Thymus regeneration in countering immunosenescence: Mechanisms, strategies and future perspectives

Immunosenescence refers to the progressive decline in immune system functionality associated with aging, with thymic involution identified as a primary driver of this process. The thymus, the central organ for T cell development, begins to atrophy from puberty onward, resulting in a marked reduction in naive T cell output and a significant decrease in the diversity of T cell receptor (TCR) repertoires. This decline compromises the immune system's capacity to mount effective responses against neoantigens and is associated with a state of chronic low-grade inflammation, termed inflammaging. The structural and functional deterioration of the thymus not only directly impairs adaptive immunity but also participates in a bidirectional crosstalk with systemic aging, creating a self-reinforcing vicious cycle. Consequently, reversing thymic involution and achieving thymic regeneration are fundamental strategies for restoring immune homeostasis, delaying immunosenescence, and ultimately combating aging. Recent years have witnessed significant advancements in thymic regeneration, with various interventional approaches demonstrating efficacy, including modulation of the growth hormone/IGF-1 axis, cytokine-based therapies, mTOR inhibitors, sex steroid ablation, stem cell and cell-based therapies, gene therapy, and tissue engineering. This review aims to systematically summarize the mechanisms of action, current research status, advantages, and limitations of these strategies. Furthermore, we explore the potential value of combinatorial approaches and future directions, providing a theoretical foundation for the clinical translation of thymic regeneration and the optimization of anti-immunosenescence interventions.