Clinical Effects of Immune Senescence

Immune senescence usually develops insidiously; its effect on health often manifests during intense physiologic stress (eg, surgery, multiple organ failure, protein-energy malnutrition, dehydration). Many chronic illnesses common in old age may adversely affect immune function in elderly persons and should be diagnosed and treated when possible. Genetic and environmental factors also probably play a significant role in the occurrence of immune dysfunction.

The clinical significance of increased autoantibodies in the elderly is unknown. Paradoxically, autoimmune disorders peak in middle age and are less common in elderly persons, which would not be expected considering what is known about decreased tolerance to self with age. On the other hand, autoantibodies may play a role in some of the degenerative diseases of aging.

Because immune senescence results from dysfunction rather than from definitive exhaustion of the immune system, it may theoretically be reversed. Hormonal and nonhormonal drug treatment (eg, growth hormone, dehydroepiandrosterone, melatonin, zinc, vitamin E) has shown promising results and may help restore efficient immune function in the elderly.

Infectious diseases: A causal relationship between immune senescence and the reactivation of infectious diseases (eg, herpes zoster, tuberculosis) is clearly established. The incidence of herpes zoster increases fivefold between the ages of 45 and 85 in association with an age-related loss of cellular immunity to the varicella-zoster virus. There is also endogenous reactivation of latent Epstein-Barr virus infection in institutionalized elderly patients. Age-related decreases in specific antibody production may partly account for the high incidence and extreme mortality associated with pneumonia, influenza, infectious endocarditis, and tetanus among the elderly. Although the etiology of nosocomial infections is complex, age-related decreases in antibody response probably play some role in the fact that 65% of all nosocomial infections occur in patients > 60. Elderly persons are also more susceptible to parasitic infections, especially those caused by metazoan and protozoan parasites.

However, the risk of infectious diseases attributable to immune senescence is difficult to differentiate from that attributable to the various pathophysiologic structural and functional alterations of different organs, which probably determine the specific location of some infections. For example, an impaired cough reflex, reduced mucociliary clearance, altered microbial flora, and increased colonization of the oropharynx lead to severe respiratory tract infections independent of immune function. The loss of bacteriostatic properties of urine together with reduced kidney ability to acidify urine and incomplete bladder emptying render elderly persons particularly susceptible to urinary tract infections. Age-related changes in the gastrointestinal tract (eg, achlorhydria, diverticula) may predispose to the development of gastrointestinal infection.

Response to immunization: Production of specific antibody is decreased when vaccines containing antigens (eg, tetanus toxoid, hepatitis B virus) are given to elderly recipients who had no prior immunity induced by natural infection. The effect of immune senescence on the antibody response to vaccines in patients with prior immunity induced by natural infection or previous immunization (eg, influenza and pneumococcal vaccines) is difficult to evaluate. As many as 30 to 40% of healthy elderly persons may not develop protective immunity after immunization with influenza vaccine. Pneumococcal vaccines are also less effective among elderly persons than among healthy younger persons.

Cancer: Immune senescence may impair the recognition and elimination of tumor cells, but there is no compelling evidence that failure of immune surveillance contributes to the increased incidence of cancer in the elderly.

Antigen-driven clonal expansion followed by neoplastic transformation may be involved in the aging-related development of chronic lymphocytic leukemia (CLL). CLL is characterized by a clonal outgrowth of B lymphocytes and accompanied by severe immunologic disturbances (eg, hypogammaglobulinemia, autoimmune manifestations).

Monoclonal gammopathy: The frequency of idiopathic paraproteinemia increases from < 1% at age 50 to 20% at age 90. Animal studies have shown an age-related increase in homogenous immunoglobulin levels after thymectomy, suggesting that T-lymphocyte dysfunction is involved in the pathogenesis of dysglobulinemia.

Degenerative diseases of aging: Immune senescence may contribute to many age-related degenerative diseases that are not ordinarily considered immunologic in etiology.

Autoantibody production tends to increase in the presence of chronic diseases that are prevalent in the elderly and is sometimes associated with organ dysfunction or with a specific disease. For example, high levels of autoantibodies directed toward components of the thyroid, pancreatic, adrenal, and pituitary glands have been associated with the respective hormone deficiency and associated diseases (eg, hypothyroidism, diabetes, hypopituitarism). Autoimmunity to heparin sulfate proteoglycan has also been associated with vascular disease in the elderly.

This link with specific diseases may explain why the presence of autoantibodies in the elderly is associated with reduced life expectancy. Conversely, the lack of organ-specific autoantibodies (ie, the absence of autoreactivity) after age 80 may represent a survival advantage.

Other altered immunologic activities may be implicated in several pathologic conditions typically associated with aging. For example, activated lymphocytes are found in atheromatous lesions and probably participate in atherosclerosis. The presence of T lymphocytes near neuritic plaques indicates that some type of immunologic response occurs in Alzheimer's disease. Also, the association of complement protein with senile plaques suggests that activation of complement pathways may contribute to neuronal cell death in Alzheimer's disease. The age-related increase in IL-6 production, a lymphokine that induces bone resorption, may be involved in the development of osteoporosis and may, if excessive, be part of the pathogenesis of late-life lymphoma, myeloma, and Alzheimer's disease.