Rejuvenation of the aging thymus: growth hormone-mediated and ghrelin-mediated signaling pathways

One of the major fundamental causes for the aging of the immune system is the structural and functional involution of the thymus, and the associated decline in de novo naïve T-lymphocyte output. This loss of naïve T-cell production weakens the ability of the adaptive immune system to respond to new antigenic stimuli and eventually leads to a peripheral T-cell bias to the memory phenotype. While the precise mechanisms responsible for age-associated thymic involution remain unknown, a variety of theories have been forwarded including the loss of expression of various growth factors and hormones that influence the lymphoid compartment and promote thymic function. Extensive studies examining two hormones, namely growth hormone (GH) and ghrelin (GRL), have demonstrated their contributions to thymus biology. In the current review, we discuss the literature supporting a role for these hormones in thymic physiology and age-associated thymic involution and their potential use in the restoration of thymic function in aged and immunocompromised individuals.

Introduction

Immune function decreases with age, owing to both quantitative and qualitative changes in the cells of the immune system and the lymphoid environment. The damaging effects of aging on immunity have been well studied and such changes are believed to lead to increased susceptibility to infection and autoimmunity, poor antibody and T-cell responses to vaccines, and diminished immunosurveillance of malignant cells. The thymus is crucial for the development, selection, and maintenance of the peripheral T-cell pool possessing a broad spectrum of T-cell receptor (TCR) specificities. While the thymus lacks its own self-renewing pool of progenitors, it is continuously seeded with lymphoid progenitors emigrating from the bone marrow. The common lymphoid progenitors (CLPs) and the early thymocyte progenitor (ETP) decline markedly with age and the ETPs have a reduced proliferative capacity and an increased rate of apoptosis [1^•]. Thus, while the thymus is capable of generating T cells throughout the life span, with advancing age, the thymic space becomes progressively filled with adipocytes accompanied by a dramatic loss of progenitors, epithelial cells, and differentiating thymocytes in the cortical and medullary areas leading to a reduction in naïve T-cell output. This process has been termed ‘thymic involution’ [1•, 2, 3, 4, 5, 6, 7, 8, 9].

The thymus is a critical organ in mammals as the lack of a thymus in humans (known as ‘DiGeorge's syndrome’) and in thymectomized neonatal mice leads to severe immunodeficiency owing to paucity of mature naïve CD4⁺ and CD8⁺ T cells. During physiological aging, the total peripheral T-cell pool is maintained by homeostatic expansion of preexisting memory T cells, predominantly CD8⁺ T cells, rather than replenishment by thymic export. Consequently, the long-lived naïve T-cell repertoire is significantly reduced (diluted) with the expansion of these peripheral memory T cells possessing a more restricted T-cell receptor repertoire thereby limiting the host's ability to mount responses against challenges with new antigens. Moreover, defects in the activity of aged naïve T cells appear to be due to the chronologic age of the naïve cells themselves rather than the age of the host. Thus, the involution of the thymus with age and the paucity of newly formed naïve CD4⁺ and CD8⁺ T cells is believed to be responsible for much of the deterioration in adaptive immunity and the resultant immune dysfunction in the elderly [1•, 2, 3, 4, 5, 6, 7, 8, 9].

While the precise mechanisms responsible for thymic involution remain to be identified, it is believed to be a complex programmed loss of multiple systems that cross communicate with each other and include the loss of the thymic architecture and epithelial cells to support and maintain thymopoiesis as well as the loss of various growth factors and hormones that assist in maintaining the thymic microenvironment. For many years, scientists have believed that, post-adolescence, the thymus simply becomes a fatty non-functional organ incapable of supporting T-cell production. However, more recent studies have demonstrated that, despite significant atrophy, the aged thymus still retains the capacity to promote T-cell differentiation and produce de novo naïve T cells when properly stimulated, albeit at a significantly reduced rate [2, 3, 4, 5, 6]. Thus, a greater understanding of the processes of thymic involution and strategies to restore thymic function and T-cell export in the aged and immunosuppressed hosts remains an important and promising therapeutic goal. For a more thorough description of the various changes in the thymus with age and its impact on thymopoiesis and immunity, please see the references [1•, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13].

There exists a complex system of communication between the neuroendocrine and immune systems. Through the use of shared ligands and receptors, these systems are capable of significant crosstalk that is believed to play an important role in physiological homeostasis [14, 15, 16]. Many hormones and neuropeptides have been shown to be potent immunoregulatory molecules that influence various aspects of immune function in healthy and diseased individuals. Many of the cells within the immune system possess receptors and demonstrate responses upon stimulation with neurohormones and similarly, neuronal and endocrine cells respond to immune-derived cytokines and growth factors under normal physiological and disease conditions. Further, immune and neuronal cells express or can be induced to express many similar cytokines, hormones, and growth factors, thus further mediating cross communication between these systems within the body. Many attempts to define the molecular mechanisms responsible for thymic involution have focused on the examination of changing levels of expression of molecules, such as cytokines, growth factors, neuropeptides and their receptors, with aging [1^•]. Mediators that are known to have some influence on thymic involution include growth hormone (GH), insulin-like growth factor-1 (IGF1), keratinocyte growth factor (KGF), nerve growth factor (NGF), interleukin-7 (IL-7), gonadotropin releasing hormone (GnRH) [9, 13, 15, 16, 17, 18, 19, 20, 21•], and increases in atrophic factors, such as IL-6 and transforming growth factor-β (TGFβ) [1•, 2]. Whether these changes in expression directly cause, or are a consequence of, involution remains unclear. In addition to direct thymic factors, aging also affects the bone marrow, demonstrating diminished lymphoid potential and reduced proliferative capacity or survival of hematopoietic stem cells (HSCs). This might also contribute to the involution process.

Several neuroendocrine hormones have long been associated with effects on immune cell function including growth-promoting effects on multiple immune cell lineages. GH is an important hormone with effects on the immune system. One of the first observations was that GH levels decreased with age, as thymic involution progresses and this impaired thymic function could be restored by the administration of GH [1•, 21•, 22•, 23, 24•, 25•]. A number of subsequent reports have demonstrated both thymopoietic and hematopoietic effects for GH, IGF1, GH secretagogues (GHS) and, more recently ghrelin and leptin, during aging [15, 16, 21•, 24•, 25•]. While the use of such hormones to promote immune reconstitution is indeed attractive considering their pleiotropic effects and low toxicity (in animals) after systemic administration, additional research is required to adequately evaluate their appropriateness as agents to promote T-cell recovery in human subjects. The remaining focus of this review shall examine the effects of two hormones, namely growth hormone (GH) and ghrelin (GRL) on T-cell and thymic functions and their potential use in boosting thymic activity in immunocompromised hosts.