Previously the review of the Neuroendocrine Theory of Aging has addressed how the body responds to stress (the Adaptive Homeostat), produces energy (the Energy Homeostat), and regulates sex hormones and the reproductive system (the Reproductive Homeostat). In this fourth chapter we review the “Immune Homeostat” (Pineal-Hypothalamus-Pituitary-Thymus axis) that is responsible for controlling the body’s ability to fight off infectious diseases, autoimmune diseases, and cancer.
The Immune Theory of Aging
One of the first scientists to recognize how the immune system influences aging was Alexander Bogomolets, the former President of the Ukrainian Academy of Sciences, and Director of the Kiev Institute of Experimental Biology and Pathology (Fig. 1). Bogomolets hypothesized that the prime mechanism in human aging was the failure of the reticuloendothelial system (RES), which directs the actions of cells (monocytes and macrophages) produced in reticular connective tissues (e.g. spleen), that remove cellular debris and pathogens from the body. Bogomolets believed that a loss of this RES function caused the connective tissues of the body to lose their physiologic elasticity, and thereby cause the body’s tissues, organs and systems to gradually lose flexibility, adaptability, and functional capacity. In his book, The Prolongation of Life, Bogomolets described the development of a serum he called antireticulocytotoxic serum (ARCS), that he believed could restore the reticuloendothelial system to more youthful levels, and thereby restore youthful vitality to the aging organism.
Bogomolets prepared antireticulocytotoxic serum by first injecting human spleen cells into horses, then removing the horse’s blood and separating the serum. This serum contained antibodies for human spleen tissue, a part of the reticuloendothelial system. Bogomolets claimed that when his serum was injected into humans in small doses it would aid the healing of wounds, help the body in its fight against invasive bacteria and cancer cells, hasten the union of broken bones, have a beneficial effect on rheumatic conditions, and be of value in the treatment of schizophrenia. World War II brought an end to the popularization of this treatment, and Bogomolets himself died shortly after the war at the age of sixty-five, without using the serum on himself.
Following his death, researchers in Kiev continued to test Bogomolets’ serum for its anti-aging effects, and though a number of positive results were reported in Germany and the Ukraine as recently as 1982, no research on ARCS was ever published in English or reprinted in Western journals. Despite being ignored in the West, current therapeutic models support Bogomolets’ approach. In 1989 Medvedev conceded that the emergence of monoclonal antibodies in medical practice, and the attempts to use them for specific targeting of drugs (particularly in anti-cancer therapy), is a modern version of Bogomolets’ approach.
The Immunologic Theory of Aging
In 1969 former UCLA Professor Roy Walford (Fig. 2) published a landmark theory in his book, The Immunologic Theory of Aging. Walford, a physician, immunologist, and gerontologist, proposed that aging is caused by the progressive breakdown of the immune system, which leads to many of the diseases of aging—especially cancer, autoimmune, cardiovascular and infectious illnesses—as well as aging itself. Notably, Walford’s theory correctly related the decline in the immune system with the progressive atrophy of the thymus.
As with the Free Radical, Cross-Linking, and other theories of aging, Walford’s Immune Theory stood alone for many years. More recently Walford’s theory has found support from a growing body of scientific evidence revealing the close interaction between the thymus and the neuroendocrine system, and the immune theory of aging can now be incorporated within the neuroendocrine theory.
It should be noted that Prof. Walford is a true Renaissance Man—an eclectic physician and a scientist who has distinguished himself with his pioneering work in many areas of science and medicine. He has traveled the world seeking answers to profound questions, and 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 with recommendations for applying his theoretical anti-aging concepts to humans. Walford is a scientist who practices what he preaches, and has personally followed a rigorous calorically-restricted diet for over 20 years.
Immune Homeostat
The immune homeostat consists of the pineal-hypothalamus-pituitary and thymus glands, plus the lymph nodes, spleen, bone marrow and various white blood cells. However, the thymus is the lynchpin of the immune homeostat. It is a small gland in the upper chest, which weighs one-third to one half ounce at birth, and reaches its peak weight of about 10 ounces at puberty when it is functioning at its highest level.
With age, numerous factors—including adrenal and sex hormones—begin to cause the thymus to atrophy. Over time as much of the active thymus tissue is lost, it is gradually replaced with fat and connective tissue. As the thymus atrophies, serum concentrations of thymic factors decrease. Concomitantly, as these levels of important immune-regulating thymic hormones decrease, the incidence of infections, cancers, and autoimmune diseases increase (Fig. 3). This age-related involution [shrinkage] of the thymus is so striking and predictable that it has been proposed as a cardinal biomarker of aging.
T-Cells and B-Cells
T-lymphocytes (T-cells) and B-lymphocytes (B-cells) are white blood cells that are produced in bone marrow. B-lymphocytes emerge from bone marrow fully mature and ready to go about the business of recognizing invaders (antigens) and signaling the production of antibodies. B-lymphocytes are activated in the liver and spleen and transform into plasma cells and memory B cells.
In contrast to B cells, T-cells emerge from marrow in an immature state. Researchers used to believe that before T lymphocytes could begin to function properly, they first had to migrate to the thymus (Fig. 4) where they “incubated” and were “programmed” to become specialized T-cells. However, it is now generally accepted that this programming can be done elsewhere, by thymic hormonal factors. After transformation/ activation, both B and T lymphocytes migrate into the blood stream, lymph nodes, and bone marrow, until they are needed.
Macrophages, the work horses of the immune system, are another type of white blood cell that coordinates with T and B cells in many immune responses. Macrophages act like garbage men to engulf (phagocytize) bacteria, viruses, and old or damaged cells for removal from the body. Early on, macrophages were recognized as being a key immune component, and were formerly referred to as the reticuloendothelial system (RES) that attracted the attention of Bogomolets.
Because macrophages usually confront antigens before the T and B cells do, many of the earlier studies on the loss of immunologic vigor with age focused on macrophages. Today we know that the decline in immune functions with aging is due primarily to changes in the T cells. T cells are responsible for protecting the body against viruses, fungi, and bacteria; for preventing the growth of cancer; and for regulating B cell antibody production to a large number of antigens. B cell changes are due to changes in T cells. But what causes the decline in T-cell functioning?
Thymus-Neuroendocrine Interactions: Major Cause of Age-Related Immune Decline
In our early twenties we have an abundance of well-functioning T-cells that regulate the immune system and help the body fight off pathogens and disease. But with the inexorable shrinking of the thymus gland over time, by about age forty the output of thymic hormones has decreased significantly and the T-cells have begun to lose their effectiveness. It is this gradual loss of functioning T-cells that is the cause of many of the age-related changes in the immune system.
The cause of the age-related decline in activity of the thymus, with subsequent decline of thymic hormones, is due to the interactions of the thymus with the rest of the endocrine system (Fig. 5). Other components of the endocrine system that influence the thymus include the thyroid and GH-Insulin axis (arms of the energy homeostat [which stimulate the thymus]), reproductive hormones (which inhibit the thymus), and the adaptive homeostat (which also inhibits thymic activity). Dr. Nicolas Fabris, Chief of Immunology at the Italian National Research Centers on Aging in Ancona, Italy, illustrated this concept of how the interaction of the neuroendocrine, nervous and immune systems result in the mutual disruptions in these systems resulting in age-associated dysfunctions and diseases (Fig. 6).
Mechanisms of Immune Regulation and Dysfunction—Thymus Programs T Cells
Dr. Fabris proposes that there are two levels of communication between the neuroendocrine and the immune systems. The first level is based on the interactions between the neuroendocrine system and the thymus. As mentioned, T lymphocytes require programming by thymic factors to become “mature,” fully functioning lymphocytes. Without this programming, the lymphocyte precursors remain unprogrammed, and immunologically ineffective.
The second level of interaction is at the periphery, between neuroendocrine signals and the cell-signaling substances (cytokines) that are secreted by immune cells during specific reactions to various antigens.
Cytokines
Cytokines are hormone-like peptide molecules produced by lymphocytes that act as messengers to affect other cells. In fact, cytokines affect all facets of the immune response. Cytokines include interleukins (IL), interferon, and chemokines (which make white blood cells move to sites of inflammation), tumor necrosis factors (TNF), and colony stimulating factors (CSF). Cytokines are classified roughly into two main groups—T-Helper Cell 1 (TH1) and T-Helper Cell 2 (TH2). TH1 responses are characterized by higher levels of IL-2 and IFN-gamma, and TH2 responses are characterized predominantly by IL-4, IL-6, and IL-10.
Cytokines as Indicators of Immune System Aging
During youth and early adulthood, TH1 and TH2 profiles remain fairly balanced. However, as age progresses, the cytokine secretion pattern shifts towards one dominated by TH2 cytokines, while TH1 responses are inhibited.
Proinflammatory cytokines include IL-1, TNF-alpha, IL-6, and interferon gamma. These are found in a number of diseases associated with advancing age, such as rheumatoid arthritis, diabetes, infection, cancer, cardiovascular disease, cerebrovascular disease, and even periodontal disease (gingivitis) (Fig. 7). Elevated levels of these proinflammatory cytokines also contribute to the development of anemia by blocking erythropoeitin, or by interfering with iron metabolism. Anemia is associated with increased mortality, poor health, fatigue, and cardiovascular and neurological problems. In fact, anemia of chronic disease (Fig. 8) is the most common form of anemia in the elderly.
One of the causes of the increased inflammation seen in aging is the increased level of IL-6. Plasma levels of IL-6 have been correlated with general functional disability in the elderly and increased incidence of rheumatoid arthritis. Interestingly, DHEA levels are inversely related to IL-6—i.e., as DHEA levels decrease, the levels of IL-6 increase. Conversely, high levels of DHEA inhibit IL-6 secretion.
Inflammatory macrophage secretion of IL-6 serves to move the balance between TH1 and TH2 responses to a TH2 response (secretion of IL-4 and IL- 10). A powerful TH2 response suppresses a TH1 response, and the individual becomes more susceptible to the consequences of a diminished TH1 response. This results in an increased frequency of infections and susceptibility to diseases such as cancer.
Revitalizing Aging Immune Function
When the immune system goes haywire, in addition to being more susceptible to infections and cancers, the body attacks itself, resulting in an autoimmune disease like amyloidosis, Lupus erythematosis (LE), or Multiple Sclerosis (MS).
It is often simplistically thought that the immune system should be stimulated to prevent or overcome an infectious disease or cancer, and that it should be suppressed in case of an autoimmune condition. However, thymic hormones do not automatically just “turn up the volume” and increase all immune activity. Rather, thymic hormones tend to reduce immunity when it is excessive, and to increase immune activity when it is deficient.
Lifestyle factors such as caloric restriction and moderate (but not severe) exercise help restore the TH2 response of older animals to one of TH1/TH2 balance.
In addition, dehydroepiandrosterone (DHEA) restores the cytokine secretion profiles and balance of old animals to those of much younger animals. In aged animals, DHEA increases IL-2 secretion, and enhances antibody production (which is depressed in aged animals). DHEA thus appears to help reverse immune senescence.
The obvious approach to dramatically and quickly restore all aspects of immune function is to replace the key deficient hormone. I believe the most effective substance to accomplish this is Thymic Protein A, developed by Dr. Terry Beardsley. Dr. Beardsley identified Thymic Protein A nearly twenty years ago as THE thymic factor responsible for “educating” the T cells, which have been shown to be very important in not only restoring TH1/TH2 balance to that of young adults, but in improving the overall response of other immune factors as well. I believe that Thymic Protein A is the single most important substance to maintain a healthy, youthful immune system, and may be the “missing link” in a comprehensive neuroendocrine-related anti-aging program. Thymic Protein A has been shown to be effective in the treatment of cancer, leukemia, AIDs, chronic fatigue and fibromyalgia, chronic and acute infections, anemia, and autoimmune diseases such as Lupus. I believe its therapeutic potential is extremely broad and varied, and includes virtually every immune-related acute and chronic disease.