The older population among humans is increasing at an unprecedented rate. With recent advances in medical technology and better nutrition, people are living longer than ever, especially in developed countries where life expectancy will have nearly doubled from ~45 in 1900 to ~80 by 2000. To provide adequate health care for the elderly, scientific study of the medical aspects of the aging process is necessary. The immune system is one function of the body profoundly affected by aging, and since the immune system interacts with every organ and tissue in the body, focused research on the immunology of aging is needed to further our understanding of the aging process as a whole.

Immunogerontology, the study of the immune system in the elderly, is a relatively new field, and large amounts of data are not yet available on some key components of the immune system as it ages. Conclusions drawn from animal studies, tissue culture studies and human studies investigating the same topic often suggest conflicting conclusions, but these discrepancies will probably be resolved once more data become available. Controversy arises in part because gerontologists have not created commonly accepted definitions of when the aging process begins or at what point an individual is considered "aged." Traditional aging studies merely compared a population of "young" individuals against a population of "old" individuals without attempting to define "young" and "old." Without a clear definition of these terms it is difficult to determine whether immunological differences observed in the aged group result from age only or are instead the results of age-related disease. To work around this problem and develop a definition of what normal aging is for a healthy older population, several studies have focused exclusively on centenarians under the assumption that an individual who lives to be 100 must be exceptionally healthy. Even though this population is extremely limited, the conclusions from these studies have helped to lay the groundwork for broader studies that include a younger elderly population.

In 1984, a collaborative study group developed the SENIEUR protocol as an attempt to define the criteria for selecting truly healthy aged individuals for immunogerontological studies. The SENIEUR protocol sets forth strict health guidelines based on clinical and laboratory data in an effort to reduce the bias present in other studies; that is, the confusion between observed phenomena caused by the natural process of healthy aging, and phenomena attributed to age-related disease. Employing the SENIEUR protocol, some recent studies have overturned several long-held assumptions about the aging of the immune system. The following paragraphs will review some of these newer findings in immunogerontology.

It is well-documented that immunocompetence declines with age; that is, as people age, the immune system begins to lose some of its functions and cannot respond as quickly or as efficiently to stimuli. Age-related changes in the immune system have been observed at all levels ranging from chemical changes within the cells, to differences in the kinds of proteins found on the cell surface, and even to alterations in entire organs. Studied separately, some of these changes may seem trivial, but when all of the changes are added up, they radically affect the overall health of the individual.

One major change that occurs as the body ages is a process termed "thymic involution." The thymus, located above the heart behind the breast bone, is the organ where T cells mature. T cells are an extremely important, highly-specialized population of lymphocytes that have many functions ranging from killing bacteria to assisting other cell types of the immune system. As humans age, the thymus naturally atrophies. The volume of thymic tissue in a 60-year-old adult is less that 5% that of a newborn, and it is postulated that if humans lived to be more than 120, the thymus would disappear altogether. Although T cells are produced continuously throughout life, over time this progressive decay of the thymus causes a sharp decrease in the number and type of T cells produced. It is not known why the thymus deteriorates in this fashion. The prevailing theory is that the thymus is an extremely energy-expensive organ that is most needed in the early stages of life when the body has not had time to develop resistance to foreign antigens. Once the immune system fully develops and can protect the host against a myriad of antigens, the thymus may be too costly to maintain, so it is evolutionarily advantageous to decrease the amount of thymic tissue and use the energy that would have supported the thymus for other purposes. However, because T cells play such a prominent role in immunity, longer-lived individuals still need a continuous supply of "fresh" T cells to protect against newly-encountered antigens, and this slow but progressive loss of thymic tissue has profound effects on the entire immune system of the aged.

Aging affects the functions of T cells in a myriad of ways. Several subpopulations of T cells are found in the thymus and in the blood circulation, among them, naive T cells and memory T cells. Naive T cells are quiescent T cells that have never been exposed to any foreign antigen, while memory T cells are long-lived antigen-activated cells that rapidly respond to a second exposure to the same antigen. When encountering a foreign antigen, naive T cells become activated, stimulate the immune system to eliminate the foreign antigens from the body, and convert into memory T cells. The memory T cells then become dormant and are only reactivated upon a subsequent exposure to that same antigen. A marked difference has been observed between young and old subjects in the subpopulations of naive and memory T cells. In newborns, the ratio of naive to memory T cells is quite high; in adults the ratio is reversed because most of the naive T cells have been exposed to antigen, and hence converted to memory cells. The elderly have almost no naive T cells at all, since as the thymus progressively deteriorates with age, fewer T cells are produced, and the naive T cell subpopulation is not replenished. Consequently, the stock of naive T cells becomes depleted and the aged immune system cannot respond as well as a young person to a "new" antigen.

In addition to the decline of certain subpopulations of T cells, important changes occur at the cell surface of all T cells. When a T cell, using T cell receptor proteins found on the cell surface, binds to an antigen, that environmental stimulus must be communicated to the interior of the T cell. Many molecules are involved in "signal transduction," the process of transmitting the antigen-binding signal across the cell membrane into the cell. Signal transduction is a cascade of chemical reactions, each dependent upon the preceding event. Aged T cells do not display the CD28 antigen, a molecule critical for signal transduction and T cell activation, on the cell surface. Without this protein, T cells remain quiescent and do not respond to foreign pathogens. One indication of a malfunctioning signal transduction pathway in T cells is that the presence of CD69 antigen on the cell surface is lower in elderly individuals. T cells are induced to display CD69 antigen only after antigen binds to the T cell receptor. If the antigen-binding signal is not transmitted to the interior of the T cell, CD69 antigen will not appear on the cell surface, and is an indication that in older people, less signal transduction is occurring.

Another defect of T cell activation among the elderly is characterized by a decrease in calcium. Calcium is a vital element that is absolutely crucial for many biochemical reactions, including signal transduction. A calcium deficiency in T cells effectively halts signal transduction by failing to stimulate enzymes, including protein kinase C, MAPK and MEK, that require calcium for proper function. Decreased amounts of calcium can also inhibit production of cytokines, proteins responsible for coordinating the interaction with antigen and amplifying the immune response.

One cytokine that has been widely studied is interleukin 2 (IL-2), a cytokine produced and secreted by T cells that induces cell proliferation and supports long-term growth of T cells. As T cells age, they lose their capacity to produce and respond to IL-2. When exposed to antigen, memory T cells will rapidly divide and proliferate to make more T cell clones to fight the antigen, but only proliferate upon stimulation with IL-2. If not enough IL-2 is produced, or if the T cells cannot respond effectively to IL-2, T cell function is greatly impaired. Changes in other cytokines such as interleukin 4, tumor necrosis factor-alpha , and gamma-interferon have also been recorded, but it is not yet known to what extent these changes influence the aging immune system.

Age-related genetic alterations occur within T cells as well. In vitro studies of human T cells cultured for long periods have shown that the cell cycle slows and eventually halts, even when the cells are grown in the presence of IL-2; that is, the T cells cease to divide and become too old to function properly. Several problems with the genetic machinery of T cells may account for this slow failure of the cell cycle. Transcription factors (like NF-kB and AP-1), proteins that use a DNA template to create RNA during the process of manufacturing protein, appear to be impaired or become inactive, which through aging contribute to the decline in T cell responsiveness by failing to activate the genes necessary for T cell stimulation. Aged T cells are more susceptible to apoptosis, or programmed cell death, due in part to the gradual loss of telomeres that cap the ends of the chromosomes to prevent DNA degradation. T cell receptor gene rearrangement problems contribute to thymic involution by making the cells less resistant to apoptosis. Thus it seems that T cells have a limited lifespan, and immunosenescence is genetically programmed.

This reduced function of T cells in the elderly also affects B cell function because T cells act in concert with B cells to regulate the production of antibodies. T cells induce B cells to hypermutate immunoglobulin genes, which in turn create the antibody diversity necessary to recognize a wide range of antigens. Aged helper T cells cannot interact as effectively with B cells, and so in the elderly, the potential antibody repertoire is more restricted than the antibody repertoire of younger people. The production of immunoglobulin M (IgM), one of five classes of antibodies, is especially affected. During infection, IgM is the first class of antibodies to respond. In the elderly the inability to ward off infections easily withstood by younger people could be linked to this diminishing IgM response. The rate of B cell maturation also decreases with age. Although B cells are produced in the bone marrow throughout life, the number of B cells generated declines with age. Having fewer mature B cells contributes to the observed decrease in the amount of antibody produced in response to infection.

Autoantibodies, antibodies that react against "self" antigens, are usually hallmarks of autoimmune disease. However, the presence of autoantibodies is often correlated to age, even in healthy aged individuals who do not have an autoimmune disease. Although interleukin 10 (IL-10) is one molecule that stimulates production of autoantibodies in patients with autoimmune disease, IL-10 does not seem to have this effect in healthy aged individuals. Instead, autoantibody production in the elderly may be linked to the functional changes in T cells described above. It appears that autoantibody production in small quantities is a normal part of aging, although the reasons behind this are not understood. One possibility is that age-related mutations in T cell genes could create a subpopulation of T cells that recognize host self-antigen. Normally, such T cells would be eliminated in the thymus before they fully matured, but thymic involution allows this destructive population of T cells to persist. These T cells could then induce B cells to produce autoantibodies against self antigens. This theory seems to be supported by a study performed in mice demonstrating that transplantation of a fetal thymus into an aged recipient with an autoimmune disease can restore immune function and thus treat autoimmunity.

Other cells of the immune system are also affected by aging. The activity of leukocytes, including macrophages, monocytes, neutrophils, and eosinophils, is reduced in the elderly, although there are very little data available on the effects of aging on these cell types. Natural killer (NK) cells, cells that secrete cytokines and kill other cells, are one cell type that has been studied extensively. It was once thought that all NK cell functions decline with age, but this theory was based primarily on mouse studies and on human studies performed without using the SENIEUR protocol. In studies where the SENIEUR protocol was employed, it was found that NK cell activity in humans changes very little over time, although one contradictory study suggests that even though the cytotoxic (cell-killing) function of NK cells is maintained, the cytokine secretory activity is impaired. Since cytokines play an important role in tumor development and warding off infection, immunosenescence of NK cells could have extensive effects on the immune system. More research of NK cells is needed to resolve these discrepancies.

What implications do all of these changes in the aging immune system have for health care of the elderly? Two areas of preventive health care have been widely studied: vaccination and nutrition.

It is well-documented that the elderly do not respond as well to vaccinations as young people. The purpose of a vaccine is to "educate" the immune system against an infectious agent. Vaccines provide a non-infectious substance containing the same antigens as the foreign pathogen to teach the immune system to recognize that foreign pathogen by creating populations of memory T cells and antibody-producing B cells and thus prevent future infection. Some vaccines, like the vaccine for smallpox, only need to be administered once to confer lifetime immunity. Other vaccines, such as vaccines for influenza, need to be administered annually because there are multiple strains of influenza virus and the dominant strain changes each year. Influenza and pneumonia are two diseases that particularly affect the elderly, and providing vaccinations is a high priority in eldercare. However, there are special challenges involved in developing vaccines targeted for older adults. In the elderly, antibody responses to vaccines are slower and not as strong as in younger people, and T cell subpopulations are not very responsive to vaccines. For reasons that are not yet clear, memory T cells from aged individuals do not react as quickly or for as great a duration as cells from younger subjects. Numerous studies have examined means of improving the efficacy of vaccines for the aged. Novel types of vaccine delivery using, for example, liposomes or naked DNA to create a more powerful immune response, are being developed. Alternative adjuvants such as IL-2 are being tested to boost vaccine efficacy. New methods of vaccination, like using nasal sprays or oral vaccines to stimulate mucosal immunity, instead of the traditional injections, are also being explored.

Nutrition plays a prominent role in immune response, and the elderly often suffer from malnutrition. Reduced caloric intake is known to slow the aging process and help maintain higher numbers of naive T cells and levels of IL-2. Vitamin E and zinc in particular are important nutrients for the proper functioning of the immune system. Long-term zinc deficiency in the elderly causes a decrease in cytokine production and impaired regulation of helper T cell activity. Vitamin E has recently been in the news as a possible treatment for Alzheimer's disease [see CSA's Discovery Guide Series: Alzheimer's Disease, by Fred Spangler], and it seems that vitamin E supplements may also boost the immune system. In both mice and humans, a daily dose of vitamin E significantly higher than the U.S. Recommended Daily Allowance improved T cell function in cell-mediated immunity. Vitamin E is also an antioxidant that can protect lymphocytes, the brain, and other tissues from destructive free radicals.

As we have seen, aging affects many components of the immune system, and since the immune system interacts with every organ in the body, a clearer understanding of the immunological changes due to aging is critical for designing effective health care for the elderly. One excellent resource that provides an overview of the research opportunities and challenges faced by immunogerontologists is the Report of the Task Force on Immunology and Aging published jointly in 1996 by the National Institute on Aging and the National Institute of Allergy and Infectious Diseases of the National Institutes of Health, U.S.A. This report is free and may be requested by writing to the NIAID Office of Communications, Bldg 31, Room 7A50, 31 Center Drive, MSC 2520, Bethesda, MD 20892-2520 USA.

Glossary

• adjuvant: a non-reactive substance incorporated into vaccines to enhance the immune response against the vaccine. Adjuvants cannot stimulate an immune response by themselves.
• antibody: proteins produced by B cells in response to stimulation by an antigen. Once a B cell encounters an antigen, the B cell produces identical antibodies that recognize and bind to only the antigen that stimulated the B cell. Each antibody has a slightly different amino acid sequence that renders it specific to only one antigen.
• antigen: a foreign substance that binds to antibody or T-cell receptors that elicits an immune response. Antigens can be proteins, carbohydrates, nucleic acids, hormones, or other substances. The immune system usually responds against only foreign antigens, but in autoimmune disease the immune system will react against self-antigens produced by the body as if the self-antigens were foreign.
• apoptosis: programmed cell death, during which the chromosomes condense, the DNA degrades, and the cell "self-destructs."
• autoimmune disease: a disease in which the immune system attacks the host's own body and causes tissue damage. The host's immune system mistakes host self-antigens for foreign antigens and mounts an immune response against tissues displaying those self-antigens. Lupus, rheumatoid arthritis, and multiple sclerosis are examples of human autoimmune disease.
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• B cells: a population of white blood lymphocytes that matures in the bone marrow and produces antibodies. B cells may be found in the bone marrow and in the blood circulation.
• CD antigens: proteins displayed on the surface of lymphocytes that can serve as biochemical markers characteristic for a particular cell type. CD stands for "cluster of differentiation" and indicates the lineage or maturational stage of lymphocytes. The internationally- recognized format for naming such molecules is CD followed by a number (CD28 antigen or CD69 antigen, for example). Some CD antigens have a well-known function, but other CD antigens have no known function.
• cytokines: proteins synthesized by cells of the immune system that interact with the immune, nervous, and endocrine systems. Cytokines can be both immunostimulatory and immunosuppressive. Interleukins, interferons, and some growth factors are examples of cytokines.
• immunocompetence: the quality or state of the immune system being functionally adequate.
• immunogerontology: the study of the aging process of the immune system.
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• immunoglobulin: another word for antibody. Immunoglobulins are subdivided into 5 classes, and are designated immunoglobulin M (IgM), IgA, IgE, IgD, and IgG
• immunosenescence: the aging of the immune system.
• leukocytes: white blood cells. B cells, T cells, monocytes, macrophages, basophils, eosinophils, neutrophils, and natural killer cells are all populations of leukocytes.
• liposomes: spherical lipid vesicles that contain a substance such as a drug or vaccine to be delivered to a particular cell type.
• lymphocytes: a population of white blood cells, of which T cells, B cell, and natural killer cells are subpopulations.
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• mucosal immunity: a part of the immune system associated with the mucosal tissues of the respiratory tract, gastrointestinal tract, and urogenital tract.
• natural killer cells: cells that attack and destroy virus-infected cells and tumor cells.
• signal transduction: a process by which a cell reacts to an environmental stimulus by transmitting the external signal across the cell membrane to the interior of the cell. Proteins displayed on the cell surface serve as receptors for specific molecules. When a molecule binds to a receptor, the binding instigates a cascade of biochemical events inside the cell that involves many enzymes, protein and ions (especially calcium). Each event is dependent upon the preceding event, and if one part of this chain is missing, signal transduction is interrupted.
• T-cell receptor: a protein complex displayed on the surface of T cells that binds to antigen. Like antibodies, T cell receptors are specific for only one antigen.
• T cells: a population of white blood lymphocytes that matures in the thymus. T cells may be found in the thymus, lymph nodes and blood circulation. T cells have many functions including assisting other cells of the immune system, killing foreign pathogens or infected cells, and even suppressing the immune response.
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• telomeres: specialized repeated DNA sequences on the ends of chromosomes that protect the chromosomes from degradation.
• thymus: an organ located behind the sternum, just over the heart, where T cells mature.
• transcription factors: proteins that help synthesize RNA using a DNA template. NF-kB protein and AP-1 protein are two well-known transcription factors.

Editor

Deborah B. Whitman, M.S.

• CSA Senior Life Science Editor: Biotechnology, Immunology, Oncogenes and Growth Factors

• B.S. (Biology, Phi Beta Kappa), Mary Washington College, Fredericksburg, Virginia

• M.S. (Biotechnology), The Johns Hopkins University, Baltimore, Maryland

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