Aging in the context of immunological architecture, function and disease outcomes.

The aging immune system demonstrates a reduced capacity to mount a robust immune response (immunosenescence), thereby increasing the susceptibility to various infectious agents, cancers and diseases in elderly individuals. Defects in immune response that develop with advanced age also result in diminished vaccine efficacy, creating a major public health burden. In addition, radiation and chemical exposure and certain disease states can accelerate the progression of immunosenescence. An area of recent clinical focus is the development of vaccine strategies that would be effective across all age groups and would afford some degree of protection to older individuals to emerging or antibiotic-resistant pathogens. Further elucidation of the mechanisms underlying immunosenescence and identification of the most crucial age-related defects in immune response will lead to more effective strategies to boost immune function in the elderly. To discuss these and other research areas, the US–Japan Cooperative Medical Science Program (US Department of State), in conjunction with the National Institute of Allergy and Infectious Diseases, the National Institute of Aging, the Radiation Effects Research Foundation, the Ministry of Foreign Affairs and the Ministry of Education, Culture, Sports, Science and Technology of Japan, hosted a meeting in June 2008 in San Francisco. Topics discussed at the workshop included relative contributions of age-related defects in the function of T cells, B cells and various innate immune cells to the immunosenescent phenotype. Presentations also explored ways to offset the deleterious effects of aging through immune reconstitution and novel vaccination strategies. Although this meeting was limited to US and Asian researchers, articles within this special issue have been written by investigators throughout the world, including Europe, Australia, Asia and North America. Within this single topic issue of Trends in Immunology are 12 papers that represent highlights of many presentations from the June meeting. This special issue also adds to this body of knowledge by exploring topics not fully discussed at the meeting, such as the evolutionary context of aging.Due to the ‘baby boomers’ and health care advances, the US population is aging [1xSee all References][1] (Figure 1Figure 1). Similar trends are also occurring in Europe [2xSee all References][2] and elsewhere. Therefore, diagnosis and treatment of diseases in the elderly is becoming an ever greater priority, translating into a need to better understand immunological dysfunction and its contribution to disease. For example, Mark Weksler (United States) and colleagues from Europe discuss the high prevalence of certain diseases in elderly patients including shingles, Alzheimer's and atherosclerotic heart disease. The authors emphasize that additional investigation of immune responsiveness (or lack thereof) and progression and severity of these diseases is essential for the development of effective therapies.Figure 1Number of people age 65 and over, by age group, selected years 1900–2006 and projected 2010–2050 (US population). Source US Census Bureau, Decennial Census, Population Estimates and Projections. Courtesy of www.agingstats.gov.View Large Image | Download PowerPoint SlideHartmut Geiger and colleagues (United States) discuss how the process of hematopoiesis is impacted by age-related alterations in the frequency and function of hematopoietic stem cell (HSC) precursor pools. The relative contributions of extrinsic factors (from the microenvironment or systemic circulation) or cell-intrinsic factors (telomere dysfunction and/or accumulation of macromolecular and cellular damage) to alterations in phenotypes of aged HSCs is considered. These alterations affect the differentiation potential of B and T cells, as well as effectors of innate immunity including granulocyte and macrophage lineages, and all are adversely affected with aging. For example, aging B cells show decreased gene expression in the areas of lineage commitment and differentiation, resulting in reduced clonotypic diversity. Indeed, Michael Cancro (United States) and colleagues suggest that it is important to consider molecular, cellular and population level changes to fully understand the impact of aging on humoral immunity. Age-related deficits in T-cell function and resultant impairment in vaccination responses also represents an area of active research interest. Laura Haynes and colleagues (United States) have developed mouse models to investigate mechanisms underlying CD4+ and CD8+ T-cell defects. In addition, Nan-Ping Weng (United States) and colleagues suggest that loss of CD28+ T cells and the concomitant accumulation of CD28− T cells underlie an important age-associated decline in immune function. In other areas of T-cell research, Mark Dowling and colleagues (Australia) argue that thymic involution might have evolved to minimize autoimmunity in young adults while at the same time, optimizing the T-cell repertoire available to recognize pathogens and protect the individual from infections. With advancing age, the naive T-cell repertoire becomes dominated by a restricted set of large T-cell clones, primarily as a result of thymic involution and T-cell death. This constriction of the repertoire contributes greatly to the inability of an individual to respond to a variety of pathogens and is therefore largely responsible for the development of immunosenescence.According to Marcelo Sztein (United States) and colleagues, information on mechanisms responsible for diminished vaccination responses in the elderly is incomplete due to the small number of clinical studies conducted with elderly subjects. Nevertheless, the Centers for Disease Control and Prevention has estimated vaccine efficacy in young adults to be 70–90%, whereas in the elderly, it is estimated to be only 17–53%; therefore, more potent vaccine formulations will be required [3xAntibody response to influenza vaccination in the elderly: a quantitative review. Goodwin, K. et al. Vaccine. 2006; 24: 1159–1169Crossref | PubMed | Scopus (543)See all References][3]. Another potentially useful approach will be to target specific immune compartments such as the intestinal mucosa. Kohtaro Fujihashi and colleagues (Japan) therefore discuss the age-related changes in mucosal immunity, including reductions in the size of gut-associated lymphoid tissues and lack of oral tolerance induction. Furthermore, they present data from both experimental and human studies suggesting that nasal vaccination might represent a more effective route of mucosal vaccination in the elderly due the slower rate of immunosenescence of this tissue compartment, a finding that could have important clinical implications. The articles by Elizabeth Kovacs (United States) and Alexander Panda (United States) and colleagues discuss the impact of aging in innate cellular immunity including the function of neutrophils, monocytes, macrophages and other cells. Recent studies have shown that age-associated changes in cell number and function can result in initiation and/or progression of infections. Reversing the multiple immune defects of immunosenescence is the ultimate goal of therapy, and indeed, Gregory Sempowski (United States) and colleagues provide experimental evidence that thymic involution, at least, could be reversible. These studies provide hope that it might be possible to intervene in the activation or suppression of developmental pathways and thereby rejuvenate the thymus and restore thymic output and function, reconstituting the aged immune system. Finally, Daryl Shanley and colleagues (United Kingdom) discuss the modern evolutionary theory of aging as it relates to the aged immune system. This theory proposes that genes that confer a selective advantage in early life survival might have detrimental effects in later life, leading to such conditions as a chronic inflammatory state (so-called inflamm-aging), which exacerbates the progression of various age-related pathologies and increased autoimmunity. We hope that you enjoy reading this authoritative issue on aging and immunosenescence, which provides guidance for future research and development in this field.