ReviewChanges in primary lymphoid organs with aging
Highlights
► Hypoxic niches are critical for sustaining bone marrow stem cell lymphopoiesis. ► ROS and IL-6 accelerate bone marrow lymphoid senescence with aging. ► HIF-1α and PPARγ2 modulate bone marrow lymphopoiesis with aging. ► Loss of stromal-thymocyte cross-talk contributes to thymic involution with aging. ► Intrathymic changes in Foxn1, KGF, and sex steroids drive thymic senescence.
Introduction
Aging-associated immune deficiency represents a key component of the overall pathophysiological effects of aging and has multiple well-documented impacts on human health and quality of life. Hallmarks of aging with respect to immune function include enhanced susceptibility to infection, poor responses to vaccination, and increased autoimmunity, all of which increase morbidity and mortality in the elderly. Even in middle-aged individuals, attenuated immune function contributes to reduced ability to combat infectious diseases such as influenza. Immune deficiency is exacerbated by conditions such as cancer and chronic viral infections. Decreased immune function commonly occurs after chemotherapy, radiation, or bone marrow/stem cell transplantation, and is compounded by age-related immune senescence.
Multiple physiological changes at the cell, organ, and system level are associated with aging. Increasingly, individual genes are being identified with age-related changes in expression or function that influence the whole organism by impacting general cellular physiology (e.g., mitochondrial function, oxidative stress, telomere length) or individual organs or tissues. Aging, like any other complex system, represents an integration of multiple inputs with downstream influences on a variety of levels; interplay between tissue-specific compartments and residents, systemic mediators, and cell-intrinsic regulators. Careful investigation into these mechanisms may provide an opportunity to identify novel avenues for therapeutic approaches to delay or reduce the effects of aging.
Bone marrow and thymus represent the two critical primary lymphoid organs negatively impacted by aging. Bone marrow serves as a reservoir for hematopoietic stem cells (HSCs) and is a critical site for sustained production of common lymphoid progenitor cells (CLPs). Whereas the thymus provides the main venue for development and education of T cell progenitors, bone marrow serves as the primary site for development of B cells. These complex tissues play a crucial role in providing cellular components of the immune system across the lifespan; however, they are highly susceptible to the combined impacts of aging. While the effect of aging on thymocyte precursors has already been addressed in this issue [1], here we present a discussion of the changes observed in bone marrow and thymus associated with aging and more specifically detail a number of the key pathways and processes dysregulated in these primary lymphoid organs that lead to immune deficiencies with aging.
Section snippets
Bone marrow
Bone marrow can be divided generally into two compartments: the HSC compartment, which includes HSCs and the products of their differentiation; and the stromal compartment, which includes mesenchymal stem cells and the stromal products of their differentiation, such as osteoblasts and adipocytes. Changes in each of these compartments are known to contribute to senescence of lymphocyte production with aging (Fig. 1).
Thymus
The thymus is the major source of self-restricted, self-tolerant naïve T cells required for robust adaptive immunity, demonstrated by the profoundly immune compromised status of athymic individuals. Lymphoid progenitor cells from bone marrow commit to the T cell lineage, differentiate into functional T cells within the thymus, and are then exported to the periphery, where they act to effect and control immune responses. The capacity of the thymus to produce T cells is determined by the
Conclusions
High demand and clinical need exist for therapies to ameliorate immune deficiency caused by aging. Substantial preclinical and clinical approaches are being explored to enhance lymphopoiesis for the elderly in primary lymphoid tissues (i.e., bone marrow and thymus). However, inadequate basic knowledge of cellular targets and molecular pathways that cause age-associated involution in these critical primary lymphoid organs creates a significant barrier to developing and implementing such
Acknowledgements
The authors acknowledge generous support of the following US Public Health Service grants and contracts: NIH HD043494 (IKC), NIH AG035302 (NRM), NIH AI082127 (NRM), NIH AI076514 (NRM, CCB), AG025150 (GDS) and HHSN272200900059C (NRM, GDS). Support from Leukaemia and Lymphoma Research; the Biotechonology and Biological Sciences Research Council, United Kingdom; and the European Union-funded FP7 projects EuroSyStem and OptiStem is recognized for CCB.
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