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

随着年龄的增长，胸腺功能的丧失可能是由于T细胞前体细胞数量的减少和胸腺微环境中关键介质的丧失。为了评估与这种丢失相关的分子变化，我们研究了逐渐老化的不同性别小鼠胸腺的转录本，以及热量限制(CR)和自由饮食(AL)的转录本。在胸腺老化过程中，参与转录调节、应激反应、炎症和免疫功能等多种生物学和分子过程的基因发生了显著变化。这些差异取决于性别和饮食等变量。有趣的是，在卡路里限制饮食的小鼠中，许多与胸腺老化相关的变化要么是沉默的，要么几乎完全逆转。这些研究对胸腺衰老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的分子途径的基因组相关性时，需要考虑性别和饮食等生物变量。此外，这些结果强调有必要考虑生物变量，如性别和饮食相互作用，以阐明影响胸腺退化的分子途径的基因组相关性。我们目前还在完成对不同年龄小鼠的这些数据的分析和确认，这些小鼠被注入了各种激素，导致胸腺细胞数量的部分恢复。对这种处理过的小鼠的胸腺进行阵列分析，可能会产生关于胸腺再生所涉及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对长寿和寿命起着关键作用。该项目的总体目标是在衰老过程中建立胸腺、脾和淋巴结的全面基因表达谱，以确定在这些不同器官系统中以年龄相关方式表达的独特和共同的基因和功能相关的基因组。我们最初的努力集中在胸腺上，因为它的退化被认为是解决与衰老相关的免疫缺陷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.