Restoring Receptor Sensitivity Part IV

By Ward Dean, MD

Introduction: The central element in the Neuroendocrine Theory of Aging as promulgated by Prof. Vladimir Dilman is the progressive loss of hypothalamic and peripheral receptor sensitivity to feedback inhibition by hormones and neurotransmitters. (1,2,3) This loss of central (hypothalamic) and peripheral receptor sensitivity causes a progressive shifting of homeostasis throughout the lifespan, causing hormonal and metabolic shifts that result in aging and the diseases of aging. This theory suggests a number of potential means to delay aging and restore a more youthful internal milieu (roughly translated, internal physiology). Dilman believed the most effective approach would be to restore hypothalamic and peripheral receptor sensitivity to more youthful levels. Accomplishing this feat would literally rejuvenate the various homeostats (adaptive, energy, reproductive, and immune), delay aging, and prolong the life span.

The first part of Chapter Seven expanded the concept of restoring receptor sensitivity (receptor upregulation), discussed causes of the loss of receptor sensitivity (receptor downregulation), and presented evidence of the receptor-sensitizing effects of Metformin, Aminoguanidine/Goats Rue, and DHEA. In the second part, some causes of receptor loss (alteration of neurotransmitter levels) and means of restoring neurotransmitter levels to normal were suggested. These included: neurotransmitter precursors like tyrosine, phenylalanine, GABA, L-dopa, tryptophan and 5-HTP; Monoamine Oxidase Inhibitors (MAOI) like Deprenyl, and St. Johns Wort; hormones like melatonin and the polypeptide-free pineal extract, Epithalamin™, and Epithalamins active component, Epithalon™, and the neuropeptide vasopressin (and vasopressin-containing posterior pituitary powder). The third part (Vitamin Research News, 2001, 15:7,1-10) reviewed the receptor-sensitizing characteristics of CaAEP, blueberries, phosphatidylserine (PS), acetyl-L-carnitine, Tribulus terrestris; Vitex agnes castus (Chaste Berry), and forskolin.

This installment will further review a list of other substances also postulated to be cell receptor sensitizers that may find a prominent place in a truly comprehensive anti-aging program.

Chromium

Dr. Mark McCarty is a leading nutritional scientist and proponent of chromium picolinate. McCarty is aware of the age-related worsening of glucose tolerance (Fig. 1). McCarty proposed in 1993 that the effects of chromium were probably due to the same receptor-sensitizing actions as the anti-diabetic biguanides metformin and phenformin. (Phenformin is an analog of metformin, which is no longer available in the US). (4) The biguanides are chemically related to the natural substances aminoguanidine and guanidine. Guanidine is the active ingredient in the herb Goats rue (Goats rue is the herbal prototype for the synthetic biguanides).
The actions shared by chromium picolinate and the other insulin receptor sensitizers include: (1) reduction in body fat; (2) increased lean body mass; (3) reduction of glucose; (4) reduction of insulin, and (5) lowered Hemoglobin A1C. McCarty also showed that most of these effects have also been demonstrated with high-chromium content brewers yeast. Furthermore, both phenformin and chromium have been demonstrated to extend the maximum lifespan of experimental animals. (5,6) Evans more recent study appears to have confirmed the near-forgotten work of Byerum from the 1930s who demonstrated that sodium chromate added to the drinking water of rats enhanced their survival. (7)

McCarty concluded that the same receptor-sensitizing mechanism of guanadine, aminoguanadine, and the drug Metformin could explain the glucose and insulin-lowering effects of chromium picolinate. He also proposed that chromium possesses cortisol-receptor-sensitizing properties as well.

Vanadyl Sulfate

Vanadyl sulfate is a biologically active form of vanadium. Vanadyl (like chromium) also enhances the actions of insulin and improves glucose tolerance by restoring muscle and hypothalamic receptor sensitivity to insulin. Vanadyl sulfate is an important supplement for both insulin dependent and non-insulin dependent diabetics. The effectiveness of vanadyl sulfate in restoring insulin sensitivity was demonstrated in a recent study in which eleven Type 2 diabetics were given 150 mg of vanadyl sulfate per day for six weeks. The majority experienced reduced blood glucose and HbA1c, improved performance on an oral glucose tolerance test (lower blood sugar and insulin), and improved lipid profile. The researchers concluded vanadyl sulfate…improves glycemic control…by enhancing skeletal muscle insulin sensitivity. (8)

Cinnamon

Cinnamon has also begun to be more widely recognized for its insulin-receptor-sensitizing effects (at last, something that tastes good is actually good for us). Scientists at the Beltsville Agricultural Research Center in Beltsville, Maryland, and the Department of Biochemistry and Biophysics, Iowa State University, studied a constituent of cinnamon known as methyl hydroxy chalcone polymer (MHCP). (9,10) They found that MHCP increased glucose metabolism fifteen times in in-vitro (cellular) studies. They proposed that MHCP inhibits the activity of tyrosine phosphatase, an enzyme that inactivates insulin receptors. Inactivation of this enzyme leads to resensitization of the insulin receptors. The researchers proposed that cinnamon may alter glucose and insulin metabolism and may be beneficial in the control of glucose intolerance and diabetes.

Statin Drugs and Red Yeast Rice Extract

A great deal has been written – both good and bad – about the lipid-lowering statin drugs like Lipitor, Zocor, Mevacor, Lescol and Pravachol. On the one hand, statins have been reported to increase bone density, reduce CRP and fibrinogen, increase HDL and reduce LDL cholesterol, and reduce overall mortality. On the other hand, statin drugs have been associated with a number of adverse side effects, ranging from muscle cramps and physical weakness, to life-threatening liver damage, which resulted in one of the drugs being removed from the market by the FDA. (Occasionally they do something right.) Biochemically, statin drugs are known to deplete CoQ10, which could partially or completely explain their adverse effects.

Recently, scientists in Ireland demonstrated that statin drugs also increase insulin [receptor] sensitivity. (11) In the study, 195 non-insulin-dependent diabetics with a mean age of 67, took simvastatin (10 mg/day), atorvostatin (5 mg/day) or placebo. Triglyceride levels dropped 20% and 26% in the atorvostatin and simvastatin groups, respectively  –  and glycosylated hemoglobin (HbA1c) (an indicator of glucose tolerance) dropped 11.2 and 7.1%. The researchers concluded that statins are useful for controlling dyslypidemia in NIDDM and for improving metabolic control.

I dont know of any study conducted to determine if CoQ10 replacement will alleviate the adverse effects of statin drugs, but anecdotal reports from many of my patients report that it does. When the decision is made to use a statin drug, I always recommend concomitant CoQ10.

Red yeast rice extract  –  a substance that has been safely consumed in China for 3,000 years  –  is the natural biochemical prototype for these synthetic statin drugs. Although red yeast rice extract appears to be much safer than the pharmaceutical statins, reports of rare elevations of liver enzymes have been received. Consequently, I believe liver enzymes should be monitored at least once after initiation of supplementation with red yeast rice extract. Also, anyone with a history of liver disease should probably use red yeast rice extract only under a physicians supervision.

Cell-Regulating and Receptor-Resensitizing Essential Fatty Acids (GLA, Hemp Oil, Flax Seed, EPA)

In the body essential fatty acids are converted into prostaglandins. Prostaglandins are cell regulators that exhibit what is, to some, a bewildering array of actions. Among these are the ability to modify pituitary responses to hypothalamic hormones, including thyroid-stimulating hormone (TSH) and adrenocorticotropic hormone (ACTH). In addition, prostaglandins help regulate the release of free fatty acids, may alter the release or effects of neurotransmitters, and restore insulin sensitivity. (12) Cyclic adenosine monophosphate (cAMP) is involved in most, if not all of these reactions. Cyclic AMP is necessary for proper cell sensitivity and biological responses. A deficiency of essential fatty acids can thus lower cell receptor sensitivity, resulting in hormonal imbalances and cellular dysfunctions that produce disease.

Good sources of essential fatty acids include: Gamma Linolenic Acid (GLA), from Evening Primrose and Borage Seed oil; Medium Chain Triglycerides (MCT), from Flax Seeds, Hemp Oil and Coconut Oil; and Eicosapentanoic Acid (EPA), from Fish Oil.

Tryptophan, 5-hydroxytryptophan (5-HTP), and Adaptogenic Substances

As mentioned previously, Dilman recommended the Dexamethasone Suppression Test (DST)  –  a standard diagnostic test for depression  –  as a biomarker for determining the biological age of the adaptive homeostat. The DST is an indicator of the sensitivity of cortisol receptors in the hypothalamus. A short DST involves measuring cortisol at 9 AM., and then giving 0.5 mg of Dexamethasone (a potent synthetic corticosteroid) orally at 11 PM. Cortisol is measured again at 9 AM the next day. A normal test is considered to be a blood cortisol level that is 40% less on the second day than the first.

Hypothalamic cortisol receptors become progressively less sensitive with age, indicated by a worsening of the DST. In a study of women undergoing surgery, Dilman showed that the bodys response to surgical stress is greater and more prolonged as age increases (Fig.2). This results in the body being pummeled by chronically elevated levels of cortisol, a catabolic (tissue-destroying) hormone. Dilman found that those who had the better responses to the DST had more rapid recoveries and fewer complications from surgery, due most likely to the more rapid normalization of cortisol levels. Scientists in Japan recently confirmed that blood cortisol levels were highest in patients with Alzheimers disease and vascular dementias. (13)

Dilmans associates used tryptophan to normalize the dexamethasone-suppression-test (DST) in depressed patients (Table A). (14) Dilman interpreted these findings as a demonstration of tryptophans ability to reestablish the equilibrium of the adaptive system  –  i.e., to normalize the stress response. Presumably, 5-hydroxytryptophan would share the effects of tryptophan. (Fig. 3)
Normalizing the stress response involves enhancing the physiological effects of cortisol, resulting in lower cortisol levels and reduced cellular damage due to chronically elevated cortisol levels. Among these damaging effects include: the loss of brain cells  –  a key factor in the development of Age Related Memory Impairment (ARMI) and Alzheimers disease  –  reduction in glucose tolerance, increased body fat, and loss of bone density (osteoporosis).

Other substances, in addition to tryptophan, which have demonstrated DST cortisol-lowering effects are adaptogenic substances like Panax (Korean) Ginseng, Siberian Ginseng (Eleutherococcus synensis), Manchurian Thorn Tree, Echinopanax elatum, Schisandra, and others. (15) [See the accompanying article on Adaptogens in this issue of VRN.]

Conclusion

This is the fourth part of Chapter Seven of the Neuroendocrine Theory of Aging. Although this chapter just seems to go on and on, it addresses what I think is one of the most profound but generally overlooked approaches to anti-aging therapy recommended by Dilman  –  that of restoring hypothalamic and peripheral receptor sensitivity to the inhibitory effects of hormones, neurotransmitters and neuropeptides.

Dilman made a major contribution in recognizing and describing the syndrome that is now known as Syndrome X. Syndrome X is a constellation of degenerative diseases, including atherosclerosis, hypertension, and diabetes, with hyperinsulinemia as their common biochemical abnormality. Dilman described this syndrome in English in The Lancet in 1971  –  and much earlier, in Russian. (16,17)
Based on his theory, Dilman believed that anti-diabetic biguanide drugs like phenformin and metformin  –  which were derived from the active ingredient in the herb, Goats Rue  –  were the most effective available anti-aging substances, as long ago as the mid-1970s. (18) Despite his numerous contributions, I think he only began to scratch the surface of utilizing receptor sensitizers (also known as upregulators, or Biological Response Modifiers, [BRMs] in current terminology) as anti-aging agents.

Next: Chapter Seven, Part Five

References:
1. Dilman, V.M. The Law of Deviation of Homeostasis and Diseases of Aging, John Wright, Littleton, 1981.
2. Dilman, V.M., and Dean, Ward. The Neuroendocrine Theory of Aging and Degenerative Disease. The Center for Bio-Gerontology, 1992, Pensacola, Florida.
3. Dilman, Vladimir. Development, Aging and Disease  –  A New Rationale for an Intervention Strategy, 1994, Harwood Academic Publishers, 820 Town Center Drive, Langhorne, Pennsylvania 19047.
4. McCarty, M. Homologous physiological effects of phenformin and chromium picolinate, Medical Hypotheses, 1993,1993, 41: 316-3224.
5. Diman, V.M., and Anisimov, V. N. Effect of treatment with phenformin, diphenylhydantoin and L-dopa on the life-span and tumor incidence in C3H/Sn mice. Gerontology, 1980, 26: 241-245.
7. Mertz, W. Chromium in biological systems. Physiol Rev, 1969, 49: 163-239.
8. Cusi, K., Cukier, S., DeFronzo, R.A., Torres, M., Puchulu, F..M., and Pereira Redondo, J.C. Vanadyl sulfate improves hepatic and muscle insulin sensitivity in Type 2 diabetes, J Clin Endocr Metab, 86: 1410-1417.
9. Anderson, R.A., Polansky, M.M., Leigh Broadhurst, C.L., et al. Isolation and characterization of a chalcone polymer from cinamon with insulin-like biological acitivity. J Amer Coll Nutr, 1998, 17: 504.
10. Radasevich, J, Deas, S., Polansky, M., et al Regulation of PTP-1 and insulin receptor kinase by fractions from cinnamon: Implications for cinnamon regulation of insulin signalling. Horm Res, 1998, 50: 177-182.
11. Paolisso, G., Barbagallo, M., Petrella, G., et al. Effects of simvastatin and atorvastatin adminitration on insulin resistance and respiratory quiotient in aged dyslipidemic non-insulin dependent diabetic patients. Atherosclerosis, 2000, 150 (1), 121-127.
12. Horobin, D.F., and Manku, M.S. An action of insulin revealed by PGE1 and prostacyclin. Washington, DC International Prostaglandin Meeting Abstracts, May 1979, p. 53.
13. Umegeki, H., Ikari, H., Nakahuta, H., et al. Plasma cortisol levels in elderly female subjects with Alzheimers disease: A cros-sectional and longitudinal study, Brain Research, 2000, 881: 241-243.
14. Ostroumova, M.N., Tsylina, E.V., Nuller, J.L., et al. Age-associated shift of homeostatic regulation in the adaptive homeostat and age-associated pathology. Hum Physiol, 1978, 4: 629-635.
15. Halstead, B.W. and Hood, L. Eleutherococcus senticosus  –  Siberian Ginseng: An Introduction to the Concept of Adaptogenic Medicine. Oriental Healing Arts Institute, Loma Linda, 1984.