Regulation of life span by members of the forkhead transcription factor family of proteins is one of the most highly investigated pathways in the field of aging. Nevertheless, despite the existence of forkhead family homologues in yeast, our knowledge of these proteins' role in yeast longevity is limited. Here, we show that yeast Hcm1p forkhead is the closest homologue of the worm PHA-4 forkhead, which regulates Caenorhabditis elegans life span. Overexpressing the yeast forkhead HCM1 or its deficiency resulted in a significant extension or reduction in yeast replicative life span, respectively. HCM1 regulates stress resistance, significantly increases the mRNA levels of several stress response genes including the catalase enzymes CTA1 and CTT1, and positively regulates life span independently of calorie restriction. Thus, HCM1 is a key regulator of life span, through a mechanism independent of calorie restriction.
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