Causes, consequences, and reversal of immune system aging

Abstract

The effects of aging on the immune system are manifest at multiple levels that include reduced production of B and T cells in bone marrow and thymus and diminished function of mature lymphocytes in secondary lymphoid tissues. As a result, elderly individuals do not respond to immune challenge as robustly as the young. An important goal of aging research is to define the cellular changes that occur in the immune system and the molecular events that underlie them. Considerable progress has been made in this regard, and this information has provided the rationale for clinical trials to rejuvenate the aging immune system.

Figure 1. Effects of aging on HSCs and lymphocyte progenitors.

Lymphopoiesis in the young (left) is characterized by robust B and T cell production in the bone marrow and thymus. The pool of HSCs includes a relatively high number of lymphoid-biased stem cells that efficiently generate lymphoid progenitors with high proliferative potential. However, with increasing age (right), the number of lymphoid-biased HSCs declines and myeloid-biased stem cells predominate, contributing to the reduced numbers of lymphoid progenitors. In addition, B cell progenitors in the bone marrow and T cell progenitors in the thymus exhibit reduced rates of proliferation and higher levels of apoptosis compared with their young counterparts. The increased expression of Ink4a and Arf in pro-B cells and Ink4a in ETPs contribute to this decreased proliferation/increased apoptosis. The decline in primary lymphopoiesis in turn results in a reduced number of naive cells that migrate to secondary lymphoid tissues such as the spleen.

Figure 2. The strength of the immune response declines with age.

Multiple age-related changes can affect the composition and function of lymphocytes in secondary lymphoid tissues. CD4⁺ Th cells exhibit activation defects and increased differentiation into Th17 cells. CD8⁺ T cells undergo an oligoclonal expansion and loss of CD28 in humans and exhibit impaired function. The number of B cells that respond to influenza is reduced, and antibody avidity in response to carbohydrate antigens is diminished. In addition, the tissue environment includes an increased concentration of inflammatory cytokines, which may be produced by stromal elements, dendritic cells, or aging B and T cells. The increased number of memory cells that occupy tissue niches and the inflammatory milieu in turn may compromise the ability of naive B and T cells migrating from the bone marrow and thymus to lodge in the tissue. Together, these changes result in diminished immune function in the elderly.

Figure 3. Selected strategies to rejuvenate the involuted thymus.

The potential of several hormones and growth factors to rejuvenate the involuted thymus has been tested in various preclinical and clinical trials. Many of these factors can be grouped into three categories. Those in the first (i), such as IL-7, bind to progenitors in the bone marrow and thymus and have only modest effects on thymopoiesis. There is little evidence that IL-7 has effects on thymic stromal cells. Instead, the benefit of IL-7 may lie in its ability to stimulate peripheral T cell survival/expansion. The second category (ii) includes hormones such as GH that have been demonstrated in preclinical and clinical trials to stimulate thymopoiesis and increase thymic size. Many GH effects are mediated through induction of IGF-1. IGF-1 can bind to receptors on thymic stroma and thymocytes, although its actions are primarily mediated through effects on the former cells. Stromal cell–derived factors presumably then act on thymocytes (curved arrow). A third category of factors (iii), typified by FGF7, bind to stromal cells but not thymocytes. Stromal cell–induced factors then act on thymocytes (curved arrow), and we have recently demonstrated that effects include downregulation of Ink4a in ETPs (82). The thymopoietic effects of several additional factors have been evaluated, and recent detailed reviews should be consulted for more information (99, 100).