Salazar Anna M, Resnik-Docampo Martin, Ulgherait Matthew, Clark Rebecca I, Shirasu-Hiza Mimi, Jones D Leanne, Walker David W
Department of Integrative Biology and Physiology, University of California, Los Angeles, Los Angeles, CA 90095, USA.
Department of Molecular, Cell, and Developmental Biology, University of California, Los Angeles, Los Angeles, CA 90095, USA.
iScience. 2018 Nov 30;9:229-243. doi: 10.1016/j.isci.2018.10.022. Epub 2018 Oct 24.
Intestinal barrier dysfunction is an evolutionarily conserved hallmark of aging, which has been linked to microbial dysbiosis, altered expression of occluding junction proteins, and impending mortality. However, the interplay between intestinal junction proteins, age-onset dysbiosis, and lifespan determination remains unclear. Here, we show that altered expression of Snakeskin (Ssk), a septate junction-specific protein, can modulate intestinal homeostasis, microbial dynamics, immune activity, and lifespan in Drosophila. Loss of Ssk leads to rapid and reversible intestinal barrier dysfunction, altered gut morphology, dysbiosis, and dramatically reduced lifespan. Remarkably, restoration of Ssk expression in flies showing intestinal barrier dysfunction rescues each of these phenotypes previously linked to aging. Intestinal up-regulation of Ssk protects against microbial translocation following oral infection with pathogenic bacteria. Furthermore, intestinal up-regulation of Ssk improves intestinal barrier function during aging, limits dysbiosis, and extends lifespan. Our findings indicate that intestinal occluding junctions may represent prolongevity targets in mammals.
肠道屏障功能障碍是衰老过程中一种进化上保守的特征，它与微生物群落失调、紧密连接蛋白表达改变以及临近死亡有关。然而，肠道连接蛋白、衰老引发的微生物群落失调和寿命决定之间的相互作用仍不清楚。在此，我们表明，蛇皮（Ssk）（一种分隔连接特异性蛋白）表达的改变可调节果蝇的肠道稳态、微生物动态、免疫活性和寿命。Ssk缺失会导致快速且可逆的肠道屏障功能障碍、肠道形态改变、微生物群落失调以及寿命显著缩短。值得注意的是，在显示肠道屏障功能障碍的果蝇中恢复Ssk表达可挽救先前与衰老相关的每种表型。在口服感染病原菌后，肠道中Ssk的上调可防止微生物易位。此外，肠道中Ssk的上调可改善衰老过程中的肠道屏障功能，限制微生物群落失调，并延长寿命。我们的研究结果表明，肠道紧密连接可能是哺乳动物中的长寿靶点。
