A functional analysis reveals dependence on the anaphase-promoting complex for prolonged life span in yeast

Defects in anaphase-promoting complex (APC) activity, which regulates mitotic progression and chromatin assembly, results in genomic instability, a hallmark of premature aging and cancer. We investigated whether APC-dependent genomic stability affects aging and life span in yeast. Utilizing replicative and chronological aging assays, the A-PC was shown to promote longevity. Multicopy expression of genes encoding Snf1p (MIGI) and PKA (PDE2) aging-pathway components suppressed apc5(CA) phenotypes, suggesting their involvement in A-PC-dependent longevity. While it is known that PKA inhibits APC activity and reduces life span, a link between the Snf1p-inhibited Mig1p transcriptional modulator and the APC is novel. Our mutant analysis supports a model in which Snf1p promotes extended life span by inhibiting the negative influence of Mig1p on the APC. Consistent with this, we found that increased M[G] expression reduced replicative life span, whereas mig1Delta mutations Suppressed the apc5(CA) chronological aging defect. Furthermore, Mig1p and Mig2p activate APC gene transcription, particularly on glycerol, and mig2Delta, but not mig1A, confers a prolonged replicative life span in both APC5 and acp5(CA) cells. However, glucose repression of APC genes was Mig1p and Mig2p independent, indicating the presence of an uncharacterized factor. Therefore, we propose that APC-dependent genomic stability is linked to prolonged longevity by the antagonistic regulation of the PKA and Snf1p pathways.