Thymic fatness and approaches to enhance thymopoietic fitness in aging

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With advancing age, the thymus undergoes striking fibrotic and fatty changes that culminate in its transformation into adipose tissue. As the thymus involutes, reduction in thymocytes and thymic epithelial cells precede the emergence of mature lipid-laden adipocytes. Dogma dictates that adipocytes are ‘passive’ cells that occupy non-epithelial thymic space or ‘infiltrate’ the non-cellular thymic niches. The provenance and purpose of ectopic thymic adipocytes during aging in an organ that is required for establishment and maintenance of T cell repertoire remains an unsolved puzzle. Nonetheless, tantalizing clues about elaborate reciprocal relationship between thymic fatness and thymopoietic fitness are emerging. Blocking or bypassing the route toward thymic adiposity may complement the approaches to rejuvenate thymopoiesis and immunity in elderly.

Introduction

A characteristic feature of immunological aging in humans is the progressive loss of thymic T cell production. Consistent with crucial role of the thymus in adult life, recent studies demonstrate that resection of thymus in children undergoing cardiac surgeries results in loss of naïve T cells [1••]. The peripheral T cell repertoire of 22-year-old thymectomized patients is similar to that of 75-year-old subjects [1••]. In all vertebrates studied to date, aging of the thymus is accelerated compared to aging of many other organs. Thymic aging is characterized by dramatic reduction in thymocyte numbers and marked perturbations in the thymic stromal cell microenvironment. In contrast to a young thymus where thymocytes are the major contributors to the thymic microenvironment, adipocytes constitute the bulk of an aged thymic cellular space [2, 3]. The adipogenic transformation of thymus by middle-age is puzzling especially since the purpose of thymus is to produce naïve T cells while adipocytes regulate energy homeostasis and have no direct role in T cell development.

According to current estimates, approximately 3 × 109 T cells have to be generated everyday to replenish the total pool of existing 3 × 1011 T cells in human body [4]. By 50 years of age approximately 80% of thymic stromal space is dysfunctional and composed of adipose tissue [2, 3] (Figure 1). During aging, the total peripheral T cell pool is maintained by homeostatic expansion of preexisting T cells rather than replenishment by thymic export [4, 5, 6, 7]. The ongoing exposure to pathogens and antigenic challenge across the life-span progressively erodes the integrity of the naïve T cell pool. Consequently, the T cell repertoire is restricted with an expansion of memory T cells and thus limits the host's ability to mount responses against new antigenic challenges [4, 5, 6, 7]. Age-related thymic involution is associated with reduced immune-surveillance, increased risk and severity of emerging infections, certain cancers, vaccination failures, and delayed T cell reconstitution in patients undergoing hematopoietic stem cell transplantations (HSCT) [8, 9, 10]. In sum, the progressive loss of thymic function leads to a decline in adaptive immunity. Therefore, the ability to enhance thymopoiesis is central to the rejuvenation of T cell mediated immune-surveillance in elderly.

The three main causes of age-related thymic involution include—(a) a reduction in numbers and intrinsic defects in hematopoietic stem cells (HSCs) [11, 12]. (b) Loss of thymic epithelial cells (TECs) and deterioration of stromal microenvironment [3, 13, 14]. (c) Extrinsic circulating factors affecting the aged microenvironment, for example, alterations in hormones/growth factors/cytokines [15]. Accordingly, several promising strategies to rejuvenate thymic function in aging have demonstrated the potential of targeting the mechanisms that correct the defects in HSCs and TECs [9, 10, 16, 17]. Given that the thymus in middle-aged healthy humans is replaced by adipocytes (Figure 1), this review highlights the importance of thymic stromal microenvironment with emphasis on ectopic thymic adipocyte development in aging. Reviewed below are studies illustrating that pro-longevity interventions such as caloric restriction (CR) and neuroendocrine factors that regulate energy balance and thymic adipogenesis can forestall thymic aging and may rejuvenate thymopoiesis.

Section snippets

Thymic adipocytes: passive aggressive or active instigators of immunosenescence?

Thymic stromal cell composition as well as organization is severely disrupted with advancing age [3, 13, 18]. This includes reduction in thymic epithelial cells (TECs), increase in fibroblasts, disruption of thymic perivascular space (PVS), and the emergence of adipocytes [2, 3, 13]. The thymic stromal compartment is divided into (a) thymopoietic niches—which are mainly composed of epithelial cells and antigen presenting cells that sustain T cell development and (b) non-thymopoietic

Perivascular space and adipocytes

In addition to PVS, thymic adipocytes are also present in several thymic zones that include interlobular septae, capsular region, subcapsular cortex, and medulla (Figure 3). Since several prior histological studies of aging thymus refer to expansion of PVS and ‘infiltration’ of adipocytes within this region, the role of thymic vasculature in thymic involution process merits revisiting.

In young mice, thymic vascular supply is primarily characterized by entry of one artery and exit of one vein at

Epithelial–mesenchymal transition (EMT) and fibro-adipogenesis in aging thymus

The primary EMT occurs during embryonic development when epiblast cells give rise to mesenchymal and neural crest cells [34]. The primary mesenchymal cells transition to secondary epithelial cells via the mesenchymal–epithelial transition (MET) process and initiate organ development. [34]. It is now well documented that with progressive aging, thymic epithelial cells (TECs) decline with a concomitant increase in thymic fibroblasts [3, 13, 26•]. Recent studies employing genetic fate-mapping,

Novel strategies for thymic rejuvenation: inhibitors of EMT and thymoadipogenesis

Several experimental approaches for thymic and T cell reconstitution during aging have been the subject of excellent review articles [7, 9, 10]. This review summarizes the strategies that target the EMT and ectopic adipogenesis mechanism as complementary strategies to rejuvenate thymopoiesis or forestall thymic aging (Figure 4).

Caloric restriction (CR) and CR mimetics: Induction of negative energy balance via CR remains one of the most robust non-genetic means of extending healthspan and

Conclusions

Although the thymus undergoes rapid adipogenic transformation, the fibrosis and fatty changes with advancing age occur in several organs and are not unique to thymus. The mechanisms behind this age-associated phenomenon are still largely unknown. Several recent studies have greatly expanded the understanding of basic mechanisms of age-related thymic regeneration in mouse models. As new data emerge and future therapeutic approaches for thymic rejuvenation are developed, preventing the

References and recommended reading

Papers of particular interest, published within the annual period of review, have been highlighted as:

  • • of special interest

  • •• of outstanding interest

Acknowledgements

I thank Yun-Hee Youm, Hyunwon Yang, Bolormaa Vandanmagsar and Anthony Ravussin in my laboratory for many exciting findings and discussions that have helped to shape this review. I also thank Don Ingram for pre-submission review of the manuscript. This research was supported by the National Institutes of Health grant NIA-R01-AG031797, the Pennington Biomedical Research Foundation and the Coypu Foundation.

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