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 aetiological 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.

The Immunoendocrine Thymus as a Pacemaker of Lifespan

“…It is generally believed that the involution of thymus starts at the age of puberty, whereas in man it starts from the first year of life [120,121], and the first signs can be seen when 9 months old [122], followed by rapid (under 10 years and between 25 and 40 years) and slow (between 10 and 25 years and over 40 years) regressions. However, it becomes more conspicuous at the onset of puberty, and the organ almost disappears in the adult age (at age of 70 years only 10% remains).…”

Hormonal control of T-cell development in health and disease

“…Even so, a number of pre-clinical and clinical approaches to rejuvenate the organ have already been developed that result in substantial improvement in thymus function, such as sex steroid ablation and administration of GH and IL-7. 34,38 Thymic hormone-mediated circuits Hormonal control of the thymus includes both endocrine and paracrine/autocrine pathways that act on thymic microenvironment cells and thymocytes via specific hormone receptors. Accordingly, hormones regulate the proliferation and survival of both lymphoid and thymic microenvironment cells, as well as selection of the T-cell repertoire, which is a mechanism partly related to the modulation of TCR activation upon MHC-peptide binding.…”

Aging of the T Cell Compartment in Mice and Humans: From No Naive Expectations to Foggy Memories

“…Finally, once naïve T cells decline below a certain point, only T cell rejuvenation will be able to replenish the lost reserve. Good news is that T cell rejuvenation is by no means impossible, as several treatments can impressively regrow an old thymus (102). Less good news is that thymic involution and loss of function with age is a complex and composite process, and it is now clear that single treatments are unlikely to restore the totality of function, including robust export of functional T cells to the periphery, to allow for improved immune defense (22, 102)}.…”