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Neuroendocrine Theory of Aging: Chapter 3, Part 1:

Energy Homeostat Dysfunction 

Ward Dean, MD

Editors Note: We recommend that Chapters I and II be read first, in order to better appreciate this article.

Introduction: The 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.  (Fig. 1?)

Part I introduced: (1) the concept of homeostasis, (2) how homeostasis shifts over our lifespans, and (3) how these changes result in growth, development and aging (Dilman [1983] proposed that the homeostatic shifting is due to a progressive loss of hypothalamic and peripheral receptor sensitivity to inhibition by hormones and other signaling substances by the four homoeostatic systems in the body).

Humans and all living organisms are characterized by their capacity to (1) reproduce, (2) adapt, (3) regulate the flow of energy, and (4) protect themselves. Consequently, we 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.

Part II discussed how aging and stress combine to accelerate changes in the adaptive homeostat, resulting in the age-related disease, “hyperadaptosis.”

The Energy Homeostat

The energy homeostat is responsible for the production, utilization and regulation of energy. Energy system dysfunction causes the age-related reduction in intensity and amount of activity as well as increased fatigue and reduced energy.   In addition, energy homeostat dysfunction causes the age-related diseases of (1) diabetes, (2) obesity, (3) “essential” hypertension, (4) atherosclerosis, (5) depression and (6) fatigue itself.  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).

(Fig 1)

Unlike the adaptive homeostat, which is represented by a classic cybernetic system (the hypothalamus-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 (discussed in this article). Second is the hypothalamus-pituitary-thyroid axis.   The third component is the intracellular production of energy by mitochondria via the Krebs (citric acid) cycle and the intramitochondrial respiratory chain. All three of these components shift in adverse directions with age, resulting in reduced activity and impaired energy production and use, 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 performs a complex balancing act (Fig. 2).  This “system” 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, gherelin, leptin, ACTH and adrenal glucocorticoids; and the neurotransmitters epinephrine, norepinephrine, dopamine and serotonin. The effects of these other hormones aren’t discussed separately because they each act similarly to one or more of the four components of the energy homeostat.

In a healthy, youthful individual, 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 (fat-mobilizing) properties. Consequently, unless a carbohydrate-rich bedtime snack has been consumed, fatty acids are mobilized from the fat stores, fats become the primary energy source, so that glucose can be  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).

(Fig. 3)

This turns the aged energy homeostat into a headless three-component system (Fig. 4).

(Fig 4)

Simultaneously, our glucose tolerance and muscles’ ability to utilize glucose decreases, and insulin levels tend to increase (Fig. 5), resulting in hyperinsulinemia.

To illustrate the progressive loss of glucose homeostasis with aging, Dilman performed a glucose tolerance test on males and females ranging in age from 1  to 80 years old (Fig. 6). It’s clear that children from 4 to 10 years old have a very finely tuned energy homeostat in that there is a slight bump in insulin, with a rapid return to normal. With age, we see that insulin goes progressively higher and stays elevated longer until finally, in the advanced years, insulin just stays up, resulting in chronic hyperinsulinemia.

Dilman proposed this concept of age-related hyperinsulinemia back in the late 1960s and early 1970s. He was roundly criticized for this by no less a person than Dr. Nathan Shock—one of the most prominent gerontologists in the world at the time. Dr. Shock wrote several paragraphs about Dilman’s “erroneous” concept and dismissed his theory as being of little value (Shock, 1977).   However, it is Shock’s ideas in this regard that have been found to be erroneous.

Today, we often hear the term “Syndrome X,” which describes an aging-related  condition characterized by hypertension, coronary artery disease, and hyperinsulinemia, which was first described in 1985 by Reaven. However, none of the articles in any of the major medical journals about Syndrome X ever mention the contributions of Vladimir Dilman and his prophetic concepts. It should be noted that Dilman described age-related hyperinsulinemia and other metabolic abnormalities as the metabolic pattern of aging, and associated it with all of the diseases of aging as early as 1975 (Table 1).

Hyperinsulinemia has been correlated with hypertension, atherosclerosis and cancer.  This combination has become known as Syndrome X. 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—and dubbed it the metabolic pattern of aging.

This combination of metabolic changes with age—increase in blood glucose, fatty acids and insulin, and reduction in growth hormone, leads to an increase in body fat and reduction in lean body mass. Consequently, even if body weight doesn’t increase with age, the percentage of body fat does, while the percentage of bone and muscle decreases. These changes are reflected in the body mass index (BMI).  Body Mass Index changes with age are so predictable that BMI  [explain how to measure BMI] appears to be a biomarker of aging (Stevens, et al, 1998).   [reference to BAM and Inner Age]

What Causes Age-Related Energy Homeostat Dysfunction?

Dilman hypothesized that a major cause of these changes was the age-related change in the number and balance of hypothalamic neurotransmitters—particularly the dopaminergic neurotransmitters (epinephrine, norepinephrine, and dopamine) and serotonin.  Unfortunately, the causes of the age-related decrease in growth hormone secretion and changes in hypothalamic sensitivity to feedback inhibition remain speculative.

(Fig. 5)

Dilman suggested that one cause may be the loss of diurnal (daily) regulation of the hypothalamus by pineal gland secretions (melatonin and other peptides].   Melatonin secretion from the pineal is one of the most dramatic age-related biomarkers known (Fig. 7). One 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.   This can be done by using the drugs Metformin, Dilantin, and Aminoguanidine, and/or natural insulin-sensitizers. Metformin (Glucophage) is an anti-diabetic drug which restores muscle and hypothalamic  insulin sensitivity and glucose utilization. Metformin users commonly report (1) enhanced sense of well-being, (2) increased energy, (3) reduced carbohydrate cravings, (4) lowered blood glucose  and insulin levels (but without causing hypoglycemia), (5) normalized lipid profile, and (6) inhibition of cancer.

Dilman believed that drugs like Metformin (bi-guanides, derivatives of the herb, Goat’s Rue) were “the most effective anti-aging drugs.” I routinely recommend 1,500-2,000 mg of Metformin daily for my patients over 35.

Dilantin is an anti-seizure medication which also restores hypothalamic sensitivity to insulin.  Dilantin raises HDL cholesterol levels, and improves 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 an overseas pharmacy like International Anti-Aging Systems (IAS) (www.antiaging-systems.com).

A dietary supplement alternative to Metformin is the herb Galega oficinalis (Goat’s rue).  Goat’s rue is the natural source of the herbal prototype of biguanide drugs like Metformin.    Another insulin sensitizing herb is Gymnema sylvestre.

4. Restore nighttime levels of growth hormone to more youthful levels: The decline in growth hormone secretion and release may be 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 drugs like GHB (Xyrem), L-dopa, niacin (vitamin B3), and the anti-hypertensive drug clonidine (Catapres).   I am equivocal about the benefits  of amino acid growth hormone releasers.  The data are all over the place, as demonstrated in a review article that Kim Pryor and I wrote (Dean and Pryor).  Although many people seem to benefit from various growth hormone releasing formulas, probably more don’t see much improvement.  I think younger people are more likely to derive benefit from growth hormone releasing amino acid formulations than older people.

5. Balance neurotransmitters (epinephrine, norepinephrine, dopamine, and serotonin): As mentioned above, one proposed 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) (Fig. 8).  It is possible to augment levels of these neurotransmitters by a number of dietary supplements (L-Phenylalanine, L-Tyrosine, Macuna puriens).  Thus, it may be possible, by balanced supplementation, to restore hypothalamic neurotransmitter balance, enhance hypothalamic sensitivity, and restore the homeostatic system to a more youthful state.

6. EDTA: Ethylene diamine tetra-acetic acid (EDTA) and other chelating agents are important in removing mitochondria-killing toxic heavy metals, as well as  metastatic calcium (calcium that has been deposited in unwanted locations like joints, arteries, and pineal gland). 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 many of the youth-promoting benefits that I have observed in many of my oral and IV chelation patients have been due to the elimination of metastatic calcium, to include that of the pineal. (See my articles on chelation therapy, which describes intravenous and oral chelation).

7. DHEA: DHEA, the most abundant steroid hormone in the body, is inhibited by insulin. Hyperinsulinemia has been speculated to be a cause of the age-related decline in DHEA (Fig. 9). DHEA-S levels have even been proposed as a biomarker of insulin sensitivity. Not surprisingly, DHEA supplementation appears to restore insulin sensitivity (Nestler, et al, 1990).  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.  The starting dose for women is usually 10-25 mg/day, unless more is clinically indicated (for example, women with Lupus and other inflammatory/autoimmune diseases can often take doses in excess of 100 mg per day, without unwanted effects).

A combination of these approaches may help to restore hypothalamic sensitivity, alleviate some of the metabolic abnormalities caused by energy homeostat dysfunction, and the energy homeostat to a more youthful state.
Next Chapter: Energy homeostat, Part 2.
References:
Dean, Ward. Biological Aging Measurement—Clinical Applications, 1988, The Center for Bio-Gerontology, Pensacola, Florida.

Dean, W., and Pryor, K.
Dilman, Vladimir, and Dean, Ward. The Neuroendocrine Theory of Aging, 1992, 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.

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.

Shock, N.W.  Systems Integration, in:  Handbook of the Biology of Aging, by Caleb Finch and Leonard Hayflick (eds), Van Nostrand Reeinhold, New York, 1977.

 

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.

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

 

[Need several References]

 

Captions for Figures:

 

Fig. 1.  Finishing times for runners of different ages in the New York Marathon (Walford, 1983).

 

Fig. 2.  The four-component growth hormone/insulin/glucose/fatty acid system that controls one aspect of the energy homeostat (Dilman, 1983).

 

Fig. 3.  Age-related decline in growth hormone (Klatz and Kahn, 1997)

Fig. 4.  Without the regulatory influence of growth hormone, the four component homeostat becomes a “headless” three component system (Dilman, 1983).

 

Fig. 5.  Age-related loss of glucose tolerance.

 

Fig. 6.  Age-related changes in insulin in response to glucose.  This shows that as we get older, insulin levels tend to rise higher and stay elevated longer, due to “insulin resistance.”  This results in obesity, diabetes, hypertension, and other diseases of aging.

Fig. 7.  Age-related decrease in melatonin levels.

Fig. 8.  Schematic illustrating age-related shift in balance of biogenic amine neurotransmitters (Dilman and Dean, 1992).

 

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