A Key to Retarding the Aging Process: Restoring Hypothalamic and Peripheral Receptor Sensitivity

By Ward Dean, MD

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 (Dilman, 1981; Dilman and Dean, 1992; Dilman and Young, 1994). This loss of central and peripheral receptor sensitivity causes a progressive shifting of homeostasis throughout the lifespan, resulting in 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”). The approach which offers the greatest promise of success is to restore hypothalamic and peripheral receptor sensitivity to more youthful levels. Accomplishing this feat should provide a wide range of therapeutic benefits.

Dilman researched means of reversing that mechanism using hypothalamic receptor sensitizers. Such sensitizers, he reasoned, would literally rejuvenate the various “homeostats.” This is an extremely fruitful area for pharmaceutical and nutritional research.

Loss of Receptor Sensitivity with Age

Neurotransmitters and hormones act through receptors on or in the cells of their target tissues (Fig. 1). Receptors are specific for particular hormones or neurotransmitters. If there is a chronic excess of one of these substances, the receptors may down-regulate — i.e., become less responsive to the stimulating (or inhibiting) action of the regulator (hormone or neurotransmitter).

 

 

Dr. George Roth (1995), of the Gerontology Research Center in Baltimore, confirmed — in agreement with Dilman — that changes in responsiveness of target tissues to hormones and neurotransmitters with age is even more important than alterations of blood levels of the hormones and neurotransmitters themselves. Dr. Roth pointed out that most published studies report decreased maximal response or sensitivity to most hormones and neurotransmitters with age. Again, this is in accordance with Dilman’s hypotheses and findings.

There are a number of proposed mechanisms for this loss of tissue responsiveness. One cause may be a decrease in number of receptors. Another may be alterations at the post-receptor (as well as the receptor level) (Roth, 1995). Dilman believed a principle cause of decreased receptor sensitivity was an alteration of membrane characteristics (Zs.-Nagy, 1979). He also believed that the level of biogenic amines (epinephrine, norepinephrine, dopamine) is one of the most important factors that determine hypothalamic sensitivity (Dilman, 1981). This hypothesis is based on findings that biogenic amine levels in the brain (particularly in the hypothalamus) decline with age, (Finch, 1973; Robinson, 1975; Robinson, et al, 1977).

Monoamine oxidase (MAO) is the enzyme in the brain that catalyzes the breakdown of the catecholamine neurotransmitters (epinephrine, norepinephrine, dopamine). MAO levels increase with age, resulting in more rapid degradation of these stimulatory neurotransmitters, in favor of the inhibitory, serotonergic neurotransmitters. Perhaps more important than the absolute values of these neurotransmitters, is the alteration in balance of the dopaminergic/adrenergic to serotonergic neurotransmitters (Fig 2).

Other causes of receptor sensitivity loss include the decline in function of the pineal gland (Dilman, 1981). The pineal is the portion of the brain that controls our sleep-wake cycles, and other circadian rhythms. Not only does the pineal’s principle hormone, melatonin, decline with age (Fig. 3.), but other pineal factors likely do as well. The pineal, unlike other endocrine glands, does not itself appear to inherently become less sensitive, as there does not seem to be any downregulation (reduction in output of melatonin) when supplemental melatonin is taken.

Roth (1995) stated — in agreement with Dilman — that increased understanding of these mechanisms should help us to devise rational therapeutic strategies to ameliorate some of the dysfunctions of old age.

What is a Receptor Resensitizer?

Obviously, there are no direct tests of receptor sensitivity. We don’t have a “Receptor Sensitometer” to directly measure receptor sensitivity. Designation of a substance as a “receptor sensitizer” is based on indirect observation, and depends on the ability of a substance to accomplish one or more of the following:

1) Reduce hypothalamic hormone output (i.e., FSH/LH) without altering peripheral hormone levels (i.e., testosterone, estrogen/progesterone).

2) Increase the effect of peripheral hormones without altering hormone levels.

3) Normalize abnormally elevated hormone levels.

4) Exert multiple beneficial effects in cells, tissues, and organs, possibly through various mechanisms.

Resensitizing our Receptors—Key to Slowing Aging Process

Any substance which acts as outlined above is likely to have a multiplicity of beneficial effects elsewhere in the body. Such is the case with the substances enumerated below which we have identified to have cell receptor-sensitizing effects. The following substances are believed to act by restoring hypothalamic (central) or peripheral (end organ) receptor sensitivity to various hormones and neurotransmitters.

Metformin/Goat’s Rue/ Aminoguanadine

Metformin is an anti-diabetic drug with profound anti-aging properties. Metformin use results in numerous beneficial effects in both diabetics and non-diabetics, including: (1) loss of body fat, (2) reduction in cholesterol and triglycerides, (3) increased HDL (so-called “good cholesterol”), (4) reduced glucose and insulin, (5) enhanced immunity, and (6) decreased atherosclerosis. Dilman was an oncologist (cancer specialist) who used Metformin as an integral part of his anti-cancer protocols. In addition, he demonstrated that Phenformin—a similar but no longer available drug—extended the maximum lifespan of experimental animals (Fig. 4).

Although Metformin is primarily used for its actions in resensitizing hypothalamic and peripheral receptors to insulin, it also restores sensitivity of receptors to other hormones as well—particularly, the adrenal hormone, cortisol. In addition, Simon, and colleagues (1992) demonstrated that Met-formin may also increase the effects of testosterone.

In another highly significant study, scientists studied the effects of Metformin in combination with Clomiphene on obese women with polycystic ovary syndrome (POS) (Nestler, et al, 1998). Clomiphene is a drug that stimulates the release of gonadotropins (LH and FSH) by the pituitary. These substances act on the ovary to stimulate the release of estrogen. In this study, forty-six women with POS were treated with 50 mg clomiphene daily for five days, along with either 500 mg of Metformin three times daily, or a placebo. The group given Metformin noted a dramatic reduction in insulin, as well as ovulation in 89 percent. On the other hand, only 12% of the women given just Clomiphene ovulated.

The authors concluded, “The ovulatory response to clomiphene can be increased in obese women with the polycystic ovary syndrome by decreasing insulin secretion with Metformin.” Now, that’s a pretty strong statement for the New England Journal of Medicine—noted for its conservative stance. Most medical articles of this nature conclude with a watered-down, mealy-mouthed equivocation, stating a need for further research. This is one more significant indicator of Metformin’s profound beneficial central (hypothalamic) effects.

Goat’s Rue (Galega oficinalis) is the herbal prototype of the biguanide class of pharmaceuticals: Metformin, Phenformin. Goat’s Rue contains the substance guanidine, which is structurally very similar to Metformin (Fig. 5) (Stern, 1969). Presumably (although the research is sparse), Goat’s Rue acts in the same manner as Metformin. Research with aminoguanidine (structurally similar to guanidine, and to which VRP’s Goat’s Rue extract is standardized) has demonstrated many benefits similar to Metformin such as:

1) Reduction in blood glucose levels (without causing hypoglycemia),

2) Inhibits cataract formation in rats (Swamy-Mruthinti, et al, 1996),

3) Delays development of atherosclerosis (Brownlee, et al, 1986),

4) Inhibits diabetic retinopathy (Hammes, et al, 1991),

5) Prevents experimental strokes (Cockroft, et al, 1996); and

6) Prevents diabetic nephropathy (kidney damage) (Soulis, et al, 1996).

Conclusion

Hormone replacement therapy (HRT) — i.e., pregnenolone, DHEA, androstenedione/androstenediol/testosterone, estrogens and progesterone, thyroid and growth hormone — is an increasing common approach to anti-aging therapy. However, the “flip-side” of the equation—i.e., the state of the hormone receptors themselves—is usually overlooked. Dilman proposed that a key element of anti-aging therapy, in accordance with the neuroendocrine theory of aging, is to restore hypothalamic and peripheral receptor sensitivity. A combination of judicious HRT, in conjunction with selected receptor sensitizers, appears to offer a unique and potentially effective approach to anti-aging.

Next: Part II of this article will describe the use of a number of additional hypothalamic resensitizers, including: Deprenyl; the amino acids 5HTP, tryptophan, GABA, acetyl-L-carnitine, phenyl-alanine, and tyrosine; the herbs Mucuna prurens (L-dopa); Vitex agnus castus (Chaste berry), Tribulus terrestris; and forskolin (Coleus forskolii); as well as several other substances like calcium aminoethanolamine phospate (Ca 2AEP), vanadyl sulfate, and succinic acid.

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