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).
Significantly, deprenyl is another of the few substances that have demonstrated the ability to extend the maximum lifespan of experimental animals in several species
3. Replace Neurotransmitter and Neuropeptide Deficits
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).
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.
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).
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 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.
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