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Neuroendocrine Theory of Aging Chapter 7, Part 2

Restoring Receptor Sensitivity Part II

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.(1,2,3) This loss of central (hypothalamic) and peripheral receptor sensitivity interferes with the bodys efforts to maintain physiological, endocrinological, and biochemical parameters within a relatively narrow range compatible with health and life. This progressive shifting of homeostasis throughout the lifespan leads to 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 previous chapter of this series expanded the concept of restoring receptor sensitivity (receptor upregulation), discussed causes of the loss of receptor sensitivity (receptor downregulation), and presented several examples of receptor sensitizers (Metformin, Aminoguanadine/ Goats Rue, DHEA). In this installment, other potential receptor-sensitizing substances will be discussed.

Restoring Hypothalamic Sensitivity by Neurotransmitter Modulation

Dilman believed that a principle cause of the loss of hypothalamic sensitivity was alterations of catecholamine neurotransmitters (epinephrine, norepinephrine, dopamine), as well as a shifting balance of the catecholamine/serotonin ratio (Fig. 1).(1) Although Dilman did not address the causes of those changes, he suggested several approaches to correct the imbalances. These suggestions included: 1: Increase neurotransmitter production with neurotransmitter precursors; 2: Decrease neurotransmitter metabolism (breakdown) with enzyme inhibitors (enzymes are substances that alter the rate of a chemical reaction); 3: Correct neurotransmitter and neuropeptide deficits; and maybe even 4: inhibit neurotransmitter reuptake (as with SSRIs like Paxil, Prozac or Zoloft), thereby increasing intrasynaptic neurotransmitter levels.

 

1. Increase Neurotransmitter Production

One way to balance brain neurotransmitters is to use neurotransmitter precursors like the amino acids tyrosine, phenylalanine, GABA, tryptophan, and 5-HTP. Durk Pearson and Sandy Shaw were the first to popularize the use of the amino acids phenylalanine and tyrosine to increase the synthesis of catecholamine neurotransmitters (Fig. 2).(4) Dr. Lane Lenard reviewed nutritional approaches to normalizing these neurotransmitter systems in his article, Circadian Rhythm Synchronicity in the April, 1999 issue of Vitamin Research News. Tyrosine, phenylalanine, GABA, tryptophan and 5-HTP have been shown – singly and in various combinations – to be of benefit in the treatment of depression by normalizing neurotransmitter levels. Dilman presented evidence that appropriate use of these substances restores hypothalamic sensitivity.(1,2,5)

2. Decrease Neurotransmitter Metabolism

Monoamine oxidase (MAO) is the enzyme that breaks down dopamine and the catecholamine neurotransmitters (epinephrine, norepinephrine, dopamine). Monoamine oxidase B is known to increase with age, causing an increased degradation of the catecholamines, and resulting in a decrease in levels of these substances.(6) GH3, the Romanian Youth Drug, is a weak, reversible monoamine oxidase inhibitor. I think the benefits of GH3 are probably due to its normalizing effect on brain neurotransmitters. Interestingly, the breakdown products of GH3 are DMAE (dimethylamino-ethanol) and PABA (paraaminobenzoic-acid). DMAE and PABA are both readily available, inexpensive dietary supplements. I think these substances together – or DMAE by itself – may mimic the effects of GH3. In fact, DMAE has demonstrated a life-prolonging effect in experimental animals (Fig. 3).

Another approach to decreasing neurotransmitter metabolism is to use deprenyl, a substance believed to act as a specific MAO-B inhibitor. Because of its ability to increase dopamine and catecholaminergic neurotransmitters (epinephrine and norepinephrine) in the brain, deprenyl is used for Parkinsons disease. However, deprenyl may have even more fundamental properties than its MAO-B-inhibiting effects. Professor Joseph Knoll (who first synthesized deprenyl) stated at the 1st Monte Carlo Anti-Aging Conference in June 2000, that he now believes that deprenyl is not only a MAO-B inhibitor, but also a powerful antioxidant and resensitizer of dopamine receptors. Furthermore, researchers in Spain discovered that deprenyl restores IGF-1 levels in aged rats to those of young rats, leading the scientists to postulate that the anti-aging effects of deprenyl could be due to restoration of hypothalamic hormones such as GH.(7)

Significantly, deprenyl is another of the few substances that have demonstrated the ability to extend the maximum lifespan of experimental animals in several species
(Fig. 4).(8)

3. Replace Neurotransmitter and Neuropeptide Deficits

L-dopa (levo-deoxyphenylalanine)

L-dopa is one of the first therapeutic breakthroughs in the treatment of Parkinsons disease. L-dopa crosses the blood-brain barrier and directly replaces the deficient neurotransmitter, dopamine. L-dopa (which is found in the herb, Mucuna pruriens), also improves the sensitivity of the adaptive homeostat to feedback suppression,(1) stimulates the release of growth hormone releasing hormone (GHRH) in humans,(9) and growth hormone in young and old rats.(10) L-dopa has also been shown to extend the maximum lifespan of experimental rats (Fig. 5).

Early studies combining L-dopa with deprenyl appeared positive, reporting extended lifespan of Parkinsons patients on this combination. Subsequently, however, as the studies progressed, the opposite seemed to be occurring, with increasing deaths occurring in patients taking these substances.(11) I think the study deserves to be repeated, as there is a question that the Deprenyl used in the study may have been contaminated.(12)

Melatonin

Melatonin is a polypeptide hormone produced by the pineal gland. Melatonin has a wide range of neurotransmitter-like and hormonal regulatory functions – one of which is its hypothetical ability to increase hypothalamo-pituitary complex sensitivity. One cause of disturbed sleep as we age is the reduction in nightly release of melatonin by the pineal gland (Fig. 6). Many people have found that bedtime doses of melatonin have restored their ability to obtain a sound, restful nights sleep.

Follicle stimulating hormone (FSH) and luteinizing hormone (LH) are pituitary hormones that stimulate the testes and ovaries. A youthful ratio of FSH/LH should be less than one (i.e., LH greater than FSH). With age, both FSH and LH rise. However, FSH increases more than LH, resulting in an FSH/LH ratio greater than one. (Fig. 7). Thus, the FSH/LH ratio is a significant biomarker of the biological age of the reproductive homeostat.

Melatonin and FSH have been shown to be antagonistic in women.(13) I think the same relationship probably holds true in men. Thus, melatonin may act to normalize (lower) gonadotropin levels, restoring them to more youthful levels. Melatonin, significantly, is also another of the few substances that repeatedly have been shown to extend the maximum life span of experimental animals (Fig. 8). This life extending effect of melatonin has only been demonstrated when the treatment was begun after maturity. It should be especially noted that lifelong treatment with melatonin beginning in youth in animal studies often resulted in shorter lifespans. It is for this reason that I do not recommend daily use of melatonin for children and young adults (younger than 25-35). I dont think occasional use by children or young adults is harmful, however.

Melatonins relatives, Epithalamin™ and Epithalon™

Epithalamin™ is a melatonin-free, pineal polypeptide fraction that is classified as a drug in Russia. Dilman and other scientists in Russia demonstrated extension of lifespan in rats that were treated with Epithalamin.(14) Professor Vladimir Anisimov, who worked in Dilmans laboratory from 1973-1979, later replicated these results in fruitflies, mice and rats.(15) Epithalamin extended the mean survival of rats by 5.3%, and the maximum lifespan by 10 months (Fig. 8).

The active polypeptide in Epithalamin is a combination of the amino acids alanine, glutamine, glycine, and aspartic acid. This synthetic pineal extract has been identified and synthesized. Called Epithalon™ this substance is now being developed as a drug in Russia. The scientists also stated that Epithalon slows down aging of reproductive function, inhibits free radical processes, and reduces the incidence of tumors.

Dilman believed that the principle mechanism and benefit of Epithalamin was to restore hypothalamic sensitivity to more youthful levels. Prof. Vladimir Khavinson,(16) principal scientist, author and owner of the patent for Epithalon, agrees that the major mechanism of Epithalon is its interaction with specific receptors. Khavinson and his associates found that effective doses of Epithalon were 16,000 to 80,000,000 times lower than those of melatonin (in fact, one of Epithalons effects is to stimulate release of melatonin). Khavinson calculated that an effective dose for humans would be in the range of 0.075 microgram per day (0.991 microgram/kg bodyweight).

Vasopressin

Vasopressin is a pituitary hormone that is best known for controlling water balance in the body. Its common name is anti-diuretic hormone (ADH), because of its property of conserving water in the body and inhibiting urine production. Because of this property, many parents of children with bed-wetting problems find it useful, as do many men with prostate problems (BPH). Vasopressin doesnt directly affect the prostate, but it does reduce urine production, resulting in fewer sleep interruptions.

Vasopressin also acts as a neuropeptide in the hypothalamus. It is well known to enhance short-term memory in normal young adults, as well as in those with age-associated memory impairment (AAMI) (see review of numerous studies in my book, Smart Drugs & Nutrients). Ive heard vasopressin described as a fast-acting cobweb cleaner. In addition, it has been shown to improve both mood and memory in those with Alzheimers disease. Not surprisingly, vasopressin content in the brain declines with age.(17)

A recent study demonstrated an additional, previously undocumented benefit of vasopressin – enhancement of slow wave sleep.(18) Subjects used a dose of 40 IU/day, administered as a nasal spray (two sprays at bedtime). Over a period of three months, researchers found the time spent in slow wave sleep (SWS) more than doubled. SWS is the most restful kind of sleep – and it is during SWS that growth hormone is released.

Perras and colleagues hypothesized that, in addition to its direct effects as a neuropeptide, vasopressin could act by other mechanisms as well, including acting as a corticosteroid receptor agonist (sensitizer).

Drs. Sydney and Constance Friedman at the University of British Columbia studied the effects of posterior pituitary powder on the lifespans of already-old rats (2 years). The scientists proposed that the alterations in water and electrolytes (principally, sodium and potassium) with age, resemble those of diabetes insipidus (a disease characterized by a deficiency of ADH, resulting in frequent urination, electrolyte abnormalities, memory disturbances, and other symptoms). They further proposed that many other signs and symptoms of aging are similar to many features of diabetes insipidus.(19) They had previously found that vasopressin (ADH) restored a youthful pattern of fluid distribution in rats(20) and improved renal function in aging men.(21)

The authors stated that, It is a truism that in age almost all functions that can be measured will show some decline [for proof, see my book, Biological Aging Measurement, Clinical Applications  – WD]. Since salt and water homeostasis is certainly central to life itself, effective therapy might well produce a measurable effect on lifespan.

To test their theory, the authors administered posterior pituitary powder (as a source of vasopressin) to two-year-old rats. The study was terminated after 180 days. Only 8 of the original 18 controls were still alive. In contrast, 22 of 36 treated rats survived (Fig. 8). The authors also reported better fur condition, increased muscular tone, absence of age-related pituitary and adrenal enlargement, and fewer skin lesions in the treated rats. The scientists concluded that therapy directed at the neurohypophyseal-adrenal
cortical integration can exert profound effects…in the aging organism. [That was pretty profound in 1964]

Desmopressin™ is synthetic vasopressin. It is indicated for diabetes insipidus, as well as nocturnal enuresis (bed-wetting), but can be taken safely and beneficially by most people. Those with hypertension, glaucoma or prostatic hypertrophy should use Desmopressin with caution and only under the care of their physician (due to its slight tendency to increase intraocular and blood pressure). Because of its multiplicity of benefits, however, I think even those for whom Desmopressin is relatively contraindicated may ultimately benefit from long-term, low-dose use. I believe vasopressin is a valuable but underused anti-aging, life-extending agent. It is available as a nasal spray by prescription, or from an overseas pharmacy like IAS

4. Inhibit Neurotransmitter Reuptake

This section (to be expanded in a future issue) will review evidence regarding the use of prescription anti-depressant medications, as well as their neurotransmitter-normalizing, receptor-sensitizing, and potential (but untested) life extending effects. Side effects, and indications will also be included. Some of the substances to be discussed include Adrafinil and Modafinil (which restore sensitivity to alpha-1 adrenergic receptor sites – receptors for noradrenaline); SSRIs like Paxil, Prozac, or Zoloft (which increase intrasynaptic serotonin by inhibiting its reuptake); benzodizepines like valium; tricyclic antidepressants like desipramine; and even catecholamine receptor inhibitors like Ritalin.

Future installments in this series (Chapter 7) describing hypothalamic and peripheral receptor-sensitizing substances will  – in addition to adding to the list – put it together in terms of categorizing and prioritizing which one(s) to use in which condition.

References:
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. Pearson, D., and Shaw, S. Life Extension, A Practical, Scientific Approach, 1983, Warner Books, New York.

5. Ostroumova, M.N. Age-associated decrease in hypothalamic pituitary complex sensitivity to dexamethasone suppression test. The effect of stress, epithalamin and phenformin. Probl Endokrinol, 1978, 24: 59-64.

6. Fowler, J.S., Volkow, N.D., Wang, G.J., Logan, J., et al. Age-related increases in brain monoamine oxidase B in living healthy human subjects. Neurobiology of Aging, 1997, 18: 4, 431-435.

7. De La Cruz, C., Revilla, E., Rodriguez-Gomez, J.A., et al. Deprenyl treatment restores serum insulin-like growth factor-I (IGF-1) levels in aged rats to young rat level. European Journal of Pharmacology, 1997, 327: 215-220.

8. Ruehl, W.W., Entriken, T.L., Muggenburg, B.A., Bruyette, D.S., Griffith, W.C., and Hahn, F.F. Treatment with L-Deprenyl prolongs life in elderly dogs. Life Sci, 1997, 61:1037-1044.

9. Chihara, K., Kashio, Y., Kita, T., Okimura, Y., et al. L-dopa stimulates release of hyopthalamic growth hormone-releasing hormone in humans. J Clin Endocrinol Metab, 1986, 62: 466-473).

10. Sonntag, W.E., Forman, L.J., Miki, N., Trapp, J.M., Gottschall, P.E., and Meites, J. L-dopa restores amplitude of growth hormone pulses in old male rats to that observed in young male rats. Neuroendocrinology, 34: 163-168.

11. DeMott, K. Selegiline, levodopa combo mortality confirmed. Internal Medicine News, July 15, 1998, 51.

12. U.S. v. Kimball (www.CERI.com)

13. Fernandez, B., Malde, J.L., and Acuna, D. Relationship between adenohypophyseal and steroid hormones and variations in serum and urinary melatonin levels during the ovarian cycle, perimenopause, and menopause in healthy women. Steroid Biochemistry, 1990, 35:2: 257 262.

14. Dilman, V.M., Anisimov, V.N., Ostroumova, M.N., et al. Increase in life span of rats following polypeptide pineal extract treatment. Exp Pathol, 1979, 17: 539-545.

15. Anisimov, V.N., Sergey, V., Mylnikov, S.V., and Khavinson, V.K. Pineal peptide preparation epithalamin increases the lifespan of fruit flies, mice and rats. Mech Age Dev, 1998, 103: 123-132.

16. Khavinson, V.Kh., Izmaylov, D.M., Obukhova, L.K., and Malinin, V.V. Effect of Epthalon on the lifespan increase in Drosophila melanogaster. Mech Aging Dev, 2000,
120: 141-149.

17. Swaab, D.F. Ageing of the human hypothalamus. Horm Res, 1995, 43: 8-11.

18. Perras, B., Pannenborg, H., Marshall, L., et al. Beneficial treatment of age-related sleep disturbances with prolonged intranasal vasopressin. J Clin Pshychopharm-acology, 1999, 19: 1, 28-36.

19. Findley, T. Amer J. Med, 1949, 7: 70.

20. Friedman, S.M., and Friedman, C.L. Prolonged treatment with posterior pituitary poweder in aged rats. Exp Gerontol, 1964, I: 37-48.

21. Ruol, A., Menozzi, L, and Furlanello, F. J Geront Suppl 31, 1963.

22. Maestroni GJ, Conti A, Pierpaoli, W. Pineal melatonin, its fundamental immuoregulatory role in aging and cancer. Ann NY Acad Sci. 1988 521:140-148.

23. Hochschild, R. Effect of dimethylaminoethanol on the lifespan of senile male A/J mice. Experimental Gerontology, 1973, 185-191.

24. Anisimov, V.N., Khavinson, V.Kh., Mikhalski, A.I., and Yashin, A.I. Effect of synthetic thyymic and pineal peptides on biomarkers of ageing, survival and spontaneous tumor incidence in female CBA mice, Mech Aging Dev, 2001, 122: 41-68.

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