Thymic rejuvenation and aging

Abstract

The thymus is a vital organ for homeostatic maintenance of the peripheral immune system. It is within this mediastinal tissue that T cells develop and are extensively educated and exported to the periphery for establishment of a functional and effective immune system. A striking paradoxical feature of this critical lymphoid tissue is that it undergoes profound age-associated involution. Thymic decline is of minimal consequence to healthy individuals, but the reduced efficacy of the immune system with age has direct etiological linkages with an increase in diseases including opportunistic infections, autoimmunity, and incidence/burden of cancer. Furthermore the inability of adults to restore immune function following insult induced by chemotherapy, ionizing radiation exposure or therapy, and infections (e.g. HIV-1) leads to increased morbidity and often mortality in the elderly. For these reasons, it is important that investigators strive to translate their understanding of mechanisms that drive thymic involution, and develop safe and effective strategies to rejuvenate the thymus in settings of clinical need. In this review, we present a discussion of the current status of thymic rejuvenation efforts associated with: sex steroid ablation, cytokines, growth factors, and hormones.

Figure 1

Young thymus produces self-tolerant T cells expressing a broad T cell receptor (TCR) repertoire this is supported in a well-delineated cortex and medulla by functionally distinct stromal cell populations. With age, there is a gradual reduction in total thymic cellularity, an increase in perivascular space (PVS), a disruption of the thymic architecture, a reduced production of naïve T cells, and a restriction in the peripheral TCR repertoire. The goal of therapeutic thymus rejuvenation is restoration of thymic architecture, increased output of naïve T cells and regeneration of a diverse the peripheral TCR repertoire.