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Immune system aging is characterized by the paradox of immunosenescence (insufficiency) and inflammaging (over-reaction), which incorporate two sides of the same coin, resulting in immune disorder. Immunosenescence refers to disruption in the structural architecture of immune organs and dysfunction in immune responses, resulting from both aged innate and adaptive immunity. Inflammaging, described as a chronic, sterile, systemic inflammatory condition associated with advanced age, is mainly attributed to somatic cellular senescence-associated secretory phenotype (SASP) and age-related autoimmune predisposition. However, the inability to reduce senescent somatic cells (SSCs), because of immunosenescence, exacerbates inflammaging. Age-related adaptive immune system deviations, particularly altered T cell function, are derived from age-related thymic atrophy or involution, a hallmark of thymic aging. Recently, there have been major developments in understanding how age-related thymic involution contributes to inflammaging and immunosenescence at the cellular and molecular levels, including genetic and epigenetic regulation, as well as developments of many potential rejuvenation strategies. Herein, we discuss the research progress uncovering how age-related thymic involution contributes to immunosenescence and inflammaging, as well as their intersection. We also describe how T cell adaptive immunity mediates inflammaging and plays a crucial role in the progression of age-related neurological and cardiovascular diseases, as well as cancer. We then briefly outline the underlying cellular and molecular mechanisms of age-related thymic involution, and finally summarize potential rejuvenation strategies to restore aged thymic function.

Age-related thymic involution is characterized by the loss of T cell development and the supporting epithelial network, which are replaced by adipose tissue. We previously showed that aging functionally impairs lymphohematopoietic progenitor cells, including thymic early T cell progenitors (ETPs), contributing to thymic involution. Considering that the thymic microenvironment is essential for thymocyte incubation, we aimed to investigate its role in age-related thymic involution and the mechanisms underlying these changes. The challenge in studying these processes led us to transplant T cell-depleted fetal thymus tissue into the kidney capsule of aged mice. This model allowed us to identify the mechanisms driving age-related changes in the thymic microenvironment and to assess whether these changes could be reversed. Flow cytometry was used to detect naïve T cells (CD62L+CD44–), including CD4 CD8 double-negative, double-positive, and single-positive T cells. Real-time PCR was used to detect and quantify signal-joint T cell receptor excision circles. We rearranged δRec-ΨJα in murine peripheral blood leukocytes to evaluate the thymic output of newly developed naïve T cells in the mice and gene expression in the thymus. Age-related thymic involution decreased naïve T cells and increased memory T cells, while fetal thymus transplantation improved thymic output and T cell production and reversed the impairment of thymopoiesis due to thymic involution in aged mice. Furthermore, the expression of key cytokines was restored and ETPs in the aged mice showed normal thymic T cell development. Our study suggests that degenerative changes in the thymic microenvironment are the primary cause of thymic dysfunction, leading to immunosenescence associated with age-related thymic involution.

The study investigated mechanisms underlying sex differences in thymic involution in Dark Agouti rats. Adverse effects of aging on thymus were more pronounced in males than in females. Thymi from old males exhibited more prominent: (i) fibro-adipose degeneration which correlated with greater intensity of thymic oxidative stress and enhanced thymic TGF-β and IL-6 expression and (ii) decline in thymopoiesis, as suggested by the number of the most mature CD4+CD8−/CD4−CD8+ single positive (SP) TCRαβhigh thymocytes. The greater accumulation of adipose tissue in old male thymus was linked with greater age-related increase in thymic expression of PPARγ and STAT3, a transcription factor regulating the expression of PPARγ downstream genes, in male than in female rats. In aged thymi of both sexes the early CD4−CD8− double negative (DN) stage of thymocyte development was affected, so relative accumulation of the least mature CD45RC+CD2− cells followed by decreased frequency of their DN and CD4+CD8+ double positive (DP) TCRαβ− descendants was observed. Additionally, in old males, because of the increased thymic expression of Nur77, a nuclear receptor involved in negative selection, and decreased CD90 (a negative regulator of thymocyte selection threshold) MFI on DP TCRαβint thymocytes, less efficient positive/more efficient negative selection was found. Moreover, in male rats, thymocyte post-selection differentiation/maturation was skewed towards CD4−CD8+ SP TCRαβhigh cells compared with age-matched females, reflecting, at least partly, greater IL-15 expression in their thymi. The study indicated mechanisms underlying sex-based differences in age-related thymic changes and consequently necessity of sex-specific approaches in designing strategies to rejuvenate thymus.

The aged adaptive immune system is characterized by progressive dysfunction as well as increased autoimmunity. This decline is responsible for elevated susceptibility to infection and cancer, as well as decreased vaccination efficacy. Recent evidence indicates that CD4 + T cell–intrinsic alteratins contribute to chronic inflammation and are sufficient to accelerate an organism-wide aging phenotype, supporting the idea that T cell aging plays a major role in body-wide deterioration. In this Review, we propose ten molecular hallmarks to represent common denominators of T cell aging. These hallmarks are grouped into four primary hallmarks (thymic involution, mitochondrial dysfunction, genetic and epigenetic alterations, and loss of proteostasis) and four secondary hallmarks (reduction of the TCR repertoire, naive–memory imbalance, T cell senescence, and lack of effector plasticity), and together they explain the manifestation of the two integrative hallmarks (immunodeficiency and inflammaging). A major challenge now is weighing the relative impact of these hallmarks on T cell aging and understanding their interconnections, with the final goal of defining molecular targets for interventions in the aging process. In this Review, Mittelbrunn and Kroemer propose that ten molecular hallmarks represent the common denominators of T cell aging.

The thymus is the primary immune organ responsible for generating self‐tolerant and immunocompetent T cells. However, the thymus gradually involutes during early life resulting in declined naïve T‐cell production, a process known as age‐related thymic involution. Thymic involution has many negative impacts on immune function including reduced pathogen resistance, high autoimmunity incidence, and attenuated tumor immunosurveillance. Age‐related thymic involution leads to a gradual reduction in thymic cellularity and thymic stromal microenvironment disruption, including loss of definite cortical‐medullary junctions, reduction of cortical thymic epithelial cells and medullary thymic epithelial cells, fibroblast expansion, and an increase in perivascular space. The compromised thymic microenvironment in aged individuals substantially disturbs thymocyte development and differentiation. Age‐related thymic involution is regulated by many transcription factors, micro RNAs, growth factors, cytokines, and other factors. In this review, we summarize the current understanding of age‐related thymic involution mechanisms and effects. Age‐related thymic involution has many negative impacts on immune function including reduced pathogen resistance, high autoimmunity incidence, and attenuated tumor immunosurveillance. This review summarizes the current understanding of how age impacts thymic development and function, as well as the mechanisms underlying age‐related thymic involution, particularly TEC transcriptional profile changes during thymic aging.

For many cancer types, incidence rises rapidly with age as an apparent power law, supporting the idea that cancer is caused by a gradual accumulation of genetic mutations. Similarly, the incidence of many infectious diseases strongly increases with age. Here, combining data from immunology and epidemiology, we show that many of these dramatic age-related increases in incidence can be modeled based on immune system decline, rather than mutation accumulation. In humans, the thymus atrophies from infancy, resulting in an exponential decline in T cell production with a half-life of ∼16 years, which we use as the basis for a minimal mathematical model of disease incidence. Our model outperforms the power lawmodel with the same number of fitting parameters in describing cancer incidence data across a wide spectrum of different cancers, and provides excellent fits to infectious disease data. This framework provides mechanistic insight into cancer emergence, suggesting that age-related decline in T cell output is a major risk factor.

Infection susceptibility, poor vaccination efficacy, age-related disease onset, and neoplasms are linked to innate and adaptive immune dysfunction that accompanies aging (known as immunosenescence). During aging, organisms tend to develop a characteristic inflammatory state that expresses high levels of pro-inflammatory markers, termed inflammaging. This chronic inflammation is a typical phenomenon linked to immunosenescence and it is considered the major risk factor for age-related diseases. Thymic involution, naïve/memory cell ratio imbalance, dysregulated metabolism, and epigenetic alterations are striking features of immunosenescence. Disturbed T-cell pools and chronic antigen stimulation mediate premature senescence of immune cells, and senescent immune cells develop a proinflammatory senescence-associated secretory phenotype that exacerbates inflammaging. Although the underlying molecular mechanisms remain to be addressed, it is well documented that senescent T cells and inflammaging might be major driving forces in immunosenescence. Potential counteractive measures will be discussed, including intervention of cellular senescence and metabolic-epigenetic axes to mitigate immunosenescence. In recent years, immunosenescence has attracted increasing attention for its role in tumor development. As a result of the limited participation of elderly patients, the impact of immunosenescence on cancer immunotherapy is unclear. Despite some surprising results from clinical trials and drugs, it is necessary to investigate the role of immunosenescence in cancer and other age-related diseases.

Age-related regression of the thymus is associated with a decline in naïve T cell output. This is thought to contribute to the reduction in T cell diversity seen in older individuals and linked with increased susceptibility to infection, autoimmune disease, and cancer. Thymic involution is one of the most dramatic and ubiquitous changes seen in the aging immune system, but the mechanisms which underlying this process are poorly understood. However, a picture is emerging, implicating the involvement of both extrinsic and intrinsic factors. In this review we assess the role of the thymic microenvironment as a potential target that regulates thymic involution, question whether thymocyte development in the aged thymus is functionally impaired, and explore the kinetics of thymic involution.

The thymus is essential for establishing adaptive immunity yet undergoes age-related involution that leads to compromised immune responsiveness. The thymus is also extremely sensitive to acute insult and although capable of regeneration, this capacity declines with age for unknown reasons. We applied single-cell and spatial transcriptomics, lineage-tracing and advanced imaging to define age-related changes in nonhematopoietic stromal cells and discovered the emergence of two atypical thymic epithelial cell (TEC) states. These age-associated TECs (aaTECs) formed high-density peri-medullary epithelial clusters that were devoid of thymocytes; an accretion of nonproductive thymic tissue that worsened with age, exhibited features of epithelial-to-mesenchymal transition and was associated with downregulation of FOXN1. Interaction analysis revealed that the emergence of aaTECs drew tonic signals from other functional TEC populations at baseline acting as a sink for TEC growth factors. Following acute injury, aaTECs expanded substantially, further perturbing trophic regeneration pathways and correlating with defective repair of the involuted thymus. These findings therefore define a unique feature of thymic involution linked to immune aging and could have implications for developing immune-boosting therapies in older individuals. Here the authors identify age-associated changes in the epithelial cell compartment of the thymus that form high-density nonproductive microenvironmental niches that contribute toward thymic involution and inhibit its repair following injury.

Successful pregnancies rely on adaptations within the mother 1 , including marked changes within the immune system 2 . It has long been known that the thymus, the central lymphoid organ, changes markedly during pregnancy 3 . However, the molecular basis and importance of this process remain largely obscure. Here we show that the osteoclast differentiation receptor RANK 4 , 5 couples female sex hormones to the rewiring of the thymus during pregnancy. Genetic deletion of Rank (also known as Tnfrsf11a ) in thymic epithelial cells results in impaired thymic involution and blunted expansion of natural regulatory T (T reg ) cells in pregnant female mice. Sex hormones, in particular progesterone, drive the development of thymic T reg cells through RANK in a manner that depends on AIRE + medullary thymic epithelial cells. The depletion of Rank in the mouse thymic epithelium results in reduced accumulation of natural T reg cells in the placenta, and an increase in the number of miscarriages. Thymic deletion of Rank also results in impaired accumulation of T reg cells in visceral adipose tissue, and is associated with enlarged adipocyte size, tissue inflammation, enhanced maternal glucose intolerance, fetal macrosomia, and a long-lasting transgenerational alteration in glucose homeostasis, which are all key hallmarks of gestational diabetes. Transplantation of T reg cells rescued fetal loss, maternal glucose intolerance and fetal macrosomia. In human pregnancies, we found that gestational diabetes also correlates with a reduced number of T reg cells in the placenta. Our findings show that RANK promotes the hormone-mediated development of thymic T reg cells during pregnancy, and expand the functional role of maternal T reg cells to the development of gestational diabetes and the transgenerational metabolic rewiring of glucose homeostasis. RANK promotes the hormone-mediated development of thymic regulatory T cells during pregnancy; loss of RANK is associated with impaired maturation of maternal regulatory T cells, leading to fetal loss and the development of gestational diabetes.