Changes in primary lymphoid organs with aging

Abstract

Aging is associated with decreased immune function that leads to increased morbidity and mortality in the elderly. Immune senescence is accompanied by age-related changes in two primary lymphoid organs, bone marrow and thymus, that result in decreased production and function of B and T lymphocytes. In bone marrow, hematopoietic stem cells exhibit reduced self-renewal potential, increased skewing toward myelopoiesis, and decreased production of lymphocytes with aging. These functional sequelae of aging are caused in part by increased oxidative stress, inflammation, adipocyte differentiation, and disruption of hypoxic osteoblastic niches. In thymus, aging is associated with tissue involution, exhibited by a disorganization of the thymic epithelial cell architecture and increased adiposity. This dysregulation correlates with a loss of stroma-thymocyte 'cross-talk', resulting in decreased export of naïve T cells. Mounting evidence argues that with aging, thymic inflammation, systemic stress, local Foxn1 and keratinocyte growth factor expression, and sex steroid levels play critical roles in actively driving thymic involution and overall adaptive immune senescence across the lifespan. With a better understanding of the complex mechanisms and pathways that mediate bone marrow and thymus involution with aging, potential increases for the development of safe and effective interventions to prevent or restore loss of immune function with aging.

Figure 1. Mechanisms of bone marrow lymphoid senescence with aging

Aging produces changes within the bone marrow (yellow shaded area), including increased production of adipocytes (A) from mesenchymal stem cells (MSC), loss of hypoxic osteoblast (OB)-enriched niches, exhaustion of hematopoietic stem cells (HSC), skewing of HSCs toward myeloid cell (M) formation, and defective production of lymphocyte progenitors (L) for B cell (B) and T cell (T) differentiation.

Figure 2. Organization and composition of young and aged thymus

Top panels show sections of 3 (left) and 24 (right) month-old thymus tissues stained with immunofluorescent antibodies to Ly51 for cTECs (green) and keratins 5 or 14 for mTECs (red). The young adult thymus is characterized by a well-organized cortical-medullary structure with clearly defined subcapsular (SC), cortical (C), medullary (M), and corticomedullary junction (CMJ) zones. The involuted aged thymus demonstrates intermingled cTECs and mTECs, loss of TECs expressing both cTEC and mTEC markers (in yellow, double positive or “dp” TECs), and TEC-free regions. Illustrated diagrams depict the general cellular composition and organization of the young and aged thymus. A key for cell types is provided at the bottom left; the bottom right panel shows molecular and cellular changes associated with the aged thymus. Other abbreviations: Dll4, delta-like 4; DN1-DP, double negative 1-double positive cells; LPCs, lymphocyte progenitor cells; SP, single positive cells