Thymic microenvironment's impact on immunosenescence.

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.

Contributions of Age-Related Thymic Involution to Immunosenescence and Inflammaging.

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.

Extracellular vesicles extracted from young donor serum attenuate inflammaging via partially rejuvenating aged T-cell immunotolerance.

Biologic aging results in a chronic inflammatory condition, termed inflammaging, which establishes a risk for such age-related diseases as neurocardiovascular diseases; therefore, it is of great importance to develop rejuvenation strategies that are able to attenuate inflammaging as a means of intervention for age-related diseases. A promising rejuvenation factor that is present in young blood has been found that can make aged neurons younger; however, the component in the young blood and its mechanism of action are poorly elucidated. We assessed rejuvenation in naturally aged mice with extracellular vesicles (EVs) or exosomes extracted from young murine serum on the basis of different spectrums of microRNAs in these vesicles from young and old sera. We found that EVs extracted from young donor mouse serum, rather than EVs extracted from old donor mouse serum or non-EV supernatant extracted from young donor mouse serum, were able to attenuate inflammaging in old mice. Inflammaging is attributed to multiple factors, one of which is thymic aging-released self-reactive T cell-induced pathology. We found that the attenuation of inflammaging after treatment with EVs from young serum partially contributed to the rejuvenation of thymic aging, which is characterized by partially reversed thymic involution, enhancement of negative selection signals, and reduced autoreactions in the periphery. Our results provide evidence for understanding of the potential rejuvenation factor in the young donor serum, which holds great promise for the development of novel therapeutics to reduce morbidity and mortality caused by age-related inflammatory diseases.-Wang, W., Wang, L., Ruan, L., Oh, J., Dong, X., Zhuge, Q., Su, D.-M. Extracellular vesicles extracted from young donor serum attenuate inflammaging via partially rejuvenating aged T-cell immunotolerance.

Aging of lymphoid organs: Can photobiomodulation reverse age-associated thymic involution via stimulation of extrapineal melatonin synthesis and bone marrow stem cells?

Thymic atrophy and the subsequent reduction in T-cell production are the most noticeable age-related changes affecting lymphoid organs in the immune system. In fact, thymic involution has been described as "programmed aging." New therapeutic approaches, such as photobiomodulation (PBM), may reduce or reverse these changes. PBM (also known as low-level laser therapy) involves the delivery of non-thermal levels of red or near-infrared light that are absorbed by mitochondrial chromophores, in order to prevent tissue death and stimulate healing and regeneration. PBM may reverse or prevent thymic involution due to its ability to induce extrapineal melatonin biosynthesis via cyclic adenosine monophosphate (AMP) or NF-kB activation, or alternatively by stimulating bone marrow stem cells that can regenerate the thymus. This perspective puts forward a hypothesis that PBM can alter thymic involution, improve immune functioning in aged people and even extend lifespan.

Induction of epithelial to mesenchymal transition (EMT) and inhibition on adipogenesis: Two different sides of the same coin? Feasible roles and mechanisms of transforming growth factor ß1 (TGF-ß1) in age-related thymic involution.

Age-related thymic involution is characterized by a loss of thymic epithelial cells (TECs) and a concomitant increase in adipocytes, but the mechanisms involved in thymic adipogenesis are still not clear. Transforming growth factor ß1 (TGF-ß1) is a pleiotropic cytokine that has been reported to be up-regulated with age in thymic stromal cells in both human and mouse. However, the exact role of TGF-ß1 in age-related thymic involution remains to be further elucidated. On the basis of previous findings, we propose a novel hypothesis that TGF-ß1 functions a dual role in age-related thymic involution. On one hand, up-regulation of TGF-ß1 promotes epithelial to mesenchymal transition (EMT) process in TECs via activating forkhead box protein C2 (FoxC2). On the other hand, TGF-ß1 inhibits the transdifferentiation of EMT-derived mesenchymal cells to adipocytes in the thymus. If confirmed, our hypothesis will not only provide further evidence supporting that the transdifferentiation of TECs into pre-adipocytes represents a source of thymic adiposity during age-related thymic involution, but also uncover a unique role of TGF-ß1 in the transdifferentiation of TECs into pre-adipocytes. Collectively, the inhibition of TGF-ß1 may serve as a strategy to hinder age-related thymic involution or even to restore thymic function in the elderly.

Thymus Size and Age-related Thymic Involution: Early Programming, Sexual Dimorphism, Progenitors and Stroma.

Age-related thymic involution is characterized by a progressive regression in thymus size and a diminishment of thymic structure. A decrease in thymic compartments leads to the reduction of thymopoiesis. Thymic involution is closely associated with immunosenescence, a degeneration of the immune system primarily due to the alterations in T-cell composition. Strategies to improve the consequences of the aging thymus are currently under investigation. A wide array of knowledge has revealed a series of factors that are essential in the overall determination of thymic function and immune response. Evidence indicates that early programming of the thymus, sexual dimorphism, and the efficiency of specific T-cell progenitors and the thymic microenvironment are all crucial determinants of immune activity from early life through advanced ages. To fully understand the processes involved in age-related thymic involution, such determinants must be considered. The central purpose of this review is to emphasize previous and most recent evidence suggesting that these factors contribute to the influence of long-term immunity and ultimately shape the progression of thymic involution in advanced age.