《生命科学》 2026, 38(6): 956-971
胸腺衰退和T细胞衰老的机制与干预策略
摘 要：
随着全球人口老龄化的加剧，免疫衰老已成为严重影响老年人健康的关键因素，而胸腺衰退是免疫衰老的核心事件。胸腺作为T细胞发育和成熟的核心器官，随年龄增长出现进行性萎缩，表现为胸腺上皮细胞减少、脂肪浸润及纤维化等结构改变，导致胸腺输出功能显著下降。胸腺结构和功能的衰退直接破坏了T细胞发育所依赖的微环境，引起胸腺定植祖细胞数量减少及阳性、阴性选择过程受损，继而导致外周初始T细胞数量锐减、T细胞受体多样性降低以及免疫耐受功能减弱，显著增加发生感染、肿瘤及自身免疫性疾病的风险。本文系统综述胸腺衰退的细胞与分子机制及其对外周T细胞库稳态的深远影响，并探讨多种促进胸腺与T细胞再生的干预策略，以期为延缓免疫衰老、促进健康老龄化提供新的理论依据与思路。
通讯作者：张惠媛 , Email:hyzhang@scu.edu.cn 胡洪波 , Email:hongbohu@scu.edu.cn
Abstract:
In the context of rapid global population aging, immunosenescence has emerged as a major determinant of morbidity and mortality in older adults. Age-associated thymic involution is recognized as a central driver of this process. This review summarizes current understanding of the cellular and molecular mechanisms underlying thymic involution, and its consequences for T-cell homeostasis, and discusses the emerging strategies to restore thymic function with the goal of delaying immune aging and promoting healthier longevity. The thymus, essential for T-cell development and the establishment of central tolerance, undergoes progressive structural and functional decline with age. This deterioration is characterized by thymic epithelial cell (TEC) loss, cortical–medullary disorganization, adipose infiltration, and fibrosis. These changes reflect coordinated remodeling of all stromal compartments. The aged TECs display impaired cytokine production and antigen presentation capacity, fibroblasts promote extracellular matrix accumulation and fibrosis, and adipocytes displace functional parenchyma while releasing immunomodulatory adipokines. Together, these alterations disrupt the thymic microenvironment required for efficient thymopoiesis. As a consequence, early thymic progenitors (ETPs) recruitment to thymus is impaired, together with their reduced T-lineage commitment and TCR gene rearrangement efficiency. More importantly, both positive and negative selection are impaired due to stromal dysfunction, highlighting the potential of autoimmunity. Thymic involution has great impact on peripheral T-cell aging. With age, thymic output of naïve T-cells diminishes remarkably, leading to contraction of TCR repertoire diversity and reduced capacity to respond to novel antigens. This diminished thymic replenishment accelerates the accumulation of senescent and terminally differentiated T-cell subsets, including TEMRA cells, CD8+CD28‒ T cells, GZMK+CD8+ T cells, virtual memory T cells, and cytotoxic CD4+ T-cells. These subsets display reduced proliferative capacity, metabolic reprogramming, telomere erosion, and a pro-inflammatory senescence-associated secretory phenotype (SASP). They contribute to chronic low-grade inflammation (inflammaging) and increased susceptibility to infections, malignancies, and autoimmunity. Persistent viral infections, such as cytomegalovirus (CMV), further drive oligoclonal T-cell expansion and repertoire skewing. Based on these mechanistic insights, the review discusses therapeutic strategies targeting thymic regeneration and T-cell rejuvenation, including cytokine-based approaches (e.g., IL-7 fusion proteins, thymosin α1), TEC-directed interventions (e.g., FOXN1 gene delivery, FGF21 signaling), and metabolic modulation through caloric restriction or inhibition of mTOR and AMPK pathways. Advances in stem cell-derived thymic organoids provide powerful platforms for modeling human thymopoiesis and hold promise for future regenerative therapies. Integration of multi-omics profiling with machine learning-based immune-age prediction is expected to enable personalized immune monitoring and guide targeted interventions. Future research should focus on deciphering dynamic cell-cell and metabolic regulation within the aging thymic niche to achieve durable restoration of immune competence in elderly individuals.
Communication Author：ZHANG Hui-Yuan , Email:hyzhang@scu.edu.cn HU Hong-Bo , Email:hongbohu@scu.edu.cn
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