A cluster of three snoRNAs 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 concern of public health. 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 as triglycerides and sterol. However, a deeper characterization of this genomic locus has revealed the presence of two other snoRNAs. Here, we have characterized at the whole organismal level, the role of each them. First, we show that each snoRNAs are expressed in the epithelium of the gut (enterocytes), and in the fat body. Second, in 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, depending of the snoRNAs, it rescues the expression of specific deregulated genes within the epithelium of the gut, involved in lipids and sterol metabolism. Consequently, these two metabolic parameters are also rescued, establishing a relationship between the lesions of the brain, the metabolic disorders, the lifespan, and each snoRNAs respectively. Finally, histological stainings as Nile Red and BODIPY C11-581/591 have revealed that the neurodegenerative lesions are due to an increase of free sterol within the brain, and lipid peroxydation in the pericerebral fat body. Altogether, these results point-out a causal relationship between the epithelium of the gut and the neurodegenerative lesions through the metabolic parameters, indicating a gut-brain axis.