

By Ward Dean, M.D.

Editors Note: We recommend that Parts I and II be read first, in order to better appreciate this article. Parts I and II, published in the March and April, 1999 issues of VRP News, are available on our website (www.vrp.com), or upon request to Customer Service.

Introduction: The modern neuroendocrine theory of aging was first conceived in 1954 by the noted Russian gerontologist, Professor Vladimir Dilman. Several years ago, I had the pleasure of working with him on our book, The Neuroendocrine Theory of Aging and Degenerative Disease.1 Over the next year, I will be elaborating and updating elements of this theory in installments in Vitamin Research News.

Part I introduced: (1) the concept of homeostasis and (2) how the progressive loss of hypothalamic sensitivity to inhibition by hormones and other signaling substances by the four homoeostatic systems in the body results in growth, development and aging. Part II discussed how aging and stress combine to accelerate changes in the adaptive homeostat, resulting in the age-related disease, hyperadaptosis.

Living organisms are characterized by their capacity to (1) reproduce, (2) adapt, (3) regulate the flow of energy, and (4) protect themselves. Consequently, these organisms have regulatory control systems (which Dilman called homeostats) that regulate and attempt to maintain homeostasis (balance) in each of these critical areas. Living systems are essentially energy-converting machines which run on fuel (food) to maintain their structure and activity.

In the next several installments, we will discuss the energy homeostat and how dysfunction of this system results in a decline in physical activity, metabolic rate, subjective feelings of reduced energy, and increased fatigue. In addition, energy homeostat dysfunction results in the age-related diseases of (1) diabetes, (2) obesity, (3) essential hypertension, (4) atherosclerosis, (5) depression and (6) fatigue.

The Energy Homeostat
The energy homeostat is the body system responsible for production, utilization and regulation of energy. Dysfunction in this system manifests as the obvious and commonly observed reduction in intensity and amount of activity with age accompanied by increased fatigue and reduced energy.

Age-related energy homeostat dysfunction is a major reason why there are so few professional athletes over age 35 who are still able to successfully perform against their younger competitors.

(Fig 1)

Unlike the adaptive homeostat (VRN, Vol. 13, No. 4, April, 1999), which is represented by a classic cybernetic system (the hypothalamo-pituitary-adrenal axis), the energy homeostat is represented by three separate but closely integrated systems. First is the inter-relationship between growth hormone, insulin, glucose and fatty acids, which we will discuss in this article. Second is the hypothalamo-pituitary-thyroid axis which was previously discussed in VRN, Vol. 12, No. 6, August, 1998). The third component is the intracellular production of energy by mitochondria via the Krebs (citric acid) cycle (which will be discussed in a forthcoming issue). All three of these components are altered in adverse directions with age, resulting in reduced activity and impaired energy production and utilization, and energy homeostat related diseases like obesity, diabetes, atherosclerosis, hypertension, depression and fatigue.

Inter-relationship Between Energy Substances & Hormones
The first and primary aspect of the energy homeostat is a four-component system that regulates the inter-relationships between the body’s two main energy-producing substances (glucose and fats), and the two main hormones (growth hormone and insulin) that control the utilization of these substances.

(Fig. 2

Other hormones and neurotransmitter substances that are also involved in the energy homeostat include the hormones prolactin, glucagon, ACTH and adrenal glucocorticoids; and the neurotransmitters epinephrine, norepinephrine, dopamine and serotonin. These hormones which regulate the body’s use of glucose and free fatty acids as energy sources are regulated by a complex balancing act. The effects of these other hormones are not discussed separately because they each act similarly to one or more of the four components of the energy homeostat.

In a healthy, youthful energy homeostat, glucose inhibits the secretion of growth hormone by acting on specific areas of the hypothalamus. Consequently, during the day, when food is consumed periodically, growth hormone secretion by the pituitary is suppressed, and insulin release by the pancreas is increased. Insulin enhances the uptake of glucose into the cells where it is either used for energy or stored as fat. During the day, the primary source of energy is glucose, and to a lesser degree, fat. Fats burn more easily in the presence of carbohydrates.

At night, when no food is consumed, blood levels of glucose decrease and insulin levels drop, thereby stimulating the release of growth hormone. Growth hormone has lipolytic, or fat-mobilizing properties. Consequently, unless a carbohydrate-rich bedtime snack has been consumed, fatty acids are mobilized from the fat stores, and fats become the primary energy source, and glucose is conserved for powering the brain and nerves. This explains why it is so important for those trying to lose body fat to avoid late dinners or bedtime snacks, which suppress the night-time release and fat-burning effects of growth hormone.

Age-Related Changes in the Four-Component Energy Homeostat
As we age, the mechanism of switching from the daytime (glucose-based) to the nighttime (fat-based) energy system is disturbed. This is because growth hormone (which was required in large amounts during periods of growth, and which is a key element in the healthy, youthful four-component energy homeostat) declines dramatically in early adulthood.

(Fig. 3)

This turns the aged energy homeostat into a headless three-component system.

(Fig 4)

Simultaneously, glucose tolerance and the ability of muscle tissue to utilize glucose decreases, and insulin levels tend to increase, resulting in hyperinsulinemia.

Hyperinsulinemia has been recently correlated with hypertension, atherosclerosis and cancer, and this combination has been dubbed Syndrome X (see VRP News, Vol. 13, No. 5 May, 1999). Dilman, however, described this relationship in the late 60s and early 70s, long before the connection was discovered by Western scientists in the 80s and 90s.

This combination of metabolic changes with age—i.e., increase in blood levels of glucose, fatty acids and insulin, and reduction in growth hormone, ultimately leads to an increase in body fat and reduction in lean body mass. Consequently, even if body weight does not increase with age, the percentage of body fat does increase, and the percentage of bone and muscle decreases. These changes are reflected in the body mass index (BMI) and are so commonly observed that the BMI appears to be a biomarker of aging.2

What Causes Age-Related Energy Homeostat Dysfunction?
The causes of the age-related decrease in growth hormone secretion and changes in hypothalamic sensitivity to feedback inhibition remain somewhat speculative. However, Dilman hypothesized that a major cause of these changes was the age-related shift in absolute level and balance of hypothalamic neurotransmitters—particularly the dopaminergic neurotransmitters (epinephrine, norepinephrine, and dopamine) and serotonin.

(Fig. 5)

Another potential cause may be the loss of diurnal regulation of the hypothalamus by secretions from the pineal gland, including melatonin and other peptide substances. Melatonin secretion from the pineal is one of the most dramatic age-related biomarkers known (Fig. 6). A cause of the drop in melatonin levels with age may be calcification of the pineal, resulting in loss or inactivation of hormone-producing pineal cells. Pineal calcification, in fact, is such a commonly found sign that radiologists performing CT scans of the brain often use the calcified pineal as a landmark.

Approaches to Improve Age-Related Alterations in the Energy Homeostat
1. Exercise: The universal anti-aging pill. Exercise has a wide-ranging beneficial effect on many age-related decrements. It restores hypothalamic sensitivity, improves glucose tolerance, reduces insulin levels and enhances growth hormone secretion.

2. Diet: As we grow older, because our bodies utilize glucose less efficiently than when we were younger, most people find a diet higher in protein and fat and lower in carbohydrates results in stabilization of energy levels, reduction in carbohydrate cravings, improvement in blood glucose and lipid profile, and reduction in body fat. Such diets are described in detail in the Zone Diet books by Dr. Barry Sears, the Atkins diet books by Dr. Robert Atkins, and Protein Power by Drs. Michael and Mary Dan Eades.

3. Restore insulin sensitivity using: Metformin, Dilantin and/or GluControl. Metformin (Glucophage) is an anti-diabetic drug which restores muscle and hypothalamic glucose and insulin sensitivity and utilization. Metformin reduces carbohydrate cravings, lowers blood glucose and insulin levels and normalizes the lipid profile. Dilman believed that drugs of this class were the most effective anti-aging drugs. I recommend 1,000-2,000 mg daily for my patients over 40. Dilantin is an anti-seizure medication which also shares this property of restoring hypothalamic sensitivity to glucose and insulin and is very effective both in raising HDL cholesterol levels, and improving the cholesterol/HDL ratio. Dilantin can be safely used in doses of 200-300 mg/day. Metformin and Dilantin are available with a prescription or from International Anti-Aging Systems (IAS) (www.anti-aging.com).

A dietary supplement alternative to Metformin is VRP’s new GluControl, which contains the herb Galega oficinalis (Goat’s rue), upon which drugs like Metformin are based.

4. Restore nighttime levels of growth hormone to more youthful levels: The decline in growth hormone secretion and release is a principle cause of the adverse changes in the energy homeostat. Growth hormone can be augmented by directly injecting small amounts of human growth hormone, or by stimulating release from the pituitary gland. Growth hormone can be prescribed by a physician or obtained without a prescription from IAS. A number of approaches to stimulate the release of growth hormone include amino acid-based formulas comprised of various combinations of arginine, ornithine, lysine, and glutamine; growth-hormone releasing hexapeptide secretagogues; and growth hormone releasing substances like GHB or its precursors, GBL or butanediol (BD). These latter two substances appear to be among the most promising of oral growth hormone secretagogues.

5. Balance neurotransmitters (epinephrine, norepinephrine, dopamine, and serotonin): One cause of the loss of hypothalamic sensitivity with age is the alteration in absolute levels and balance of hypothalamic biogenic amine neurotransmitter levels (epinephrine, norepinephrine, dopamine, and serotonin). Consequently, dietary supplementation with precursors of these neurotransmitters may restore hypothalamic neurotransmitter balance, enhance hypothalamic sensitivity and normalize the metabolic shifts of aging.

6. EDTA: Ethylene diamine tetra-acetic acid (EDTA) is a powerful chelator of metastatic calcium (calcium that has been deposited in unwanted locations). Although no clinical studies have ever evaluated the ability of EDTA to decalcify an aging pineal gland, I believe that such would be the case if the study were performed. I have believed for many years that the near-miraculous benefits that I have observed in many of my IV chelation patients have been at least partially due to decalcification of the pineal. I also believe that similar results may be obtained by using products, like Oral ChelatoRx.

7. DHEA: DHEA release is inhibited by insulin. Hyperinsulinemia has been speculated to be a cause of the age-related decline in DHEA. DHEA-S levels have even been proposed as a biomarker of insulin sensitivity. Conversely, DHEA supplementation appears to restore insulin sensitivity.3 Consequently, this is just one more reason for people over 35 to supplement their diets with physiological levels of DHEA. I recommend 12.5-100 mg of DHEA daily, depending on sex and age. Women efficiently convert DHEA to testosterone and require less DHEA than men. Consequently, I rarely recommend more than 25 mg/day for women, unless clinically indicated.

Utilization of a combination of these approaches should help to restore hypothalamic sensitivity, alleviate some of the metabolic abnormalities caused by energy homeostat dysfunction, and reverse changes due to energy homeostat dysfunction.

Next Issue: Energy homeostat, Part 2.

References for Neuroendocrine Theory:
1. Dilman, Vladimir, and Dean, Ward. The Neuroendocrine Theory of Aging, 1992, The Center for Bio-Gerontology, Pensacola, Florida.

2. Stevens, June, Jianwen Cai, Pamuk, Elsie R., et al. The effect of age on the assoication between body mass index and mortality. The New England Journal of Medicine, Vol 338, No 1, 1998, 1-7.

3. Nestler, John E., Clore, John N., and Blackard, William G. Regulation of dehydroepiandrosterone metabolism by insulin, and metabolic effects of dehydroepiandrosterone in man. The Biologic Role of Dehydroepiandrosterone in Man, 1990, by M. Kalimi and W. Regelson (eds), de Gruyter, New York.

Dean, Ward. Biological Aging Measurement—Clinical Applications, 1988, The Center for Bio-Gerontology, Pensacola, Florida.

Dilman, Vladimir, and Young, Jack. Development, Aging and Disease, 1994, Harwood Academic Publishers, Langhorne, Pennsylvania.

Klatz, Ronald, and Kahn, Carol. Grow Young with HGH, 1997, Harper Collins, New York.

Walford, Roy L., Maximum Life Span, WW Norton & Company, New York, 1983