Immunosenescence: what does it mean to health outcomes in older adults?
Introduction
Aging of the immune system results in a loss of adaptive immune function with relative preservation of innate immunity. There is a decline in the absolute number of B cells and helper (CD4+) and cytotoxic (CD8+) T lymphocytes with a relative increase in natural killer (NK) cells, such that the overall lymphocyte count does not change with aging. Thymic involution and a decline in naïve T cell output with increasing age, together with a lifetime of exposure to a variety of pathogens, leads to a dramatic reduction in the naïve T cell pool and a relative increase in the proportion of memory T cells. Within the total memory pool, arguably, the most dramatic functional changes occur in the CD8+ T cell subset, where progressive exhaustion of this compartment leads to the loss of costimulatory molecules (CD28), shortening of telomeres, and terminal differentiation to end stage cells that are resistant to the usual apoptotic mechanisms that control the size of memory T cell clones responding to a particular pathogen [1]. These changes are associated with an increase in levels of inflammatory cytokines, or ‘inflammaging’, which may also contribute to the dysregulation of the cell-mediated immune response [2]. This review will focus on strategies that could promote more effective adaptive immune responses to infectious agents and to prophylactic vaccines, and will also suggest possible methods to measure these responses in the older adult population.
Section snippets
Drivers of immunosenescence: role of latent infections
Early studies showed that human somatic cells have a finite number of replicative cycles [3] and more recently, these observations have been extended to T lymphocytes under conditions of repetitive stimulation and proliferation in long-term culture (reviewed in [4]). The term replicative senescence is used to describe the stage at which telomeres are shortened to a crucial length such that a lymphocyte proliferative response can no longer be elicited and CD8+ T cells show permanently suppressed
Translation of age-related changes in T cells to outcomes of vaccination in older adults
A multitude of changes in the immune system occur with aging (Table 1) but the specific mechanisms that increase risk for influenza illness and limit the protective effects of vaccination are poorly understood. While serum antibody titers against influenza (by the hemagglutination inhibition assay) have been used to predict influenza vaccine efficacy and have been correlated with age-related changes in T cells, mechanistic links have not been made. This may be due to the fact that
Increasing thymic output
Strategies to improve CD8+ T cells responses to vaccination range from those targeted to the general stabilization of different T cell subsets to those that provide enhanced stimulation of an antigen-specific response. Since thymic involution appears to be one of the key elements of changes that occur in the immune system with aging, thymic rejuvenation techniques have been sought over many years and are now reaching the early stages of clinical trials. While a variety of growth factors,
Conclusions
Recent studies on immunosenescence have provided a more detailed understanding of cellular changes and how they might mediate reduced responses to infectious agents and to vaccines. Translating these new findings to the elderly population will require novel strategies that specifically address particular facets of cellular immune function that undergo changes with age, both within the naïve and memory populations. With the increasing age of the population, enhancing immune responses to new and
References and recommended reading
Papers of particular interest, published within the period of review, have been highlighted as:
• of special interest
•• of outstanding interest
Acknowledgements
We thank Laura Haynes from the Trudeau Institute for her review of the manuscript and for sharing her experience with vaccine adjuvants in aged mouse models. Janet E McElhaney's work is supported by National Institutes of Health Grants R01 AI068265 and U01 AI074449. Rita B Effros’ work is supported by National Institutes of Health Grant RO1 AG 023720 and by Geron Corporation and TA Therapeutics Ltd.
References (47)
- et al.
Inflammaging and anti-inflammaging: a systemic perspective on aging and longevity emerged from studies in humans
Mech Ageing Dev
(2007) - et al.
The serial cultivation of human diploid cell strains
Exp Cell Res
(1961) - et al.
Is immunosenescence infectious?
Trends Immunol
(2004) - et al.
Age-associated decline in T cell repertoire diversity leads to holes in the repertoire and impaired immunity to influenza virus
J Exp Med
(2008) - et al.
Memory CD8+ T cells vary in differentiation phenotype in different persistent virus infections
Nat Med
(2002) - et al.
Identification of two major types of age-associated CD8 clonal expansions with highly divergent properties
Proc Natl Acad Sci U S A
(2008) - et al.
Immune phenotype and intracellular cytokine production of peripheral blood mononuclear cells from postmenopausal patients with osteoporotic fractures
Exp Gerontol
(2001) - et al.
CD8+CD28− T suppressor cells and the induction of antigen-specific, antigen-presenting cell-mediated suppression of Th reactivity
Immunol Rev
(2001) - et al.
Rapid decline of influenza vaccine-induced antibody in the elderly: is it real, or is it relevant?
J Infect Dis
(2008) - et al.
T cell responses are better correlates of vaccine protection in the elderly
J Immunol
(2006)