The Immune Homeostat

Ward Dean, MD

Introduction: The modern neuroendocrine theory of aging was first conceived in 1954 by the noted Russian gerontologist, Professor Vladimir Dilman. Several years ago, I had the pleasure of working with him on our book, The Neuroendocrine Theory of Aging and Degenerative Disease.

Dilman’s theory, in essence, is that aging is caused by a progressive loss of sensitivity by the hypothalamus and related structures in the brain to negative feedback inhibition. This loss of sensitivity not only enables us to grow and develop, but is the cause of post-maturational diseases, aging and death. The neuroendocrine theory explains the cause of the major diseases of aging which contribute to over 85% of deaths of middle-aged and elderly individuals. These diseases include: (1) obesity, (2) atherosclerosis, (3) hypertension, (4) diabetes, (5) cancer, (6) autoimmune disorders, (7) metabolic immunodepression, and (8) hyperadaptosis.

Two other diseases — depression and menopause — although not fatal, also occur regularly with age. Several of these diseases (hyperadaptosis, and metabolic immunodepression) have strange-sounding names, but as one gains an understanding of Dilman’s theory, these names will not seem so strange.

In this installment we will review the cause of the decline of the body’s resistance to disease, how the cause of this decline is related to the neuroendocrine theory, and how immunity can be restored.

The Immune Theory of Aging

UCLA’s former Professor Roy Walford (Fig. 1) is a true “Renaissance Man.” Prof Walford is an eclectic physician and scientist who has distinguished himself with his pioneering work in many areas of science and medicine. He has traveled the world to seek answers to his many questions. He has used himself as a human research subject by participating in the Biosphere project. He is best known in academic circles, however, for his work in the field of biomedical gerontology. In this regard, he has extensively researched the effects of caloric restriction in experimental animals, and has authored several books on this subject. Walford is a scientist who practices what he preaches, and has personally followed a rigorous calorically-restricted diet for nearly 20 years. His books (1983; 1986) contain his personal recommendations for applying his caloric restriction anti-aging regimen to humans.

Another of Walford’s credits is that he was also a leader in researching the relationship between aging and the immune system, summarizing his findings in his landmark 1969 book, The Immunologic Theory of Aging. In this theory, Walford proposed that aging was caused by a progressive breakdown in the functioning of the immune system, which resulted in many of the diseases of aging—especially cancer, autoimmune, cardiovascular and infectious illnesses.

The key to a healthy immune system lies largely with the thymus gland, which is found just beneath the breastbone. The thymus reaches maximum size during puberty, and progressively atrophies thereafter. Simultaneously, as the thymus atrophies, the level of thymic hormones decreases, while the incidence of a number of age-related diseases increases (Fig. 2). Walford proposed that it was the alteration in thymic function which resulted in the aging process and diseases of aging.

For many years, the immune theory of aging stood separately, along with the free radical theory, cross linking theory, and other theories of aging. Although the Immune Theory correctly related the decline in the immune system with the progressive atrophy of the thymus, the theory did not adequately explain the cause of this dysfunction. In recent years there has been increasing evidence of the close interaction between the thymus and the neuroendocrine system, such that the immune theory of aging can now be incorporated within the neuroendocrine theory.

Neuroendocrine-Thymus Interactions: The “Immune Homeostat”

Just as the “Adaptive Homeostat” (Hypothalamus-Pituitary-Adrenal axis) and the “Energy Homeostat” (Hypothalamus-Pituitary-Thyroid axis) control the body’s ability to deal with stresses and produce energy, respectively, the “Immune Homeostat” (Hypothalamus-Pituitary-Thymus axis) determines the body’s ability to fight off infectious diseases, autoimmune diseases, and cancer.

It is now becoming clear that the decline in activity of the thymus gland, with subsequent decline of thymic hormones, is due to the interactions of the thymus with the rest of the endocrine system (Fig. 3) (Marchetti, et al, 1991; Fabris, 1991; Goya, 1991; Kelley, et al, 1988). Dr. Nicolas Fabris, Chief of Immunology at the Italian National Research Centers on Aging in Ancona, Italy, is one of the foremost researchers in the world on the mutual interdependence of the neuroendocrine and immune systems. Fabris illustrated this concept of how the interaction of the neuroendocrine, nervous and immune systems result in the mutual disruptions in these systems that result in age-associated dysfunctions and diseases (Fig. 4).

Mechanisms of Immune Regulation and Dysfunction

Dr. Fabris proposes that there are two levels of interaction between the neuroendocrine and the immune systems. The first level (Fig. 5) is based on the interactions between the neuroendocrine system and the thymus gland, with the thymus being responsible for the proliferation and differentiation of “immature” stem cells into mature, virus and bacteria-killing T-lymphocytes. However, as the amount of thymic hormones that are produced decreases with age, so too does the effectiveness of the body’s T-cell population decline (Kelley, et al, 1988). It is the changes in the T-cells that are directly responsible for most age-related changes in the immune system.

The second level of interaction (Fig. 6) is at the periphery, between neuroendocrine signals and the cell-signalling substances which are secreted by immune cells during specific reactions to various antigens.

Therapeutic Approach

Dilman’s approach to developing anti-aging therapeutic protocols, based on the neuroendocrine theory, involved a multi-pronged approach. This included: (1) Restoration of neuroendocrine rhythmic activity and sensitivity to feedback regulation; (2) Normalization of metabolic shifts (i.e., re-establishing the optimum internal milieu); (3) Counter-action of adverse hormonal effects on target tissues; and (4) Utilization of substitution therapy. These approaches are not mutually exclusive — i.e., a regimen may have more than one mechanism. For example, melatonin supplementation not only can restore melatonin levels to those of young, healthy adults, but also helps to restore neuroendocrine rhythmic activity and hypothalamic sensitivity, normalize metabolism, and prevent the adverse effects of stress. Listed below are examples of therapeutic regimens that have been demonstrated to enhance immune integrity.

Hormonal Replacement Therapy

• Melatonin: There is a clear connection between decreasing pineal gland function and progressive impairment of thymic and immune function (Cardarelli, 1990). Maestrone, et al (1988), also found that the circadian (time-related) release of melatonin plays an important role in maintaining the functional capacity of the immune system. Both of these papers presented strong evidence that melatonin is a physiologic “up-regulator” of the immune system, and that supplementation with melatonin has a general “immunoaugmenting” effect. These authors also reported that melatonin has “astonishing anti-stress properties.” Pierpaoli, et al (1991) showed that melatonin administration at night to laboratory mice prolonged the maximum life span of treated animals by six months over that of controls (Fig. 7).

• Thymic Hormone: A number of animal extracts and synthetic thymic hormones have demonstrated the ability to dramatically reverse thymic atrophy and restore levels of immunity to much more youthful levels. In addition to being among the most effective immune-enhancing agents known, thymic extracts and thymic hormones are among the few agents that are documented to extend the life spans of experimental animals (Fabris, et al, 1972; Cardarelli, 1989).

Among the available preparations are: Thymolip and Thymex-L are commercially available oral extracts of calf thymus manufactured by Thymoorgan Pharmazie in Vienenburg, Germany. These products have been documented to restore a broad range of immune factors in elderly humans (Jankovic, et al). Thym-Uvocal is an injectable European preparation of a well-defined combination of oligopeptides derived from thymus glands of healthy calves. Thym-Uvocal is available from IAS.

Thymic Protein A is a synthetically produced copy of a thymic protein that has been demonstrated to have immune-enhancing properties (Beardsley, et al, 1983). Dr. Julian Whitaker (1997) states that Thymic protein A “is likely the most powerful natural stimulant of the immune system ever discovered.” He recommends one to three packets a day, taken sublingually when sick (I have known cancer patients and very debilitated patients who took six packets daily). Dr. Whitaker also recommends that a maintenance dosage be taken on a daily basis to support age-impaired immune systems. Thymic Protein A is extremely safe, with no adverse effects noted in any dose.

• Growth Hormone (GH): Growth hormone administration causes thymic regeneration and restoration of immune capacity in mice (Kelley, et al, 1988). These benefits are likely to accrue not only from injectable exogenous HGH, but also from GH stimulating secretagogues and amino acids.

• DHEA: As would be expected from its many and diverse beneficial effects, DHEA administration in doses of 50 mg/day has been found to be an effective immune stimulant in both women (Casson, et al, 1993) and men (Yen, et al, 1995).

• Thyroid Hormone: Thyroid hormone replacement stimulates antibody synthesis and thymic hormone secretion in aged mice and humans and promotes regeneration of the thymus (Fabris, 1986). (Also, see my article on hypothyroidism in a previous issue of Vitamin Research News, or on the VRP website).

• Aromatase Inhibitors (Indole 3 Carbinol): Elevated levels of testosterone (as occurs dramatically during puberty and young adulthood) is believed to be a principal cause of thymic atrophy, as the thymus does not atrophy significantly in eunuchs. Conversely, it has also been hypothesized that in males, at least, it may be the increased conversion of testosterone to estrogen that actually causes thymic atrophy. In this regard, aromatase inhibitors — substances that prevent the conversion of testosterone to estrogen — may inhibit thymic atrophy and promote thymic regrowth. Aromatase-inhibitor drugs like clomiphene may be used. Alternatively, the dietary supplement indole-3-carbinol can effectively and rapidly block testosterone conversion and lower estrogen levels, thereby reversing thymic atrophy.

• Coconut Oil: Dr. Ray Peat (1995) predicted in his newsletter that “coconut oil, with a proper balance of protein, carbohydrate and other nutrients, will delay atrophy of the thymus…and will restore thymus function that has been lost as a result of stress or aging. Direct supplementation with progesterone, pregnenolone and thyroid hormone would undoubtedly be more powerful, but the use of dietary coconut oil is a simple and practical way to support the normal balance of these hormones.”

Restore Hypothalamic Sensitivity

• Metformin: Anti-diabetic biguanide drugs like Metformin — or the herb Goat’s Rue (which contains guanidine, the herbal prototype of Metformin — may improve overall metabolism and may stimulate thyroid function, thus leading to an improvement in cell-mediated immunity (Dilman, 1981). In this regard, Vinnitsky (1988) found that an analog of Metformin had a significant protective effect against chemically-induced carcinoma in animals. Miscellaneous Supplements

• Arginine: Fabris (1991) reported that treatment of healthy elderly people with arginine (no dose stated) resulted in restoration of blood thymic hormone levels to youthful values after several months. I believe a reasonable dose to accomplish this would be 1 to 3 grams daily.

• Zinc: Fabris, and colleagues (1990, 1991) showed that zinc supplementation in old age could restore thymic activity, and improve various immune parameters as well as some age-related hormonal deficits. Conclusion The immune system is clearly an integral portion of the neuorendocrine system, which exhibits typical age-related decrements. By using a number of nutritional and/or pharmacological substances, many aspects of impaired immune function can be restored to more youthful, healthy levels. Fabris (1991) concluded that “age-related thymic involution is not an irreversible process, …functional recovery can be achieved even in old age, … [and] thymus regrowth can be induced in old age by other endocrine manipulations….”

References

1. Beardsely, T.R., et al. Induction of T-cell maturation by a cloned line of thymic epithelium. Proceedings of the National Academy of Sciences, USA, 1983, 80: 19, 6005-6009.
2. Casson, P.R., Andresen, R.N., Herod, H.G., et al. Oral dehydroepiandrosterone in physiologic doses modulates immune function in postmenopausal women. Am J Obstet Gynecol, 1993, 169: 1536.
3. Cardarelli, Nate. The Thymus in Health and Senescence, Vol II. CRC Press, Boca Raton, Florida.
4. Cardarelli, Nate. The role of a thymus-pineal axis in an immune mechanism of aging. J Theor Biol, 1990, 145: 397-405.
5. Dilman, V.M. The Law of Deviation of Homeostasis and Diseases of Aging, John Wright, Littleton, 1981.
6. Dilman, V.M., and Dean, Ward. The Neuroendocrine Theory of Aging and Degenerative Disease. The Center for Bio-Gerontology, 1992, Pensacola, Florida.
7. Doria, G., Adorini, L., Sabbadini, E., et al. Immunoregulation in aging. In: Ann NY Acad Sci, Vol 521, by Pierpaoli, W., and Spector, N.H. (eds), NY Acad Sci, New York, 1988, 182-188.
8. Fabris, N. Neuroendocrine-immune interactions: A theoretical approach to aging. Arch Gerontol Geriatr, 1991, 12, 219-230.
9. Fabris, N. Neuroendocrine-immune aging: An integrative view on the role of zinc. In: The Aging Clock—The Pineal Gland and Other Pacemakers in the Progression of Aging and Carcinogenesis, Ann New York Acad Sci, Volume 719, by Pierpaoli, W., Regelson, W., and Fabris, N., NY Acad Sci, New York, 1994, 353-368.
10. Fabris, N., Mocchegiani, E., Mariotti, S., et al. Thyroid function modulates thymic endocrine activity. J Clin Endocrinol Metab, 1986, 62: 474-478.
11. Fabris, N., Mocchegiani, E., Muzzioli, M., and Provinciali, M. Neuroendocrine-thymus interactions: Perspectives for intervention in aging. In: Neuroimmunomodulation: Interventions in Aging and Cancer, Ann NY Acad Sci, Vol 621, by Pierpaoli, W. and Spector, N.H., (eds). NY Acad Sci, New York, 1988, 72-87.
12. Fabris, N., Mocchegiani, E., Muzzioli, M., and Provinciali, M. Role of zinc in neuroendocrine-immune interactions during aging. In: Physiological Senescence and Its Postponement, Ann New York Acad Sci, Vol 621, by Walter Pierpaoli and Nicola Fabris, (eds.),1991, NY Acad Sci, New York, 314-326.
13. Fabris, N., Muzzioli, M., and Mocchegiani, E. Recovery of age-dependent immunological deterioration in Balb/c mice by short-term treatment with L-thyroxine. Mech Ageing Dev, 1982, 18: 327-343.
14. Goldstein, Allan L., Thurman, Gary B., Low, Teresa L. K., et al. Thymosin: The endocrine thymus and its role in the aging process, in: Physiology and Cell Biology of Aging (Aging, Vol 8), by A. Cherkin, et al. Raven Press, New York, 1979, 51-60.
15. Goya, Rodolfo. The immune-neuroendocrine homeostatic network and aging. Gerontology, 1991, 37: 208-213.
16. Jankovic, B.D., Korolija, P., Isakovic, K, et al. Immunorestroative effects in elderly humans of lipid and protein fractions from the calf thymus: A double-blind study. In: Neuroimmunomodulaton: Interventions in Aging and Cancer, Ann NY Acad Sci, Vol 521, by Pierpaoli, W., and Spector, (eds). N.H. NY Acad Sci, New York, 1988, 247-259.
17. Kelley, K.W., Davila, D.R., Brief, S., et al. A pituitary-thymus connection during aging. In: Neuroimmunomodulaton: Interventions in Aging and Cancer, Ann NY Acad Sci, Vol 521, Pierpaoli, W., and Spector, N.H. (eds). NY Acad Sci New York, 1988, 88-98.
18. Maestroni, Georges J.M., Conti, Ario, and Pierpaoli, Walter. Pineal melatonin, Its fundamental immunoregulatory role in aging and cancer. In: Neuroimmunomodulaton: Interventions in Aging and Cancer, Ann NY Acad Sci, Vol 521, Pierpaoli, W., and Spector, (eds). N.H. NY Acad Sci New York, 1988, 140-148.
19. Marchetti, B., Morale, M.C., Batticane, N., et al, Aging of the Reproductive-Neuroimmune Axis—a crucial role for the hypothalamic neuropeptide luteinizing hormone releasing hormone, In: Physiological Senescence and Its Postponement, Ann New York Acad Sci, Vol 621, by Walter Pierpaoli and Nicola Fabris, (eds.),1991, 159-173.
20. Marchetti, B., Peiffer, A., Morale, M.C., Batticane, N., et al. Transgenic animals with impaired Type II glucocorticoid receptor gene expression—A model to study aging of the neuroendocrine-immune system. In: The Aging Clock—The Pineal Gland and Other Pacemakers in the Progression of Aging and Carcinogenesis, Ann New York Acad Sci, Volume 719, by Pierpaoli, W., Regelson, W., and Fabris, N. NY Acad Sci, New York, 1994, 308-327.
21. Peat, Raymon. Death of the Thymus. Ray Peat’s Newsletter, 1995, Vol. 3, No. 5.
22. Pierpaoli, W., Dall’Ara, A., Pedrinis, E., and Regelson, W. The pineal control of aging—The effects of melatonin and pineal grafting on the survival of older mice. In: Physiological Senescence and Its Postponement, Ann New York Acad Sci, Vol 621, by Walter Pierpaoli and Nicola Fabris, (eds.),1991, 291-313.
23. Vinnitsky, V.B. Neurohumoral mechanisms of the formation of antitumoral activity. In: Neuroimmunomodulaton: Interventions in Aging and Cancer, Ann NY Acad Sci, Vol 521, by Pierpaoli, W., and Spector, N.H. (eds). NY Acad Sci, New York, 1988, 195-214.
24. Walford, R.L. The Immunologic Theory of Aging. Munksgaard, Copenhagen, 1969.
25. Walford, R.L. Maximum Life Span, W.W. Norton & Company, New York, 1983.
26.Walford, R.L. The 120 Year Diet—How to Double Your Vital Years, Simon and Schuster, New York, 1986.
27. Whitaker, Julian. Give your immune cells a natural “shot in the arm.” Dr. Julian Whitaker’s Health & Healing, March, 1997, Vol 7, No. 3, 1-2.
28. Yen, S.S.C., Morales, A.J., and Khorram, O. Replacement of DHEA in aging men and women. Potential remedial effects, in: Dehydroepiandrosterone (DHEA) and Aging, Ann NY Acad Sci, Vol 774, by Francis L. Bellino, Raymond A. Daynes, Peter J. Hornsby, David H. Lavrin, and John E. Nestler, eds.,M1995, New York, 128-142.