GENETIC ANALYSIS OF IMMUNOSENECENCE

免疫衰老是老年人免疫应答的一个特征性现象，但人们对这一现象的认识却很少。在老年人（和小鼠）中，这种免疫失调的特征在于创伤性损伤或感染后的预后差，对实验引入的免疫刺激的反应弱，但许多促炎细胞因子水平升高。我们发现果蝇也表现出类似的免疫衰老。特别是，老年苍蝇具有升高的抗菌肽水平，但对免疫攻击的反应较差。控制促炎细胞因子和抗菌肽产生的先天免疫识别和信号系统在昆虫和哺乳动物之间高度保守。因此，对果蝇免疫衰老的详细研究将为人类类似过程提供新的见解。我们假设，老年文件有一个减弱的免疫反应，这导致持续感染和抗菌肽水平升高。这将在目标1中直接审查。我们进一步提出了两种可能的机制，免疫反应是由老化调制。 在目标2中，我们将在分子细节上研究胰岛素/胰岛素样信号传导的可能性，这是已知的寿命的关键调节剂，直接影响免疫力。在目标3中，我们将扩大这种方法，并使用fonA/ard遗传筛选来识别影响先天免疫功能障碍随年龄增长的进展的新途径。

Immune senescence is a pooriy understood phenomenon characteristic of the immune response of the aged. In aged humans (and mice), this immune disregulafion is characterized by poor a prognosis following traumatic injury or infection, a weak response to experimentally introduced immune sfimulafion, but an elevated level of many pro-inflammatory cytokines. We have found that Drosophila melanogaster also exhibits a similar immune senescence. In particular, aged flies have elevated levels of anfimicrobial pepfides but respond pooriy to immune challenge. The innate immune recognition and signaling systems that control pro-inflammatory cytokine and antimicrobial peptide production are highly conserved between insects and mammals. Therefore, the detailed examinafion of immune senescence in flies will lead to new insights into similar processes in humans. We hypothesize that aged files have a weakened immune response, which leads to persistent infections and elevated levels of antimicrobial peptides. This will be directly examined in Aim 1. We further propose two possible mechanisms by which the immune response is modulated by aging. In Aim 2, we will investigate in molecular detail the possibility that the Insulin/ Insulin like Signaling, which is known to be a critical modulator of lifespan, directly affect immunity. In Aim 3, we will broaden this approach and use a fonA/ard genetic screen to identify novel pathways affecting the progression of innate immune dysfunction with age.