Increasing ACP7 production in C. elegans extended lifespan when the protein was secreted from the intestine

Increasing ACP7 production in C. elegans extended lifespan when the protein was secreted from the intestine

On August 27, Cell Reports published a study of proteins that the C. elegans intestine exports from its cells. C. elegans are roundworms about a millimeter long. Increasing ACP7 production in the intestine raised median lifespan by 10% and increased the age reached by 10% of the worms by 22%.

Proteins exported from a cell pass through the endoplasmic reticulum, an internal system that assembles and transports them. The authors placed TurboID, a labeling enzyme, in the endoplasmic reticulum. This enzyme attaches biotin to nearby proteins. They then used mass spectrometry to compare the labeled proteins in worms aged 3, 8, and 13 days.

The samples contained both proteins that had already left the cells and proteins that were still moving through the secretory pathway. A computational model classified 238 of the detected proteins as extracellular or secreted. The abundance of 191 proteins changed with age, and 89 had human homologs. To validate this selection, the authors fluorescently labeled four candidates. They detected all four outside the intestine and in coelomocytes, cells that take up proteins from the fluid in the body cavity.

ACP7 abundance increased with age. To determine which properties of ACP7 were linked to lifespan, the authors altered one feature of the protein at a time. Removing the 21-amino-acid signal peptide, the sequence at the beginning of the protein that directs it into the secretory pathway, caused ACP7 to remain in the intestine and eliminated its effect on lifespan. In the ACP7-7A variant, seven substitutions in the metal-binding region preserved secretion but disabled the enzyme's ability to remove phosphate groups. This variant also failed to extend lifespan. ACP7 extended lifespan only when it could leave the intestine and its catalytic site remained active.

The authors produced human ACP7 in cultured cells. They detected the protein in the culture medium, and a biochemical assay showed that it removed a phosphate group from an artificial substrate. For the worm ACP7, computational screening identified 28 extracellular candidate proteins from which the enzyme might remove such groups. These candidates can now be tested to determine which one connects ACP7 activity to longevity in C. elegans.