**2. Hallmarks of age-related thymic atrophy**

During aging, the thymus undergoes progressive atrophy [36]. In addition to a reduction in thymic mass (size and thymocyte numbers), there is substantial remodeling of the thymic microstructure. The thymus is characterized by two primary compartments, namely the cortex and the medulla. In between the cortex and medulla, there is a zone termed the corticomedullary junction (CMJ) (**Figure 1a**). These two compartments contain specialized thymic epithelial cells (TECs), cortical (cTECs) or medullary (mTECs), and these cellular compartments are responsible for different stages of thymocyte development and selection [37, 38]. Regarding thymic microstructure, the aged, involuted thymus, in addition to an overall decline in TEC-associated markers, such as keratin and major histocompatibility complex class-II (MHC-II), also manifests altered ratios of cTECs to mTECs, and an overt change in microstructure due to disrupted

**51**

**thymus**

**Figure 1.**

*while K5<sup>+</sup>*

*SC = subcapsule.*

*Age-Related Thymic Atrophy: Mechanisms and Outcomes DOI: http://dx.doi.org/10.5772/intechopen.86412*

tissue in the thymus is also observed [40]. Increased senescent cells (β-Gal<sup>+</sup>

*distinct compartmental region. Normally, K8+*

**3. Mechanisms of age-related thymic atrophy**

CMJ, resulting in a disorganized medullary region (**Figure 1b**). A decline in MHC-IIhi expressing TECs is a sign of the reduction of mature mTECs [39, 40]. Additionally, increased numbers of fibroblasts [39] and accumulation of adipose

*Thymic microstructural changes characterized by K8 and K5 fluorescent staining. In the aged thymus, the CMJ is not clear, because the medulla is disorganized and medullary TECs are dispersed and do not form a* 

 *TECs (red) are primarily localized in the medullary region. A) Young (~2 months old) murine thymus; B) aged (>18 months old) murine thymus. C = cortex, M = medulla, CMJ = corticomedullary junction,* 

, p21+

atrophied thymus, contributing to diminished stromal cellularity [39].

Thus, this result could explain decreased thymic output with age [45].

also present, and it has been demonstrated that TECs contribute to the senescence observed in the aged thymus [39, 41, 42]. This possibly contributes to an increased inflammatory environment (increased levels of IL-6, IL-1β, etc.) within the involuted thymus [30, 43]. Additionally, there is augmented apoptosis in TECs of the

**3.1 Mechanisms of diminished thymic input and output associated with aged** 

Perhaps the most noted outcome of age-related thymic atrophy is diminished thymic output and thymopoesis. This attracts attention and has led many groups to examine whether the bone marrow (BM) derived hematopoietic stem cell (HSC) lymphoid progenitors are sufficiently able to seed the thymus during aging. This is because HSCs are reduced [9] with a myeloid biased development in advanced age [44]. There have been many studies investigating this aspect of thymopoiesis and it is suggested that age-related HSCs contain defects [9] that could contribute to insufficient entry of early T-cell progenitors (ETPs) into the aged thymus [10].

Mechanisms of diminished thymic input resulting in thymic involution and declined thymic output are mainly based on bone marrow transplantation (BMT) experiments using mouse models. In these models, transferring aged HSCs into young mice could not rejuvenate the thymic involution induced by irradiation prior to bone marrow transplantation [46]. Additionally, the HSC progenitors have been shown to exhibit an age-related skewed proportion within the HSC pool towards myeloid lineage versus lymphoid lineage [44, 47–49]. It has also been observed that early stage thymocytes, defined as the ETPs in the triple negative-1 (TN1) thymocyte population, from aged mice demonstrated decreased differentiation

, and TAP63<sup>+</sup>

 *TECs (green) are primarily localized in the cortical region,* 

) [41] in the aged thymus are

#### **Figure 1.**

*Thymus*

such as Forkhead box N1 (FoxN1) [16].

derived CD4SPFoxP3+

non-hematopoietic defect, which suggests that the primary age-related atrophy of the thymus is derived from HSC niche cells [11, 12] and thymic stromal cells, or ETP niches [13, 14]. The myriad of changes that characterize thymic atrophy first occur within the thymic niche and then extend to the ETPs as a result of age. We believe that these substantial age-related alterations in thymic microstructure and microenvironment, which provide important thymic factors, contribute more heavily to the diminished thymopoiesis observed in the elderly [7, 13] The primary thymic stromal cells are thymic epithelial cells (TECs), including two subpopulations distinct in their localization, function, and molecular expression patterns, namely medullary TECs (mTECs) and cortical TECs (cTECs) [15]. Compelling evidence show that age-related thymic atrophy is tightly associated with postnatal TEC homeostasis, which is regulated by TEC autonomous transcription factors (TFs),

Age-related changes to immune system function, often referred to as immunosenescence [17–20], are generally thought of as immune insufficiency, such as reduced anti-infection and vaccine immunity [21] and reduced tumor surveillance [22, 23]. However, self-reactive immune responses are elevated in the elderly, which is a result of inflammaging, a chronic, low-grade, systemic inflammatory phenotype in the absence of acute infection observed in aged individuals [24–31]. Immunosenescence and inflammaging are antagonistic phenotypes, but they actually comprise two sides of the same coin in terms of age-related immune dysregulation [19, 20, 32, 33]. It has been proposed that the basal inflammatory state defined by inflammaging greatly contributes to many age-related degenerative diseases, including neurodegenerative diseases, such as Alzheimer's disease, metabolic

Here, we will outline the cellular and molecular mechanisms underlying the occurrence of age-related thymic atrophy including some of the aforementioned hallmarks, and its effects on general T cell output. We will also describe its effects on the establishment of central T cell immune tolerance via a combination of both mechanistic arms of central tolerance: thymocyte negative selection and thymic-

believe many aspects of the adaptive immune system's role in the development of inflammaging can be attributed to these thymic manifestations. Finally, in light of new trends in T cell immune system aging, we will expand on some future research goals in the field of thymic atrophy interventions and therapeutics as a potential conduit for normalizing aged T cell-mediated immunity. This is of clinical signifi-

During aging, the thymus undergoes progressive atrophy [36]. In addition to a reduction in thymic mass (size and thymocyte numbers), there is substantial remodeling of the thymic microstructure. The thymus is characterized by two primary compartments, namely the cortex and the medulla. In between the cortex and medulla, there is a zone termed the corticomedullary junction (CMJ) (**Figure 1a**). These two compartments contain specialized thymic epithelial cells (TECs), cortical (cTECs) or medullary (mTECs), and these cellular compartments are responsible for different stages of thymocyte development and selection [37, 38]. Regarding thymic microstructure, the aged, involuted thymus, in addition to an overall decline in TEC-associated markers, such as keratin and major histocompatibility complex class-II (MHC-II), also manifests altered ratios of cTECs to mTECs, and an overt change in microstructure due to disrupted

cance for combating age-related neurological and cardiovascular diseases.

**2. Hallmarks of age-related thymic atrophy**

T regulatory (tTreg) cell generation. We will discuss why we

diseases, and cardiovascular diseases, among others [30, 34, 35].

**50**

*Thymic microstructural changes characterized by K8 and K5 fluorescent staining. In the aged thymus, the CMJ is not clear, because the medulla is disorganized and medullary TECs are dispersed and do not form a distinct compartmental region. Normally, K8<sup>+</sup> TECs (green) are primarily localized in the cortical region, while K5<sup>+</sup> TECs (red) are primarily localized in the medullary region. A) Young (~2 months old) murine thymus; B) aged (>18 months old) murine thymus. C = cortex, M = medulla, CMJ = corticomedullary junction, SC = subcapsule.*

CMJ, resulting in a disorganized medullary region (**Figure 1b**). A decline in MHC-IIhi expressing TECs is a sign of the reduction of mature mTECs [39, 40]. Additionally, increased numbers of fibroblasts [39] and accumulation of adipose tissue in the thymus is also observed [40].

Increased senescent cells (β-Gal<sup>+</sup> , p21+ , and TAP63<sup>+</sup> ) [41] in the aged thymus are also present, and it has been demonstrated that TECs contribute to the senescence observed in the aged thymus [39, 41, 42]. This possibly contributes to an increased inflammatory environment (increased levels of IL-6, IL-1β, etc.) within the involuted thymus [30, 43]. Additionally, there is augmented apoptosis in TECs of the atrophied thymus, contributing to diminished stromal cellularity [39].
