Intestinal barrier dysfunction links metabolic and inflammatory markers of aging to death in Drosophila
Intestinal barrier dysfunction links metabolic and inflammatory markers of aging to death in Drosophila
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DOI：
10.1073/pnas.1215849110
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发表时间：
2012-12-26
影响因子：
11.1
通讯作者：
Walker, David W.
中科院分区：
文献类型：
--
作者：
Rera, Michael;Clark, Rebecca I.;Walker, David W.
衰老的特征是疾病和死亡的风险不断增加，但对潜在的病理生理学知之甚少。事实上，人们对单个器官系统的功能衰退与衰老的综合生理学和生物体死亡概率的关系知之甚少。在这里，我们表明，肠道屏障功能障碍与寿命在一系列果蝇基因型和环境条件，包括线粒体功能障碍和饮食限制。无论实际年龄，肠屏障功能障碍预测即将死亡的个别苍蝇。炎症通路的激活与人类的衰老和年龄相关疾病有关，并且在果蝇中报道了免疫相关基因表达的年龄相关增加。我们发现，年龄相关的抗菌肽表达增加与肠道屏障功能障碍密切相关。事实上，在老化过程中增加的抗微生物肽表达可用于鉴定表现出肠屏障功能障碍的个体果蝇。类似地，肠屏障功能障碍在识别先前与衰老相关的全身性代谢缺陷的个体果蝇中比实际年龄更准确，包括受损的胰岛素/胰岛素样生长因子信号传导，如Akt激活减少和dFOXO靶基因上调所证明的。因此，肠道完整性的年龄依赖性丧失与代谢和免疫信号的改变有关，并且关键地是死亡的预兆。我们的研究结果表明，肠道屏障功能障碍可能是一个重要的因素，在其他物种的衰老，以及，包括人类的病理生理。
Aging is characterized by a growing risk of disease and death, yet the underlying pathophysiology is poorly understood. Indeed, little is known about how the functional decline of individual organ systems relates to the integrative physiology of aging and probability of death of the organism. Here we show that intestinal barrier dysfunction is correlated with lifespan across a range of Drosophila genotypes and environmental conditions, including mitochondrial dysfunction and dietary restriction. Regardless of chronological age, intestinal barrier dysfunction predicts impending death in individual flies. Activation of inflammatory pathways has been linked to aging and age-related diseases in humans, and an age-related increase in immunity-related gene expression has been reported in Drosophila. We show that the age-related increase in expression of antimicrobial peptides is tightly linked to intestinal barrier dysfunction. Indeed, increased antimicrobial peptide expression during aging can be used to identify individual flies exhibiting intestinal barrier dysfunction. Similarly, intestinal barrier dysfunction is more accurate than chronological age in identifying individual flies with systemic metabolic defects previously linked to aging, including impaired insulin/insulin-like growth factor signaling, as evidenced by a reduction in Akt activation and up-regulation of dFOXO target genes. Thus, the age-dependent loss of intestinal integrity is associated with altered metabolic and immune signaling and, critically, is a harbinger of death. Our findings suggest that intestinal barrier dysfunction may be an important factor in the pathophysiology of aging in other species as well, including humans.