Mechanisms that Regulate Thymic Involution and Age-Associated Changes in T-Cells

随着年龄的增长，胸腺功能丧失可能是由于 T 细胞祖细胞数量减少和胸腺微环境中关键介质的丧失所致。为了评估与这种损失相关的分子变化，我们检查了不同性别和限制热量（CR）与随意（AL）饮食的逐渐衰老小鼠胸腺的转录组。参与各种生物和分子过程的基因，包括转录调节因子、应激反应、炎症和免疫功能，在胸腺衰老过程中发生显着变化。这些差异取决于性别和饮食等变量。有趣的是，在热量限制饮食的小鼠中，与胸腺衰老相关的许多变化要么减弱，要么几乎完全逆转。这些研究为与胸腺衰老相关的分子机制提供了有价值的见解，并强调在阐明影响胸腺退化分子途径的基因组相关因素时需要考虑性别和饮食等生物变量。此外，这些结果强调需要考虑性别和饮食相互作用等生物变量，以阐明影响胸腺复旧分子途径的基因组相关性。我们目前还正在完成对不同年龄小鼠的这些数据的分析和确认，这些小鼠注射了各种激素，导致胸腺细胞数量部分恢复。对此类治疗小鼠的胸腺进行阵列分析可能会产生有关胸腺再生的常见分子过程的有价值的数据。目前尚不清楚某些淋巴器官或细胞成分是否在长寿和寿命中发挥关键作用。该项目的总体目标是在衰老过程中产生胸腺、脾脏和淋巴结的全面基因表达谱，以识别在这些不同器官系统中以年龄依赖性方式表达的独特和常见基因以及功能相关的基因组。我们最初将工作重点放在胸腺上，因为胸腺的退化被认为是解决与衰老相关的免疫缺陷问题时需要克服的最重要的障碍之一。

The loss of thymic function with age may be due to diminished numbers of T-cell progenitors and the loss of critical mediators within the thymic microenvironment. To assess the molecular changes associated with this loss, we examined transcriptomes of progressively aging mouse thymi, of different sexes and on caloric-restricted (CR) vs. ad libitum (AL) diets. Genes involved in various biological and molecular processes including transcriptional regulators, stress response, inflammation and immune function significantly changed during thymic aging. These differences depended on variables such as sex and diet. Interestingly, many changes associated with thymic aging are either muted or almost completely reversed in mice on caloric-restricted diets. These studies provide valuable insight into the molecular mechanisms associated with thymic aging and emphasize the need to account for biological variables such as sex and diet when elucidating the genomic correlates that influence the molecular pathways responsible for thymic involution. Moreover, these results emphasize the need to account for biological variables such as sex and dietary interactions to elucidate the genomic correlates that influence the molecular pathways responsible for thymic involution. We are also currently completing the analysis and confirmation of these data from mice of various ages infused with various hormones that result in a partial restoration in thymocyte numbers. Array analysis of the thymi of such treated mice may yield valuable data on the common molecular processes involved in thymic regeneration. It is unclear whether certain lymphoid organs or cellular components play a critical role in longevity and lifespan. The overall goal of this project is to produce a comprehensive gene expression profile in the thymus, spleen, and lymph nodes during the aging process to identify unique and common genes and functionally related groups of genes that are expressed in age-dependent manner in these different organ systems. We have initially focused our efforts on the thymus, as its involution is believed to be one of the most significant obstacles to overcome in addressing the immunological deficits associated with aging.