Department of Integrative Biology and Physiology, University of California, Los Angeles, CA 90095, USA.
Proc Natl Acad Sci U S A. 2012 Dec 26;109(52):21528-33. doi: 10.1073/pnas.1215849110. Epub 2012 Dec 12.
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.
衰老是疾病和死亡风险不断增加的特征，但潜在的病理生理学机制仍不清楚。事实上，人们对于个体器官系统的功能衰退如何与衰老的整体生理学以及生物体死亡的概率相关知之甚少。在这里，我们表明，肠道屏障功能障碍与一系列果蝇基因型和环境条件下的寿命有关，包括线粒体功能障碍和饮食限制。无论生理年龄如何，肠道屏障功能障碍都可以预测个体果蝇的即将死亡。炎症途径的激活与人类的衰老和与衰老相关的疾病有关，并且据报道，果蝇的免疫相关基因表达随着年龄的增长而增加。我们表明，与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，在衰老过程中表达增加的抗菌肽可用于识别表现出肠道屏障功能障碍的个体果蝇。同样，肠道屏障功能障碍比生理年龄更能准确识别与衰老相关的系统性代谢缺陷的个体果蝇，包括胰岛素/胰岛素样生长因子信号受损，这表现为 Akt 激活减少和 dFOXO 靶基因的上调。因此，肠道完整性随年龄的丧失与代谢和免疫信号的改变有关，而且，这是死亡的先兆。我们的研究结果表明，肠道屏障功能障碍可能也是其他物种（包括人类）衰老病理生理学中的一个重要因素。
