Peptide C43-4 is the first known activator of APC/C-Cdh1, the complex that keeps cells in healthy quiescence, and it extended lifespan in yeast and roundworms
Peptide C43-4 is the first known activator of APC/C-Cdh1, the complex that keeps cells in healthy quiescence, and it extended lifespan in yeast and roundworms
A University of Saskatchewan laboratory identified a short peptide, C43-4, that activates the APC/C-Cdh1 complex: a molecular machine that tags surplus cellular proteins for destruction, keeping the cell in quiescence rather than letting it slide into senescence. In both yeast and the roundworm C. elegans, the peptide extended lifespan through a conserved longevity pathway. In worms, the effect depended on daf-16 (a FOXO homolog) and aak-2 (an AMPK homolog).
Every cell carries the APC enzyme, which tags excess proteins with a biochemical label for degradation. In one form, paired with the protein Cdc20, APC drives cell division. In another, paired with Cdh1, it holds the cell in quiescence: alive and functional, but not dividing. It is this second form, APC/Cdh1, that deteriorates with age. The authors showed that in aging quiescent yeast cells, APC substrates are no longer degraded on schedule and instead accumulate. This failure is considered a molecular hallmark of aging, after which the cell enters irreversible decline.
On September 16 the laboratory published its results in the journal Genetics. Chemical activators of APC targeting the Cdc20 branch are already in clinical trials as anticancer agents, so far without success. One such activator extended the lifespan of dividing yeast cells but did nothing for quiescent ones, which require a tool that works specifically through Cdh1. The library of short peptides that bind the Apc10 subunit came from the lab's earlier work on reversing drug resistance in breast cancer; in that study, C43-4 first showed it could halt tumor growth in mice. Out of the entire library, only C43-4 extended yeast lifespan in quiescence, and only through Cdh1.
C43-4 carries its own D-box signal (the RxxL motif), the same tag that natural APC substrates use to mark themselves for recognition by Apc10. Sequence similarity to Htz1, a cellular stress sensor protein, pointed to six amino acids in the peptide worth testing by point substitution. Only one of them, designated D7 and located outside the D-box signal, proved critical: without it, C43-4 no longer bound Apc10 and lost its entire lifespan effect. The peptide therefore acts through precise target recognition rather than as a nonspecific foreign protein. Synthetic C43-4, added to cells externally without any membrane carrier, extended lifespan even when administered on day seven of aging, after cells had already entered the process.
To confirm the effect is not limited to yeast, C43-4 was integrated into the genome of the roundworm C. elegans, and those animals also lived longer. The effect disappeared in worms lacking aak-2 and was substantially weakened in worms lacking daf-16. These are the same AMPK and FOXO gene families that regulate lifespan across many species, including mammals. The underlying pathway is therefore evolutionarily conserved, operating in both yeast and worms.
The authors specifically highlight the relevance of the Cdh1 branch to the brain: in humans, disruptions in APC/Cdh1 function are linked to memory loss, microcephaly, and epilepsy, and beta-amyloid in Alzheimer's disease inactivates Cdh1.
The need for methods of activating APC/Cdh1 in the aging brain cannot be overstated
the authors write.
The precise mechanism by which C43-4 binds Apc10 is described by the authors as a subject for future work, as are trials in mammals.