15.6: Age Changes

Distinguishing age changes from other changes in the immune system is difficult for various reasons. Reasons include limited understanding of this complex system; confounding influences from changes in nonspecific defense mechanisms; diverse and rapidly changing methods of research; controversy over the interpretation of results; and diversity in the factors affecting it. Examples of such factors include chronic exposure to sunlight; cirrhosis; malnutrition; diabetes mellitus; cancer; chemotherapy; radiation therapy; anesthesia; surgery; and stress. Common age-related increases in most of these factors reduce immune system effectiveness. Finally, comparing immune systems between individuals reveals an age-related increase in heterogeneity. Therefore, unless otherwise noted, the immune system changes described below represent average age-related changes that may be due in part to aging of the system.

Trends

As the age of a population increases, the proportion of people with a declining immune function increases and the level of immune function within the individual decreases. Decreases in immune function include reductions in the speed, strength, and duration of immune responses and in the regulation of the immune system. These age changes are a major reason for the higher susceptibility of elders to Coronavirus COVID-19, which spread as a national and worldwide pandemic starting in early 2020.

Developmental Changes

Most developmental changes in the immune system occur before the end of puberty and result in the formation of a mature immune system. The few developmental changes after this period may be considered age changes, most of which result in declining immune system functioning.

Macrophages and Langerhans Cells

Age changes and age-related changes in macrophage production and numbers have not been well studied, suggesting that these changes are small. However, the rate of production of Langerhans cells falls below the rate of destruction, leading to significant decreases in cell numbers. Areas of skin chronically exposed to sunlight have much greater reductions than do unexposed areas. These reductions lead to decreases in the processing and presentation of antigens in the epidermis, causing increasing risks of skin infection and cancer and decreasing delayed-hypersensitivity reactions, including allergic reactions. The latter change causes a reduction in signs and symptoms (e.g., local swelling, itching, rash) that warn of the presence of potentially harmful substances (e.g., topical medications) and are used in skin tests to detect previous exposure to tuberculosis (e.g., tine test).

Thymus and T Cells

The thymus begins to shrink during or shortly after puberty and continues to do so until about age 50, when it may be only 5 percent of the original size. Thymic hormone production declines in a parallel fashion, and circulating levels of these hormones reach zero by age 60. These changes cause a precipitous decline soon after puberty in the conversion of unspecialized lymphocytes to T cells and the clonal selection of T cells. Lymphocyte conversion and clonal selection for T cells finally cease, ending the development of immune response capabilities against additional antigens.

Though changes in T cells in human lymph tissues have not been well studied, healthy people seem to retain a steady rate of production of antigen-specific T cells in lymphoid tissue since the total number of T cells in the blood remains stable. However, declining thymic hormone causes reduced maturation of T cells, resulting in a decrease in the ratio of mature to immature T cells in the blood. This change decreases the number of circulating T cells that can respond to and combat each antigen. The degree of change varies considerably between individuals because of differences in aging, abnormal conditions, diseases, and other factors. Up to 25 percent of older people may show no decrease in T-cell functioning, while approximately 50 percent have moderate declines. The remaining 25 percent experience major decreases in T cell responses to an antigen.

B Cells

As with T cells, B-cell production from B-cell clones that were established early in life seems to remain steady in many people since the total number of these cells in the blood usually remains stable. However, the number of circulating B cells decreases in some individuals. Ordinary changes in B-cell numbers are not important since limitations in B-cell functioning derive from decreases in T-cell stimulation of B cells rather than from changes in B cells themselves.

Immune Responses

Decreases in immune system function result not only from developmental changes in the immune system but also from age-related changes in immune responses.

Processing and Presentation

Aging seems to have little or no effect on the functioning of macrophages and Langerhans cells during the initial processing and presentation stage of an immune response. However, the effectiveness of macrophages and Langerhans cells during an immune response decreases with aging because they receive less IL-2 stimulation from hT cells that bind to them. The effectiveness of Langerhans cells also declines because their total number decreases with age.

Age-related changes in the ability of macrophages and Langerhans cells to convert T cells into specialized T cells (hT cells, etc.) are unclear. However, when T cells from older people are experimentally stimulated to reproduce, fewer T cells can reproduce and those which reproduce do so fewer times. These decreases seem to be caused by a combination of declining production of IL-2 and declining T-cell responsiveness to IL-2. Since the progeny from T cells control all subsequent aspects of the immune response, age-related reductions in T-cell proliferation lead to reductions in all the subsequent parts of an immune response. Part of the decline in cell reproduction may result from loss of telomeres.

Regardless of reductions in the proliferation of T cells or specialized T cells, there is an age-related decline in both the production and effectiveness of IL-2 from hT cells. This decline stems from a decrease in IL-2 receptors on T cells and specialized T cells. By reducing the positive feedback effects of IL-2, these changes diminish the intensity of both the cell-mediated and humoral parts of an immune response, reducing all its defensive capabilities. Delayed-hypersensitivity responses also decline, reducing their roles in defense and as warning mechanisms.

Since aging decreases the ratio between TH-1 hT cells and TH-2 hT cells, immune responses become unbalanced. This loss of balance causes reductions in certain aspects of the response while producing excesses in other aspects including IL-6 production and autoimmune responses. The extra IL-6 contributes to loss of bone matrix and unwanted inflammation. The excess inflammation contributes to increased damage from free radicals and age-related diseases (e.g., atherosclerosis, arthritis, Alzheimer's disease, kidney disease). These and other adverse effects from weaker, unbalanced, and poorly regulated immune responses form the basis for the immune theory of aging (see Chapter 2).

The average activity level of NK cells, which receive stimulation from cT cells, does not change. However, total NK-cell activity becomes more heterogeneous between individuals. Additional NK-cell heterogeneity develops because of individualized increases and decreases in NK cells for different types of cancer. People with a reduction in NK-cell activity may have an increased risk of developing cancer.

Finally, age-related decreases in IL-2 may contribute to a decline in sT-cell numbers or effectiveness, which may be a main factor in the age-related reduction in the regulation of the immune system. This reduction is evident as an increase in the production of autoantibodies, which are antibodies against self-antigens. No significant consequences from autoantibodies resulting from aging have been discovered. However, while they are suspected of contributing to age-related detrimental changes such as seminiferous tubule degeneration, they may be beneficial by helping rid the body of abnormally altered proteins. Autoantibodies resulting from processes other than aging may contribute to abnormal or disease conditions such as rheumatoid arthritis.

B-cell Participation and Antibodies

Aging seems to have little or no direct effect on the ability of B cells to bind to antigen, be activated, or perform their other functions during a primary immune response. As mentioned previously, however, all aspects of B-cell participation decline with aging because B cells receive less IL-2 stimulation from hT cells. Consequently, more antigen is needed to prompt antibody production, antibody production is slower, antibody production ends sooner, a lower peak antibody concentration is achieved, and the antibody level declines faster. Furthermore, the effectiveness of antibodies against certain antigens declines because some antibodies bind less well to their antigens and because of the increased variability in the proportions of the different classes of antibodies. Of note is a decline in IgE. Finally, there is an increase in autoantibody production.

The first six changes contribute to the age-related decline in the effectiveness of primary immune responses. The decline in IgE contributes to the age-related decline in allergic reactions. All changes in B cells and antibodies develop slowly until approximately age 60, after which they occur more rapidly.

Memory

As primary immune responses diminish with aging, they leave the body with fewer memory cells and less residual antibody for memory. Furthermore, residual antibody dissipates faster. As immune memory declines with aging, the speed and strength of the initial secondary immune response against an antigen also decline. Therefore, the higher the age at which an antigen is first encountered, the greater injury caused by a second encounter with that antigen. The antigen also may cause injury many times because additional secondary responses may be needed before acquired active immunity develops. Because of these changes, aging is accompanied by a decline in the effectiveness of initial vaccinations.

Though memory produced from primary immune responses declines substantially with aging, there is much less of a decline in the ability to maintain memory produced during youth or young adulthood. Therefore, secondary immune responses resulting from such early memory remain effective, especially if the antigen is encountered occasionally, as occurs with booster doses of vaccines.

Furthermore, since the decline in establishing memory becomes particularly evident after age 60 and advances more rapidly afterward, vaccinations should be received well before age 60. However, vaccines can be beneficial at any age, especially for those who are weakened by other factors and are at high risk for exposure to certain bacterial pneumonias (e.g., pneumococcal pneumonia) or strains of influenza virus.

Consequences

In conclusion, age changes in the immune system contribute to a decline in the ability to maintain homeostasis because they decrease resistance to harmful foreign materials and lead to an increase in the incidence and severity of infections and cancer. The risks increase with the age at which antigens or carcinogenic factors are first encountered. The risks also increase, though less so, with the number of years between encounters with an antigen. The effects on the immune system of many other age-related factors magnify these consequences, as do many age-related changes in nonspecific defense mechanisms. By contrast, the undesirable effects of allergic reactions decrease with aging.

There is an increased incidence of renewed injury from the bacteria causing tuberculosis (TB) and the virus causing chickenpox. In both cases the disease-causing agent may reside within body cells indefinitely, where it is hidden from immune cells after the disease seems to have disappeared. As immune memory against these diseases fades and age-related changes and factors such as stress weaken the immune system, the bacteria or virus is no longer held in check. TB bacteria, which reside in lung cells, may then cause a reactivated infection and additional lung damage. The chickenpox virus, which resides close to the spinal cord in sensory neurons, will be transported down sensory neurons to the areas of the skin they serve. Once there, the virus can cause excruciating pain and severe skin eruptions known as herpes zoster or shingles.

Finally, age changes in the immune system increase the progress and the severity of effects from HIV infection.

Minimizing Consequences

Since the consequences of declining immune system effectiveness often lead to a reduced quality of life and lower life expectancy, researchers are seeking ways to prevent, reduce, or delay the deterioration of the immune system caused by aging. Though some success has been achieved in animals (e.g., diet regulation), no practical and effective methods for humans are available. Other research is aimed at restoring immune system effectiveness lost because of age changes. Studies with animals involving supplements (e.g., thymic hormones, sex hormones) and other drugs have been somewhat successful, but safe and effective methods for aging humans have not been developed. A potential hazard from stimulating immune functioning is the activation of harmful immune activities (e.g., autoimmunity, allergic reactions) along with beneficial ones.

Though there are no practical methods for controlling aging of the human immune system, steps can be taken to help minimize other undesirable changes in this system, including avoiding or reducing factors known to suppress immune system functioning. Other actions may reduce the risks of developing the adverse consequences of decreases in immune functioning. These actions include receiving vaccinations in a timely fashion and minimizing exposure to potentially harmful agents such as bacteria, viruses, and carcinogens. Finally, risks can be reduced by preventing or treating abnormal conditions and diseases that promote infections and cancer.