Abstract
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.
Highlights
The aged immune system has various characteristics
We showed that thymic involution disrupts negative selection, as revealed by the enhanced release of self-reactive T cells recognizing conventional (Tcon) cells
We hypothesize that age-related thymic involution shifts signaling strength from strong to intermediate and relatively enhances polyclonal thymic Treg (tTreg) generation ; while in some cases, antigen-specific interactions exhibit an even weaker signal, resulting in diminished antigen-specific tTreg cells and increased antigen-specific Tcon cells interphotoreceptor retinoid-binding protein (IRBP) from the atrophied thymus of Forkhead box N1 (FOXN1) conditional gene knock-out (cKO) mice compared to control [13]
Summary
The aged immune system has various characteristics. One of which is immunosenescence, which describes the vast and varied changes in the structure and function of the immune system as a result of age [1–4]. The atrophied thymus declines in its capacity to establish central tolerance, thereby, causing increased self-reactive T cells to escape to the periphery and participate in the process of inflammaging.
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