A thymus-centric perspective on immune ageing: Mechanisms, cross-species insights, and therapeutic directions

Immunosenescence is a biological process accompanying ageing, characterized by increased susceptibility to infections, reduced vaccine efficacy, and the development of chronic low-grade inflammation. Although immunosenescence is systemic, the relative contribution and compensability of each organ in the adaptive immune axis remain debated. We consolidate current evidence supporting a thymus-centric model of immune ageing. In this model, early and progressive thymic involution, marked by thymic epithelial cell attrition, FOXN1 decline, and architectural disruption, emerges as the principal constraint on de novo naive T‑cell production and T-cell receptor (TCR) repertoire renewal. In contrast, age‑related changes in bone marrow and spleen often exhibit partial compensability through peripheral redistribution and clinical interventions, sustaining counts but not restoring de novo diversity. We evaluate mechanisms of thymic involution, inter-organ communication, and cross-species parallels, identifying shared features across animal models. Quantitative readouts, including age-associated declines in sjTRECs and TCR-β repertoire diversity, further support the thymus-centricity. Clinically, constrained thymopoiesis may undercut vaccine responsiveness and reduce the efficacy of cancer immunotherapies (chimeric antigen receptor T-cell and immune checkpoint inhibitors) in older adults. We assess genetic, pharmacological, and bioengineering strategies to preserve or restore thymic function and outline translational paths and endpoints for future trials.