Investigating the role of cytosolic mitochondrial double-stranded RNA in cellular senescence and aging

项目摘要/摘要 这项应用研究线粒体RNA、炎症、衰老和衰老之间的关系。 细胞衰老是组织和组织衰老的一个公认的驱动因素，这一过程被认为是部分 通过诱导慢性衰老相关的分泌表型(SASP)而介导。因此， 作为一种促进健康衰老的策略，选择性地以衰老细胞为靶点是非常有兴趣的。我们的工作 已经证明线粒体功能障碍是细胞衰老的标志和SASP的驱动因素 通过靶向它们，我们也许能够抑制有害的SASP，这种已知的SASP有助于衰老。 线粒体双链RNA(MtdsRNA)存在于细胞质中时，已知尤其是 免疫原性，并引发炎症反应。我们观察到衰老的细胞含有更多的 胞质mtdsRNA的增加以及RNA感受器的表达增加。此外，我们发现， MtdsRNA转染细胞引发炎症反应和线粒体DNA抑制 在衰老细胞中转录，降低SASP。最后，我们观察到mtdsrna需要胞质 DNA传感器cGAS诱导炎症提示RNA和DNA传感通路之间存在相互作用 这一过程。这导致我们假设胞质mdsRNA在调节SASP和 这可能是一个新的干预目标，以提高老龄化期间的健康寿命。 在这个项目中，我们将剖析衰老细胞胞浆中mtdsrna增加的机制，如 以及调查RNA传感通路的激活是否对SASP起作用。此外，我们还将探索 线粒体DNA和RNA在SASP发生发展中相互作用的机制。 我们的最终目标是确定针对衰老细胞的新干预措施，以缓解与年龄相关的功能障碍。

PROJECT SUMMARY/ABSTRACT This application investigates the relationship between mitochondrial RNA, inflammation, senescence, and aging. Cellular senescence is a well-established driver of tissue and organismal aging, a process thought to be partly mediated via the induction of a chronic Senescence-associated secretory phenotype (SASP). Consequently, there is great interest in selectively targeting senescent cells as a strategy to promote healthy aging. Our work has demonstrated that mitochondrial dysfunction is a hallmark of cellular senescence and a driver of the SASP and that by targeting them we may be able to suppress the detrimental SASP known to contribute to aging. Mitochondrial double-stranded RNA (mtdsRNA) when present in the cytosol is known to be especially immunogenic and trigger an inflammatory response. We observed that senescent cells contain increased levels of cytosolic mtdsRNA together with increased expression of RNA sensors. Furthermore, we found that transfection of cells with mtdsRNA triggers an inflammatory response and inhibition of mitochondrial DNA transcription in senescent cells, decreases the SASP. Finally, we observed that mtdsRNA requires the cytosolic DNA sensor cGAS to induce inflammation suggesting an interplay between RNA and DNA sensing pathways in the process. This led us to hypothesize that cytosolic mdsRNA plays a role in the regulation of the SASP and may be a novel target for interventions to improve healthspan during aging. In this project, we will dissect the mechanisms by which mtdsRNA increases in the cytosol of senescent cells as well as investigate if activation of RNA sensing pathways contributes to the SASP. Additionally, we will explore the mechanisms mediating the interplay between mitochondrial DNA and RNA in the development of the SASP. Our ultimate goal is to identify new interventions that target senescent cells to alleviate age-related dysfunction.