Julia W. Albright

Aging, immunity, and infection

Human Aging: Present and Future Demographics Infectious Diseases of the Aging Limits on Life Expectancy and Future Prospects Theories of Senescence Chapter Summary References Aging and Altered Resistance to Infection Relatively Common Bacterial Infections of Aging Humans Selected Examples of Age-Associated Susceptibility to Bacterial Infections Bacterial Interactions with Mucosal Surfaces Antibiotic Resistance and Bacterial Variation Viral Infections in Aging Humans Protozoan Parasites in Aging Subjects. Fungal Infections in Aging Subjects Chapter Summary References Senescence of Natural/Innate Resistance to Infection Pattern Recognizing Receptors of Innate Immunity Phagocytic Cells: Monocytes/Macrophages Microbial Evasion of Phagocytic Destruction Age-Related Changes in Macrophages Phagocytic Cells: Neutrophils Natural Killer/Lymphokine-Activated Killer Cells Chapter Summary References Aging of Adaptive/Acquired Immunity Aging of the Thymus and Thymus-Derived (T) Cells The Functions and Diversity of Peripheral T Cells Summary: Known and Cognizable Effects of Aging T Cells Differentiation, Functions, and Aging of B Cells Chapter Summary References Nutrition, Longevity, and Integrity of the Immune System RCI-Mediated Delay of Immunosenescence How Does RCI Promote Life-Span Extension? Dietary Restriction vs Malnutrition References Epilogue Index

Aging of innate immunity: functional comparisons of NK/LAK cells obtained from bulk cultures of young and aged mouse spleen cells in high concentrations of interleukin-2

The technique of bulk cultivation of aged mouse spleen cells in high concentration of IL-2 was employed to obtain NK/LAK cells in sufficient number and enrichment for studies on the effects of aging on their functions. The yield and enrichment were equivalent to that of young mouse spleen cells. The aged and young mouse NK/LAK cells were equivalent also in their functional competence to proliferate, kill target cells and produce IFNgamma; i.e. they did not display age-associated defects typical of freshly-isolated NK/LAK cells. In two respects, however, the NK/LAK cells derived from aged mouse spleen were altered: (a) in the efficiency of nuclear translocation of transcription factors STAT 5A and 5B, and (b) in the deficiency in production of mRNA transcripts representing several chemokines. We recommend caution in the use of bulk cultivation in IL-2 to obtain NK/LAK cells for studies on aging. However, it does appear from this study that aging may severely affect chemokine production, at least in the case of NK/LAK cells.

Effects of aging on the dynamics of lymphocyte organ distribution in mice: use of a radioiodinated cell membrane probe

We have employed a derivatized aminostyrylpyridinium dye, [125I]I2P-Di-6-ASP, to provide a relatively stable tag on mixed mouse splenocytes and purified B and T cells for the purpose of tracking the distribution of those cells among the organs of normal young (4 months) and aged (> 26 months) recipient mice. Cells from both young and aged donor spleens were studied. Special emphasis was placed on localization of donor cells in the spleens of the recipients because the majority of circulating lymphocytes localize in the spleen and the spleen is the principal organ of primary immune response. There was a profound difference in the efficiency of splenic acquisition of donor cells between young and aged recipients, a difference not found in the liver, lungs, kidneys or heart. In contrast young and old donor lymphocytes lodged equally well in the spleens of recipients of the same age. It was clear that the competence of the splenic microenvironment to serve as a lodging site for circulating lymphocytes deteriorated with age. Such a change could contribute significantly to the deficient immune response of aged subjects. We suggest that aging results in significant change in the splenic extracellular matrix to serve as an adhesive substratum for lymphocytes. Our data point to a need for detailed studies on age-related changes in components of the extracellular matrix within lymphoid tissues. The novel compound which we employed for cell labeling is both radioactive and fluorescent and should be quite suitable for such studies.

The decline of immunological resistance of aging mice to trypanosoma musculi.

Aged mice of several strains studied developed much more severe infections of Trypanosoma musculi (mouse-specific parasite) than did young adults. Reduced resistance of the aged mice, assessed from the resistance conferred on irradiated recipients by transfer of normal and infected donor spleen cells, resulted from a much slower development of immunity to the parasite, reflecting depleted immune competence, and from the expression in aged mice of an altered internal milieu unfavorable for normal function of lymphoid cells. An analysis of antibody-dependent cytotoxic reactions against T. musculi revealed no differences; therefore, intrinsic changes in antibody-dependent cytotoxic effector cells are not responsible for the decline in resistance to trypanosomes. The possibility that quantitative or qualitative changes in humoral antibody production might account for defective resistance of aged mice was minimized by demonstrating that antibodies play a minor role in the recovery from infection with T. musculi. Evidence of a significant role (possibly indirect) of macrophages in resistance to T. musculi was obtained. Altogether, our data raise the possibility that the decline in natural killer activity that is susceptible to amplification by macrophage-derived interferon may account for the defective resistance of aged mice to trypanosomes.

Senescence of Natural/Innate Resistance to Infection

It has been realized for decades that in humans and higher vertebrates there are, in addition to the adaptive immune system, accessory mechanisms and systems that contribute to overall immune defense against infectious organisms. They have been grouped under the heading “natural” or “innate” immunity. They include the reticuloendothelial system comprising “fixed” and “mobile” (circulating) monocytes (Mo’s) and macrophages (MPs), polymorphonuclear (PMN) cells (especially neutrophils and eosinophils that can discharge antimicrobial peptides such as defensins), natural killer (NK) and other “naturally cytotoxic” (NC) cells, and the complement (C) system; all of which have been preserved and handed down during the evolution of higher vertebrates from primitive vertebrates and invertebrates.

A Gut Reaction: Aging Affect Gut-Associated Immunity

The digestive functions of the intestinal tract are familiar to everyone. The immunoprotective functions of the intestinal tract are not. Not long ago, when relatively little was known about the structure and function of the intestinal immune system, it was reasonable to conclude that aging affected gastrointestinal (GI) immunity to a minor extent, if at all. However, there were gerontologists who were not convinced because – given excessive functional potential beyond what is normally required – it was doubtful whether experiments involving whole animals or complex ex vivo systems were reliable. To illustrate the point, consider the following quotation: ‘‘The multiorgan system that composes the gastrointestinal tract has a large reserve capacity, and thus there is little change in gastrointestinal function because of aging in the absence of disease.’’ Although that quotation was directed at the digestive function of the GI system, it may reasonably be argued that it embraces the immunological function as well. We intend to develop that argument in this chapter. First, however, we will provide a review of current understanding and

Aging of Adaptive/Acquired Immunity

It is appropriate to begin this chapter by quoting from an article (1) written by Philippa Marrack and John Kappler: Spurred on by the great immunochemists of the early twentieth century, immunologists acted for many years as though one antigen was as good as another. Antigens were used because they were cheap or convenient, so we learned a lot about the properties of immunity to materials such as sheep red blood cells, egg albumin, dinitrophenol, and so on. What immunologists found out, of course, was tremendously important, and most of the principles that are the foundation of modern immunology were learned with these models. This course of action, however, was to some extent misleading, because the fact of the matter is that, in real life, most infectious organisms have spent their millions of years of coevolution with the immune system developing mechanisms of manipulating the system. The upshot is that no invading organism behaves exactly like a sheep red blood cell and, if immunologists really want to understand how infectious diseases interact with their hosts, they have to study the disease and host themselves. Artificial substitutes simply will not do.

Nutrition, Longevity, and Integrity of the Immune System

In his masterpiece, Thales to Dewey (1), the philosopher, Gordon H. Clark, wrote the following in a discussion of epistemology: “knowledge is explanation, and to explain a matter is to state its cause.” If that be true (not relatively, of course), then we know very little about the fascinating effects of dietary manipulation on longevity and on immune capabilities. We are able to describe the effects but not to explain them.

Aging and Altered Resistance to Infection

Altogether, microbial and parasitic diseases constitute the leading cause of morbidity and mortality worldwide. They affect preferentially the very young and the elderly, the two age groups that are deficient in immunological competence. This chapter is a review of some of the organisms that are particularly devastating to the elderly. A portion of the chapter deals with the remarkable variability that those microorganisms are capable of manifesting in order to ensure their adequacy to reproduce in their hosts.

Age-Related Decline in Immunological Resistance to Infection

The health problems of the world’s elderly population are now, and will continue to be, of global concern. According to World Health Organization (WHO) data, the population of elderly people will grow faster among the populations of the developing, rather than the developed, nations during the foreseeable future. Many of those developing nations may be referred to as “tropical”; in those nations, parasitic diseases have long been a major health problem. Is the prevalence of a parasitic diseases likely to be a significant factor affecting the health of emerging elderly populations in developing tropical countries? There is very little information with which to formulate an answer to that question. There has been almost no interest in the matter of parasitic infections in the aged; it was considered to be of moderate theoretical interest at best. Now, however, it appears that it could become a matter of considerably greater interest, both theoretical and pragmatic.