From Primary Cultures to the Aging Organism Lessons from Human T Lymphocytes

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Rita B. Effros

One of the prominent clinical features of human aging is the dramatic increase in morbidity and mortality due to infections. Aging is also the most significant risk factor for developing cancer. Both phenomena are related to the age-associated decline in immune function, particularly within the T cell compartment, the part of the immune system that patrols the body for cells that appear foreign, which would indicate they are infected or cancerous. Development of long-term cell culture protocols for analyzing the effect of chronic antigenic stimulation on primary T cells from young adult donors has led to the identification of multiple characteristics of the terminal stage of replicative senescence in this cell type. These include inability to divide, altered cytokine patterns, resistance to apoptosis, shortened telomeres, reduced antiviral cytolytic function, and loss of expression of a major signaling molecule, CD28. Many elderly persons have high proportions of T cells with similar characteristics, and the abundance of these cells has been correlated with such deleterious outcomes as poor response to vaccination, osteoporotic fractures, reduced immunity to infection, and even early mortality. Thus, cell culture studies have provided novel insights into the cellular basis for an important facet of immune system aging that has significant effects on a variety of human age-related pathologies.

Introduction

Among the most significant clinical problems associated with aging are infections and cancer. Indeed, influenza and pneumonia rank as the 5th leading cause of death in U.S. adults age 65 and older. In addition to actual mortality, morbidity and prolonged periods of illness due to infections are substantially increased with age. With respect to cancer, epidemiological studies show that old age—even more than known harmful lifestyle factors, such as smoking—is the greatest risk factor for the development of cancer. One of the major contributory factors to the age-related changes in infection and cancer is the waning protective function of the immune system.

The complex changes that occur within the immune system of aged humans are due both to intrinsic events, such as the decrease in thymic size and function, as well as to environmental factors, mainly the lifelong exposure to various pathogens. The combined effects of these intrinsic and extrinsic factors lead to major alterations in immune function with age, changes that have been implicated in the deleterious effects of pathogens and cancer in the elderly. Ironically, vaccination, which is aimed at manipulating the immune system in ways that would prevent infection or retard cancer progression, is far less effective in the elderly (McElhaney et al., 1998). Even immune memory to certain pathogens that is generated early in life declines during aging.

In order to develop strategies for enhancing immune function of the elderly, a thorough understanding of the mechanisms responsible for age-associated immunological changes is clearly essential. In this chapter, we will focus on one particular component of the immune system, the T lymphocyte, and demonstrate how primary cell culture analysis of T cells has led to novel insights into an important and previously unrecognized facet of the immune system in elderly humans, namely, the accumulation of cells with characteristics of replicative senescence. Information from theses studies provides evidence suggesting that senescent T cells may affect not only immune function per se, but a variety of age-related pathologies. The high correlation between characteristics identified in vitro and T cells present in vivo suggests that the long-term T cell culture model will also be informative for evaluating therapeutic interventions to retard or prevent a variety of deleterious clinical problems associated with aging.

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