Neuroendocrine Theory of Aging Chapter 7, Part 3

Restoring Receptor Sensitivity

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 sensitivity to feedback inhibition by hormones and neurotransmitters. (1-3) 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), discussing causes of loss of receptor sensitivity (receptor downregulation), and presenting evidence of the receptor-sensitizing effects of Metformin, Aminoguanadine/ Goats Rue, and DHEA. In the second part some causes of receptor loss (alteration of neurotransmitter levels) and approaches to 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).

This installment will review a number of other substances that are also postulated as cell receptor sensitizers, which all may find a prominent place in a comprehensive anti-aging program.

Ca-2 AEP

The calcium salt of 2-aminoethanol phosphate (Ca-2-AEP) has been known as vitamin MI in German literature. Ca-2-AEP is an essential factor for cell membrane integrity and cell sensitivity. It binds fatty acids and electrolytes to the cell membrane structure that generates the cells electrical charge. Studies over the last 30 years have shown that Ca-2-AEP is essential for neurotransmission, nerve impulse generation, and muscular contractions. Ca-2-AEP also acts as a cell membrane sealer and protector, and increases the activity of various neurotransmitters (i.e., improves receptor sensitivity). Deficiencies of 2-AEP have been implicated in various degenerative disorders, including multiple sclerosis, diabetes, osteoporosis, lung diseases, and cellular aging. (4) There are no studies that I know of which demonstrate the effects of Ca-AEP on receptors. However, because of its benefits to cellular membranes, and the wide-ranging benefits attributed to it, I think Ca-AEP may obviously improve cellular membrane signaling and receptor sensitivity.

Blueberries, Spinach, Strawberries

Scientists from the US Dept. of Agriculture, Tufts University, studied the effects of dietary supplements of strawberries, spinach or blueberries on age-related deficits in old (19 months) rats. (5,6) The scientists found that these supplements enhanced cognitive behavior, signal transduction (transmittal of a neurotransmitter or hormonal signal), psychomotor performance, and muscarinic receptor sensitivity (muscarinic receptors are responsible for some of the stimulatory actions of acetylcholine on smooth muscles and glands).

The scientists concluded that dietary supplements with fruit or vegetable extracts that are high in phytonutrient antioxidants can actually reverse some of the age-relatedneuronal/behavioral dysfunctions. The blueberry-supplemented animals showed the greatest increases in several sophisticated tests of neurotransmitter receptor sensitivity. These analytical tests of receptor-sensitivity included carbachol-stimulated GTPase activity (Fig. 1), oxotremorine-enhanced release of dopamine (Fig. 2), and rod walking (a
test of psychomotor performance) (Fig. 3). (5) The scientists found that the greatest age-related reversals and neurotransmitter receptor sensitivity improvement were caused by blueberries, followed by spinach and strawberries.


Phosphatidylserine (PS)

Dilman recommended the Dexamethasone Suppression Test (DST) as a biomarker for determining the biological age of the adaptive homeostat. The DST is shown, in most studies, to become worse with age. In a study of women undergoing gynecologic surgery, Dilman showed that the bodys response to surgical stress is greater and more prolonged as age increases (Fig. 4). He also found that those who had the better responses to the long DST had more rapid recoveries and fewer complications from surgery.

The DST is also a standard diagnostic test for depression. In a study on the antidepressant effects of the phospholipid phosphatidylserine, the DST was used to confirm the efficacy of phosphatidylserine. The study involved 30 elderly depressed patients. After 60 days, on 400 mg phosphatidylserine per day, the majority of patients noted improvements in mood, which were confirmed with psychological testing and the DST. Improvement in the DST confirms that phosphatidylserine is a cortisol receptor sensitizer — resulting in normalized levels of cortisol, and better utilization of these reduced amounts of cortisol.

Thus, although phosphatidylserine is best known as a cognitive-enhancing brain nutrient (see review in: Smart Drugs II — The Next Generation), phosphatidylserine is also a very effective antidepressant. The antidepressant effects of phosphatidylserine are believed to be due to its normalization of the adaptive homeostat (hypothalamo-pituitary-adrenal axis) (Fig. 5).

Cortisol is the bodys principal anti-inflammatory hormone, which, as previously stated, rises during stress and aging. Chronic elevations of cortisol (whether from stress or aging itself) result in elevations of glucose and insulin, loss in bone density, and decrease in muscle mass. When these changes are pronounced, they can cause a Cushingoid appearance (Fig. 6).

Phosphatidlyserine, by normalizing cortisol-receptor sensitivity, may thereby protect against cortisol-induced brain damage, weight gain, muscle atrophy, and accelerated aging (see review in: (Kidd and Dean, 1997). (7)

In addition to normalizing cortisol receptors, scientists have also demonstrated that phosphatidylserine improves receptor sensitivity to prolactin. (8) Prolactin levels tend to increase with age. Elevations in prolactin are also associated with reduced libido and increased incidence of impotence in men, reduced levels of growth hormone, and increased body fat. Normalizing prolactin receptors may be a contributing mechanism in the many positive effects of phosphatidylserine. In this regard, S-adenosylmethionine [SAMe] has also been reported to restore prolactin receptor sensitivity. Finally, it is probably the acetylcholine receptor-sensitizing effects of
phosphatidylserine that contribute to its beneficial effects on cognitive performance. (9)

Acetyl-l-Carnitine (ALC)

Stress can also upset the reproductive homeostat (hypothalamo-pituitary-ovarian axis) in animals and humans. For example, chronic stress often causes hypothalamic amenorrhea in women, and suppresses testosterone in male rats. (10) Italian scientists investigated the effect of ALC on rats subjected to chronic stress, and found that ALC normalized blood testosterone levels, as well as hypothalamic beta endorphin (BEP) and gonadotropin releasing hormone (GnRH) concentrations (Fig. 7). The scientists hypothesized that ALC restored luteinizing hormone (LH) pulsatility by stimulating gonadotropin releasing hormone (GnRH) release from the hypothalamus. They proposed that these effects were due to ALCs ability to activate (i.e., resensitize/upregulate) cholinergic, serotonergic, and GABA-ergic neurotransmitter systems. (11) Furthermore, Pattacchioli, et al, emphasized that ALC has also been demonstrated to reduce the age-related loss of cortisol receptors as well (12) [In this regard, I think ALC could probably be synergistic with PS in normalizing the adaptive homeostat (H-P-A axis), as well].

In a previous article I discussed the youth-restoring effects of ALC on mitochondrial membranes (Dean, 1997) in terms of ALCs ability to completely restore mitochondrial cardiolipin levels in old mice to those of young mice. (13) I think it may be this fundamental membrane-rejuvenating effect which causes the multiple receptor-sensitizing effects of ALC.

Tribulus terrestris (Puncture vine)

Tribulus is an herb that has been used since ancient times in India and Eastern Europe as a treatment for both male and female sexual problems. It has been tested in Bulgaria for its efficacy in enhancing sperm quality and mobility, and for increasing libido and sexual performance in experimental animals, and in both men and women. It has been claimed to stimulate ovulation, and to alleviate perimenopausal and postmenopausal symptoms in women. It is also widely used as a body-building and ergogenic substance.

The actions of Tribulus are complex. Tribulus is a non-hormonal product that seems to have hormonal effects. Tribulus administration purportedly results in an increase of LH levels by 72%, and free testosterone levels by 41%. (14) It is believed to act at the hypothalamic level by increasing the secretion of LH (but not FSH), resulting in an elevation of testosterone. Tribulus is also believed to have a direct sensitizing action on the Leydig cells of the testes, which produce testosterone in response to LH. Since Tribulus also enhances spermatogenesis, it presumably acts by enhancing the activity of FSH upon the Sertolli (sperm-producing) cells in the testes, since FSH levels do not increase.

Because of the variety of beneficial effects of Tribulus on the hypothalamo-pituitary-gonadal (H-P-G) axis of both men and women, and its normalizing action on the hormonal profile (without resulting in loss of feedback inhibition), I think Tribulus may be a premier resensitizer of the HPG axis. Although Tribulus has been used by men more frequently than by women, I think Tribulus can be used with equal benefit by women. Tribulus appears to be a means of reducing the requirement for hormone replacement therapy in both men and women. In addition, by its receptor-sensitizing effects, it is likely that Tribulus can enhance the benefits of hormone replacement therapy, while simultaneously minimizing adverse effects and receptor downregulation.

Vitex agnus castus (Chaste Berry)

Chaste berry (Vitex) is an herb that has traditionally been used to treat a variety of menopausal symptoms in women. It appears to act at the hypothalamic level, by increasing secretion of LH and decreasing FSH. (15) This helps to restore gonadotropin levels to a more youthful profile (Fig. 8). Chaste berry also causes a relative increase in progesterone and a relative decrease in estrogens. Although Chaste berry has primarily been used by women, I believe that it may have beneficial effects on men, as well. Experience with this herb in men is limited, however.


Forskolin is an extract of an Ayurvedic herb, Coleus forskohlii. Coleus has been used traditionally for a wide variety of conditions, including cardiovascular disease, abdominal colic, respiratory disorders, painful urination, insomnia, and convulsions. (16) One explanation for the diversity of benefits attributed to forskolin is its ability to activate the enzyme, adenylate cyclase (Fig. 9). Adenylate cyclase, in turn, increases cyclic adenosine monophosphate (cAMP) in cells. Cyclic AMP is an extremely important signal carrier, or cell-regulating compound. It activates many other enzymes involved in diverse cellular functions, and is necessary for the proper biological response of cells to hormones. It is required for cell communications in the hypothalamic/pituitary axis and for the feedback control of hormones. Cyclic AMP is essential to synthesize and regulate thyroid hormones, growth hormone, cortisol, DHEA, testosterone, melatonin and other hormones. Adenylate cyclase is incorporated into all cellular membranes, and it is only the specificity of the receptor which determines which hormone will activate it in a particular cell. Forskolin appears to bypass the need for direct hormonal activation of adenylate cyclase.

Conditions in which a decreased level of cAMP is thought to be a major factor include asthma and other allergic conditions, psoriasis, angina, hypertension, congestive heart failure, glaucoma, obesity, hypothyroidism, and depression. Forskolin has even shown promise as an anti-cancer agent. (17) Although forskolins effect on receptors has been mixed, (it appears to restore or bypass beta receptors, but may enhance desensitization of nicotinic cholinergic receptors by mechanisms other than its cAMP-stimulating effects) overall, I think that forskolins receptor-agonizing (resensitizing) properties predominate, as indicated by its broad range of beneficial therapeutic effects.18,19


The above-discussed substances all share a number of characteristics. They all have positive effects on a number of pathological conditions. They all have multiple mechanisms of action. They all are either demonstrated or hypothesized to restore receptor sensitivity — most to more than one stimulating hormone or neurotransmitter — and to improve neurotransmitter and/or hormonal response. Finally, they are all virtually without toxicity.

Ca-AEP and forskolin are likely broad-spectrum and non-specific. ALC and SAMe seem to operate to enhance the adaptive, energy and reproductive homeostats; Blueberries may improve the energy homeostat (muscarinic/cholinergic receptor sensitizer); and Tribulus and Vitex most likely act on the reproductive homeostat.

Choice of which of these substances to use depends on the homeostat(s) that are principally involved, (i.e., reproductive, energy, immune, or adaptive). Obesity, for example, could involve contributions from dysfunction of the energy, adaptive, or reproductive homeostats, and diabetes is due to energy and/or adaptive homeostat dysfunction.

Additional receptor-sensitizing substances and their uses will be discussed in the next installment.

1. Dilman, V.M. The Law of Deviation of Homeostasis and Diseases of Aging, John Wright PSG, Boston, 1981.

2. Dilman, V.M., and Young, J.K. Development, Aging and Disease — A New Rationale for an Intervention Strategy. Harwood Academic Publishers, Chur, Switzerland, 1994.

3. Dilman, V.M., and Dean, W. The Neuroendocrine Theory of Aging and Degenerative Disease, The Center for Bio-Gerontology, Pensacola, Florida, 1992.

4. Nieper, H.A. Revolution in Technology, Medicine and Society. MIT Verlag, Oldenburg, 1985.

5. Joseph, J.A., Shukitt-Hale, B., Denisolva, N.A., Prior, R.L., et al. Long-term dietary strawberry, spinach, or Vitamin E supplementation retards the onset of age-related
neuronal signal-transduction and cognitive behavioral deficits. J Neurosci, 1998, 18: 19, 8047-8055.

6. Joseph, J.A., Shukitt-Hale, B., Denisolva, N.A., Bielinski, D., et al. Reversals of Age-Related declines in neuronal signal-transduction, cognitive and motor behavioral deficits with blueberry, spinach, or strawberry dietary supplementation. J Neurosci, 1999, 19: 18: 8114-8121.

7. Kidd, P. M., and Dean, W., Phosphatidylserine: The remarkable brain cell nutrient. VRP Nutritional News, Vol. 11, No. 6, June, 1997, 1-7.

8. Di Carlo, R., Muccioli, G., Ghe, C., Bellussi, G., Ravetti, D., and Genazzani, E. Phosphatidylserine activity on prolactin brain receptors of aged rabbits. Prog Neuro Psychopharmacol & Biol Psychiat, 1988, 12: 915-926.

9. Pepeu, G., Vannucchi, M.G., and Spignoli, G. Cognitive deficits and cholinergic mechanisms in aging brain: Investigations on potentially useful drugs. Ann Inst Super Sanita, 1988, 24: 3, 411-416.

10. Genazzani, A.D., Petraglia, F., Algeri, I., Gastaldi, et al. Acetyl-L-carnitine as possible drug in the treatment of hypothalamic amenorrhea. Acta Obstet Gynecol Scand, 1991, 70: 487-492.

11. Bidzinska, B., Petraglia, F., Angioni, S, et al. Effect of different chronic intermittent stressors and ALC on hypothalamic beta-endorphin and GnRH and on plasma testosterone levels in male rats. Neuroendocrinology, 1993; 57: 985-990.

12. Patacchioli, F.R., Amenta, F., Ramacci, M.T., Taglialatela, G., Maccari, S., and Angelucci, L. Acetyl-L-carnitine reduces the age-dependent loss of glucocorticoid receptors in the rat hippocampus: An autoradiographic study. J Neuroscience Research, 1989, 23: 462-466.

13. Dean, W. Rejuvenating effects of ALC (acetyl-L-carnitine), Vitamin Research Products Nutritional News, 1997, 11: 10, 1-6.

14. Chemical Pharmaceutical Institute, Sofia, Bulgaria. Review of scientific literature. Product Literature.

15. Wright, J.V., and Morgenthaler, J. Natural Hormone Replacement for Women over 45. Smart Publications, Petaluma, 1997.

16. Ammon, H.P.T., and Muller, A.B. Forskolin: From Ayurvedic remedy to a modern agent. Planta Medica, 1985, 51: 473-477.

17. Agarwal, KC and Parks, R.E. Forskolin: A potential antimetastatic agent. Int J Cancer, 1983, 32: 801-804.

18. Leamon, K.B., Padgett, W., and Daly, J.W. Forskolin: Unique diterpene activator of adenylate cyclase in membranes and intact cells. Proc Natl Acad Sci USA, 1981, 78: 3363-67.

19. Laurenza, A., Sutkowski, E.M., and Seamon, K.B. Forskolinn: A specific stimulator of adenylyl cyclase or a diterpene with multiple sites of action? TIPS, 1989, 10: 442-446.

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