Ribosomal Stress and Age-Related Dysfunction of the Intestinal Barrier

With advancing age, the intestinal barrier responsible for keeping pathogens out of tissues becomes ever less effective. This contributes to rising levels of chronic inflammation. Researchers here note that intestinal barrier dysfunction correlates with markers of ribosomal stress, and that this form of cell stress can be induced by metabolites generated by microbes present in the intestine. It is one of the ways in which age-related shifts in the prevalence of different microbial species in the gut can become harmful to health.

The interaction between the gut microbiome and aging is becoming a well-studied area, so one might expect to see a growing focus on specific mechanisms in the years ahead, and potentially ways to interfere more specifically. For now, only very general approaches exist to adjust the gut microbiome populations towards a more youthful configuration, such as fecal microbiota transplantation and flagellin immunization.

Upon exposure to internal or environmental insults, ribosomes stand sentinel. In particular, stress-driven dysregulation of ribosomal homeostasis is a potent trigger of adverse outcomes in mammalians. The present study assessed whether the ribosomal insult affects the aging process via the regulation of sentinel organs such as the gut.

Analyses of the human aging dataset demonstrated that elevated features of ribosomal stress are inversely linked to intestinal barrier maintenance biomarkers during the aging process. Ribosome-insulted worms displayed reduced lifespan, which was associated with the disruption of gut barriers. Mechanistically, ribosomal stress-activated Sek-1/p38 signaling, a central platform of ribosomal stress responses, counteracted the gut barrier deterioration through the maintenance of the gut barrier, which was consistent with the results in a murine insult model. However, since the gut-protective p38 signaling was attenuated with aging, the ribosomal stress-induced distress was exacerbated in the gut epithelia and mucosa of the aged animals, subsequently leading to increased bacterial exposure.

Moreover, the bacterial community-based evaluation predicted concomitant increases in the abundance of mucosal sugar utilizers and mucin metabolic enzymes in response to ribosomal insult in the aged host. All of the present evidence on ribosomal insulting against the gut barrier integrity from worms to mammals provide new insights into the roles of ribosomes in the regulation of human longevity and susceptibility to gut-associated chronic diseases.

Link: https://doi.org/10.1016/j.redox.2022.102565

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