Rogue causes intestinal cells in aging flies to lose their specialized identity: suppressing it extended median lifespan from 39 to 48 days
Rogue causes intestinal cells in aging flies to lose their specialized identity: suppressing it extended median lifespan from 39 to 48 days
On October 27, Genes & Development published a study from Amir Orian’s laboratory at the Technion, Israel Institute of Technology. Working with flies, the authors traced how enterocytes, the intestinal cells that digest food, lose their specialized identity with age: levels of an enzyme decline, Rogue appears, and it reactivates a mechanism that suppresses protein synthesis in stem cells.
Orian explained in 2019 how a cell maintains its mature state:
“Maintaining a differentiated, mature state requires continuous work by active molecular mechanisms. It is a little like a relationship: getting it started is only the beginning; keeping it going takes work.”
Biologists Helen Blau and David Baltimore expressed the same idea in 1991. In 2021, Orian’s laboratory searched for such mechanisms by switching off 362 genes one at a time. These genes are associated with ubiquitin, a tag that cells use, among other things, to mark proteins for destruction. Switching off 17 of these genes erased the specialized identity of mature enterocytes. One of them, nonstop, encodes an enzyme that removes ubiquitin tags; aging flies have less of this enzyme.
To find out which genes become active in cells that have lost their specialized identity, the authors used a fluorescent label to mark every cell that had ever been an enterocyte, then measured gene activity in these cells. Cells that had lost their specialized identity showed increased activity of 205 genes. Many belong to programs used by other cell types, including intestinal progenitor cells and neurons. One was Rogue, which is absent from young enterocytes.
Rogue works with the protein Orb2 to suppress protein synthesis: in the fly brain, the pair shortens the tails of messenger RNAs, chains of nucleotides at their ends, reducing the amount of protein produced from these RNAs. When Rogue was activated in the enterocytes of young flies, the mature enterocyte protein LamC disappeared and Delta, a stem cell marker, appeared. The intestinal barrier also broke down, allowing dyed food to leak throughout the body. Without Orb2, Rogue no longer had this effect. Suppressing Rogue in old, five-week-old flies restored LamC and intestinal barrier integrity, while Delta disappeared.
Rogue and Orb2 bring P-bodies back into enterocytes. These clusters of proteins and RNA suppress protein synthesis. In the young intestine, P-bodies occur only in stem cells, where they restrain the production of proteins characteristic of mature cells. Switching off P-body proteins in old flies also restored LamC and eliminated Delta.
In fly embryos, the enzyme Kdo and the CTLH complex work together to clear maternally supplied P-body proteins by tagging them with ubiquitin for destruction. This is why Kdo was named after Marie Kondo, the Japanese organizing consultant. The authors of the new study proposed that the same pair continually removes these proteins from young enterocytes. When Kdo or components of CTLH were switched off in young flies, P-body proteins accumulated and the cells lost their specialized identity.
As nonstop levels decline, the Rogue gene, which nonstop kept repressed in young cells, becomes active. Rogue binds messenger RNAs whose tails average 19 nucleotides in length, compared with 32 in the control experiment, and it binds Kdo RNA most strongly. Kdo protein levels fall; without Kdo, components of CTLH break down and P-bodies return. When Rogue was switched off along with nonstop or Kdo, young enterocytes largely retained their specialized identity.
At 29 °C, half the flies had died by day 39. Suppressing Rogue in enterocytes extended this median lifespan to 48 days, an increase of 23%. Activating Rogue shortened it to 31 days, while suppressing Kdo reduced mean lifespan from 39 to 32 days.