The snakeskin (Ssk) gene joins the short list of genes that can be manipulated to either reduce and extend life span in a short-lived laboratory species, flies in this case. Loss of Ssk causes intestinal dysfunction, and in flies the intestine is probably the most important organ in late life decline and mortality, much more so than is the case in mammals. Increasing Ssk in old flies reduces all of the features of intestinal dysfunction normally associated with aging, and the flies live longer as a result. The composition of gut microbial populations appears to be important in this effect, but it is unclear as to how exactly Ssk is mediating those populations, even given a fair amount of research linking changes in microbial populations with the cellular mechanisms that Ssk is known to be involved in.
Occluding junctions play critical roles in epithelial barrier function, restricting the free diffusion of solutes between cells, as well as in the regulation of paracellular transport. In vertebrates, the occluding junctions are called tight junctions and their functional roles are well characterized. A functionally analogous structure, called the septate junction (SJ), exists in invertebrates, such as the smooth SJs (sSJs) of Drosophila, which are found in endodermally derived epithelia, such as the midgut.
Age-related alterations in intestinal epithelial junction expression and localization have been observed in flies and mammals, yet the causal relationships between changes in occluding junction function, intestinal homeostasis, and organismal aging are only beginning to be understood. Age-onset microbial dysbiosis is tightly linked to intestinal barrier dysfunction in both flies and mice. Critically, however, the question of whether manipulating intestinal occluding junction expression can delay age-onset dysbiosis and/or positively affect lifespan has not been addressed in any organism.
In this study, we show that Snakeskin (Ssk), an sSJ-specific protein, plays an important role in controlling the density and composition of the gut microbiota and that upregulation of Ssk during aging can prolong Drosophila lifespan. More specifically, loss of intestinal Ssk in adults leads to rapid-onset intestinal barrier dysfunction, changes in gut morphology, altered expression of antimicrobial peptides (AMPs), and microbial dysbiosis. Critically, we show that these phenotypes, including intestinal barrier dysfunction and dysbiosis, can be reversed upon restored Ssk expression.
Consistent with a critical role for intestinal junction proteins in organismal viability, loss of intestinal Ssk in adult animals leads to the rapid depletion of metabolic stores and rapid death. Importantly, restoring Ssk expression in flies showing intestinal barrier dysfunction prevents early-onset mortality. Moreover, intestinal upregulation of Ssk in normal flies protects against microbial translocation, limits age-onset dysbiosis, and prolongs lifespan. Our findings support the idea that occluding junction modulation could prove an effective therapeutic approach to prolong both intestinal and organismal health during aging in other species, including mammals.