Age-related thymic involution: Mechanisms and functional impact

Abstract

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.

Keywords: T cells; aging; thymic epithelial cells; thymic involution; thymus.

FIGURE 1

Effects of age on thymic development and function. Age‐related thymic involution leads to a gradual reduction in thymic cellularity and thymic stromal microenvironment disruption, including the loss of definite cortical‐medullary junctions, a reduction in cTECs and mTECs, fibroblast expansion, an increase in perivascular space (PVS), and more. The disrupted thymic stromal microenvironment disturbs thymocyte development causing decreased ETP and DP frequency, increased DN frequency, and abnormal CD3⁺ DN cell accumulation. The young thymus is able to produce functionally competent T cells expressing a broad TCR repertoire, whereas the aged thymus produces fewer naïve T cells with a restricted TCR repertoire

FIGURE 2

Age‐related thymic involution mechanisms. Both positive and negative regulators of thymic involution have been identified. Positive regulators include Foxn1, E2F3, myc, Wnt4, FGF21, KGF, IL‐7, IL‐22, miR‐181a‐5p, Lamin‐B1, Leptin, GH, IGF‐1, Ghrelin, and GHSR, which exhibit reduced activity with age. Negative regulators include Axin, LIF, OSM, IL‐6, SCF, IL‐1β, miR‐125a‐5p, miR‐205‐5p, and follistatin, which exhibit increased activity with age. In addition, CR can attenuate age‐related thymic involution, while obesity and sex hormones exacerbate age‐related thymic involution