Department of Biological Sciences, University of Maryland, Baltimore, MD 21250, USA.
Genetics. 2012 Jul;191(3):989-1002. doi: 10.1534/genetics.112.140640. Epub 2012 May 2.
Immunosenescence, the age-related decline in immune system function, is a general hallmark of aging. While much is known about the cellular and physiological changes that accompany immunosenescence, we know little about the genetic influences on this phenomenon. In this study we combined age-specific measurements of bacterial clearance ability following infection with whole-genome measurements of the transcriptional response to infection and wounding to identify genes that contribute to the natural variation in immunosenescence, using Drosophila melanogaster as a model system. Twenty inbred lines derived from nature were measured for their ability to clear an Escherichia coli infection at 1 and 4 weeks of age. We used microarrays to simultaneously determine genome-wide expression profiles in infected and wounded flies at each age for 12 of these lines. Lines exhibited significant genetically based variation in bacterial clearance at both ages; however, the genetic basis of this variation changed dramatically with age. Variation in gene expression was significantly correlated with bacterial clearance ability only in the older age group. At 4 weeks of age variation in the expression of 247 genes following infection was associated with genetic variation in bacterial clearance. Functional annotation analyses implicate genes involved in energy metabolism including those in the insulin signaling/TOR pathway as having significant associations with bacterial clearance in older individuals. Given the evolutionary conservation of the genes involved in energy metabolism, our results could have important implications for understanding immunosenescence in other organisms, including humans.
免疫衰老，即免疫系统功能随年龄增长而下降，是衰老的普遍特征。虽然我们已经了解了伴随免疫衰老的细胞和生理变化，但对于这一现象的遗传影响却知之甚少。在这项研究中，我们结合了感染后细菌清除能力的年龄特异性测量值，以及感染和创伤后转录反应的全基因组测量值，利用黑腹果蝇作为模型系统，鉴定了导致免疫衰老自然变异的基因。我们对 20 个源自自然的近交系进行了测量，以评估它们在 1 周龄和 4 周龄时清除大肠杆菌感染的能力。对于其中的 12 个品系，我们使用微阵列在每个年龄的感染和受伤的果蝇中同时确定了全基因组的表达谱。这些品系在两个年龄段的细菌清除能力上都表现出显著的遗传基础变异；然而，这种变异的遗传基础随年龄的变化而急剧变化。只有在年龄较大的组别中，基因表达的变异才与细菌清除能力显著相关。在 4 周龄时，感染后 247 个基因的表达变化与细菌清除能力的遗传变异有关。功能注释分析表明，参与能量代谢的基因，包括胰岛素信号/TOR 通路中的基因，与老年人的细菌清除能力有显著关联。考虑到参与能量代谢的基因在进化上的保守性，我们的研究结果可能对理解其他生物体（包括人类）的免疫衰老具有重要意义。
