Forkhead box O (FOXO) transcription factors have a conserved function in 
regulating metazoan lifespan. A key function in this process involves the 
regulation of the cell cycle and stress responses including free radical 
scavenging. We employed yeast chronological and replicative lifespan assays, as 
well as oxidative stress assays, to explore the potential evolutionary 
conservation of function between the FOXOs and the yeast forkhead box 
transcription factors FKH1 and FKH2. We report that the deletion of both FKH 
genes impedes normal lifespan and stress resistance, particularly in stationary 
phase cells, which are non-responsive to caloric restriction. Conversely, 
increased expression of the FKHs leads to extended lifespan and improved stress 
response. Here we show the Anaphase-Promoting Complex (APC) genetically 
interacts with the Fkh pathway, likely working in a linear pathway under normal 
conditions, as fkh1Δ fkh2Δ post-mitotic survival is epistatic to that observed 
in apc5(CA) mutants. However, under stress conditions, post-mitotic survival is 
dramatically impaired in apc5(CA) fkh1Δ fkh2Δ, while increased expression of 
either FKH rescues APC mutant growth defects. This study establishes the FKHs 
role as evolutionarily conserved regulators of lifespan in yeast and identifies 
the APC as a novel component of this mechanism under certain conditions, likely 
through combined regulation of stress response, genomic stability, and cell 
cycle regulation.