A stress response pathway involving sirtuins, forkheads and 14-3-3 proteins.

A conserved sir2 deacetylase gene can determine longevity of yeast, flies and worms. Recently we have reported a molecular mechanism of action of the C. elegans homologue sir-2.1. Our study revealed a novel stress-dependent pathway for lifespan determination in which SIR-2.1 binds to 14-3-3 proteins and a forkhead transcription factor DAF-16 to activate transcription of DAF-16 target genes. DAF-16 has long been known as a central protein in the regulation of lifespan that interfaces with multiple pathways. Recent studies by us and other laboratories suggest that DAF-16 requires co-factors for full activity. In this prospective we review recent literature highlighting the role of SIR-2.1, 14-3-3 and other DAF-16 co-factors in DAF-16 activation.