Gao Arwen W, El Alam Gaby, Lalou Amélia, Li Terytty Yang, Molenaars Marte, Zhu Yunyun, Overmyer Katherine A, Shishkova Evgenia, Hof Kevin, Bou Sleiman Maroun, Houtkooper Riekelt H, Coon Joshua J, Auwerx Johan
Laboratory of Integrative Systems Physiology, Interfaculty Institute of Bioengineering, École Polytechnique Fédérale de Lausanne, 1015 Lausanne, Switzerland.
Laboratory Genetic Metabolic Diseases, Amsterdam Gastroenterology, Endocrinology and Metabolism, Amsterdam Cardiovascular Sciences, Amsterdam UMC, University of Amsterdam, 1105 Amsterdam, AZ, the Netherlands.
iScience. 2022 Jan 5;25(2):103734. doi: 10.1016/j.isci.2022.103734. eCollection 2022 Feb 18.
The mitochondrial unfolded protein response (UPRmt) is a promising pharmacological target for aging and age-related diseases. However, the integrative analysis of the impact of UPRmt activation on different signaling layers in animals with different genetic backgrounds is lacking. Here, we applied systems approaches to investigate the effect of UPRmt induced by doxycycline (Dox) on transcriptome, proteome, and lipidome in two genetically divergent worm strains, named N2 and CB4856. From the integrated omics datasets, we found that Dox prolongs lifespan of both worm strains through shared and strain-specific mechanisms. Specifically, Dox strongly impacts mitochondria, upregulates defense response, and lipid metabolism, while decreasing triglycerides. We further validated that lipid genes and were required for Dox-induced UPRmt and longevity in N2 and CB4856 worms, respectively. Our data have translational value as they indicate that the beneficial effects of Dox-induced UPRmt on lifespan are consistent across different genetic backgrounds through different regulators.
线粒体未折叠蛋白反应（UPRmt）是衰老及年龄相关疾病一个很有前景的药理学靶点。然而，目前缺乏对不同遗传背景动物中UPRmt激活对不同信号层影响的综合分析。在此，我们运用系统方法研究强力霉素（Dox）诱导的UPRmt对两种基因不同的线虫品系N2和CB4856转录组、蛋白质组和脂质组的影响。从整合的组学数据集中，我们发现Dox通过共同机制和品系特异性机制延长了两种线虫品系的寿命。具体而言，Dox对线粒体有强烈影响，上调防御反应和脂质代谢，同时降低甘油三酯。我们进一步验证，脂质基因分别是Dox诱导N2和CB4856线虫中UPRmt和长寿所必需的。我们的数据具有转化价值，因为它们表明Dox诱导的UPRmt对寿命的有益影响通过不同调节因子在不同遗传背景中是一致的。
