A Cluster of Three <scp>snoRNAs</scp> Including Jouvence Required in the Gut Determines Lifespan and Confers Neuroprotection Through Metabolic Parameters

In our society, the aging of the population is a major public health concern. Recently we have identified a new snoRNA (jouvence) in Drosophila, and showed that its deletion (F4) reduces lifespan, while its overexpression increases it. F4 deleted flies also present neurodegenerative lesions and a deregulation of metabolic parameters such as triglycerides and sterols. However, a deeper characterization of this genomic locus has revealed the presence of two additional snoRNAs. Here, we have characterized, at the whole-organism level, the role of each of them. First, we show that each snoRNA is expressed in the epithelium of the gut (in the enterocytes), and in the fat body. Second, in the context of the F4 deletion, the re-expression of each snoRNA in the enterocytes or in the fat body is sufficient to improve lifespan and protect against neurodegeneration in old flies. In addition, according to snoRNA, it rescues the expression of specific deregulated genes within the epithelium of the gut that are involved in lipid and sterol metabolism. Consequently, these two metabolic parameters are also rescued, establishing a relationship between each snoRNA and the lesions of the brain, the metabolic disorders, and the lifespan. Finally, histological stainings revealed that the neurodegenerative lesions are due to an increase of free sterol within the brain and lipid peroxidation in the pericerebral fat body. These results point to a causal relationship between the snoRNAs' function in the epithelium of the gut and the neurodegenerative lesions through the metabolic parameters, revealing a gut-brain axis.