The Metabolic Pattern of Aging

By Ward Dean, MD

Introduction: The seeds of the neuroendocrine theory of aging were originally sown by Prof. Vladimir Dilman in the 1960s. Dilman’s theory explained and preceded by decades the currently popular Syndrome X. Syndrome X is a symptom complex manifested by hyperinsulinemia (excess blood insulin), hypertension, and coronary artery disease. While mainstream medicine is finally beginning to recognize the role of insulin resistance in these conditions, Dilman’s comprehensive hypothesis explained not only the link between hypertension and coronary artery disease, but also most other commonly occurring age-related diseases, including obesity, diabetes, and cancer. Dilman elegantly detailed the role of insulin resistance while addressing the critical aspect of the progressive loss of central and peripheral receptor sensitivity to feedback inhibition by hormones and neurotransmitters. (1-3) The neuroendocrine theory details how this loss of central and peripheral receptor sensitivity affects the body’s four principal hemostats — energy, adaptive, reproductive, and immune — resulting in a progressive shifting of homeostasis throughout the lifespan. This causes hormonal and metabolic shifts that result in aging and the diseases of aging.

Metabolic Pattern of Aging

Dilman referred to the characteristic age-related physiological and biochemical alterations that occur with the shifting of homeostasis in the body’s principal homeostats as the metabolic pattern of aging (MPA). This metabolic pattern includes: (1) reduced receptor sensitivity to insulin (insulin resistance); (2) obesity; (3) increased mobilization and utilization of fats and resultant altered lipid profile (characterized by elevated VLDL, LDL, triglycerides, and total cholesterol); (4) relative hypercortisolemia (elevated cortisol and decreased DHEA) and alteration in the dexamethasone sensitivity test (DST); (5) decreased androgen output in men; (6) increased gonadotropins (LH and FSH); (7) decreased cellular immunity and increased incidence of autoimmune antibodies; (8) elevated blood pressure; and (9) functional hypothyroidism (Table 1).

Dilman demonstrated that the metabolic pattern of aging is characteristic of the age-related diseases that are caused by the neuroendocrine mechanism. These diseases include: (1) obesity; (2) diabetes (and pre diabetes); (3) hypertension; (4) atherosclerosis; (5) depression; (6) diseases related to immune dysfunction (Metabolic Immunodepression) and (7) cancer.

Dilman also described an age-related syndrome which he named (8) Hyperadaptosis. Hyperadaptosis is also sometimes known as adrenal maladaptation syndrome, or even adrenal burnout. Hyperadaptosis results from cortisol resistance and hypercortisolemia. Hyperadaptosis is, to the adaptive homeostat (hypothalamo-pituitary-adrenal axis), what diabetes is to the more complex energy homeostat.

Another condition which Dilman included as a disease is (9) the climacteric, or menopause. The reason Dilman referred to the climacteric as a disease is because he defined a disease as any chronically altered (post-maturational) change in a physiological, biochemical or metabolic parameter. Although similar changes occur in men over time, the shift does not occur as dramatically in men as it does in women. Also, the climacteric reflects the ending of the cycling of hormone levels in women (which of course, does not occur in men) (Table 2).

Dilman clearly showed that the aging related diseases caused by the neuroendocrine mechanism share many aspects of the metabolic pattern of aging (Table 3).

Syndrome X and the Neuroendocrine Theory

In 1988, Stanford’s Dr. Gerald Reaven proposed a new condition — Syndrome X. Syndrome X, as described by Reaven, included insulin resistance, hyperinsulinemia, impaired glucose tolerance (IGT), and altered lipid profile (high triglycerides, low HDL, high LDL and VLDL), which resulted in hypertension and coronary artery disease. (4) Reaven overlooked the role of hyperinsulinemia (and other metabolic changes) that occur in the other diseases of aging which share this metabolic pattern. Although Syndrome X is now widely recognized by physicians and scientists, Dilman’s name is rarely cited, despite the fact that further research findings with every passing year confirm that his early theoretical concepts and research findings were correct.

Anti-Aging Approaches Based on the Neuroendocrine Theory

Dilman proposed a number of ways to delay aging and restore a more youthful internal milieu based on his theory. These anti-aging measures include: (1) hormonal replacement therapy; (2) prevention of adverse hormonal effects; (3) normalization of metabolic processes; (4) enhancement of intracellular bioenergetics; and (5) restoration of hypothalamic and peripheral receptor sensitivity. The largely unrecognized and undeveloped approach, which I think offers the greatest imwww.e promise of success, is number five — restoring hypothalamic and peripheral receptor sensitivity to more youthful levels.

Dilman predicted that restoring central and peripheral receptor sensitivity would literally rejuvenate the various homeostats, thereby retarding aging and delaying the onset of age-related, chronic degenerative diseases. He tested a number of pharmaceutical and nutritional regimens designed to accomplish this goal. Among the most effective anti-aging/ receptor-sensitizing substances he found were the anti-diabetic biguanide drugs (Phenformin, Metformin) and the anti-seizure medication, Dilantin (Phenytoin). He demonstrated the ability of both phenformin and Dilantin to normalize the metabolic pattern of aging and increase the maximum lifespan of experimental animals over a quarter of a century ago. (5) The biguanide Metformin (Glucophage) is now widely used in research and clinical medicine.

The herbal prototype of metformin is the herb Galega officinalis (Goat’s Rue), which contains the bioequivalent of the substance aminoguanidine, which is closely related to the drugs phenformin and metformin. A number of other receptor sensitizers have been described in previous articles in this series, which are summarized in Table 4.

This array of hypothalamic and peripheral resensitizers may seem overwhelming and confusing at first. Note that the Receptors/Homeostats affected are sorted roughly in descending order from left to right (i.e., the receptors/ homeostats on the left are generally affected by more substances than those on the right), and the receptor sensitizing substances are sorted in descending order of the number of receptors known to be affected from top to bottom. Those substances at the top of the chart are known or thought to affect more receptors than substances at the bottom of the chart.

Use of these substances remains an art or matter of judgment, as comparative studies of combinations of substances that act on the same receptors or homeostats have rarely been done. Consequently, optimum combinations of these substances remain an area that is ripe for further research.

When selecting receptor sensitizers, I suggest that only one substance in a closely related class be taken. For example, Metformin, aminoguanidine, and Goat’s Rue Extract probably all share very similar properties, due to their similar chemical structure and biological effects. Alternatively, if more than one similar-acting substance is taken, the dose of each should probably be reduced proportionately. This principle should also apply to combinations of GH3, Centrophenoxine, or DMAE plus PABA, which also all act in a similar fashion.

References

1. Dilman, V. The Law of Deviation of Homeostasis and Diseases of Aging, 1981.
2. Dilman V., and Dean, W. The Neuroendocrine Theory of Aging and Degenerative Disease, Pensacola, FL, 1992.
3. Dilman V., and Young, J. Development, Aging and Disease, Harwood Academic Press, Langhorn, Pennsylvania, 1994.
4. Reaven, G.M. Role of insulin resistance in human disease. Diabetes, 1988, 37: 1595-1607.
5. Dilman, V., and Ansimov, V. Increase of hypothalamus sensitivity to inhibitory action of estrogens, caused by L-dopa, Dilantin, epithalamin and phenformin in old rats. Biull Eksp Biol Med, 1975, 79: 96-98.