Intestinal barrier dysfunction: an evolutionarily conserved hallmark of aging.

A major challenge in the biology of aging is to understand how specific age-onset pathologies relate to the overall health of the organism. The integrity of the intestinal epithelium is essential for the wellbeing of the organism throughout life. In recent years, intestinal barrier dysfunction has emerged as an evolutionarily conserved feature of aged organisms, as reported in worms, flies, fish, rodents and primates.

Intestinal Snakeskin Limits Microbial Dysbiosis during Aging and Promotes Longevity.

Intestinal barrier dysfunction is an evolutionarily conserved hallmark of aging, which has been linked to microbial dysbiosis, altered expression of occluding junction proteins, and impending mortality. However, the interplay between intestinal junction proteins, age-onset dysbiosis, and lifespan determination remains unclear. Here, we show that altered expression of Snakeskin (Ssk), a septate junction-specific protein, can modulate intestinal homeostasis, microbial dynamics, immune activity, and lifespan in Drosophila.

Broad activation of the ubiquitin-proteasome system by Parkin is critical for mitophagy.

Parkin, an E3 ubiquitin ligase implicated in Parkinson's disease, promotes degradation of dysfunctional mitochondria by autophagy. Using proteomic and cellular approaches, we show that upon translocation to mitochondria, Parkin activates the ubiquitin-proteasome system (UPS) for widespread degradation of outer membrane proteins. This is evidenced by an increase in K48-linked polyubiquitin on mitochondria, recruitment of the 26S proteasome and rapid degradation of multiple outer membrane proteins.

Regulation of synaptic Pumilio function by an aggregation-prone domain.

We identified Pumilio (Pum), a Drosophila translational repressor, in a computational search for metazoan proteins whose activities might be regulated by assembly into ordered aggregates. The search algorithm was based on evolutionary sequence conservation patterns observed for yeast prion proteins, which contain aggregation-prone glutamine/asparagine (Q/N)-rich domains attached to functional domains of normal amino acid composition. We examined aggregation of Pum and its nematode ortholog PUF-9 by expression in yeast.