A new DAF-16 isoform regulates longevity

Abstract

FOXO (single forkhead box O) transcription factors have emerged as a major convergence point for the regulators of cell function, including the insulin/IGF1 signalling (IIS) pathway. The IIS is involved in various biological processes, including regulation of longevity. In the worm Caenorhabditis elegans, the FOXO transcription factor DAF-16a has a major role in the IIS pathway. DAF-16a is one of two isoforms and regulates the worm's longevity, stress response and dauer diapause, but it is not clear how DAF-16 achieves its specificity in regulating these various biological processes. Now a new DAF-16 isoform has been identified, DAF-16d/f, which is also important in the regulation of lifespan. A series of experiments involving gene-expression manipulation suggests that combinatorial interactions between the various DAF-16 isoforms act to fine-tune IIS-mediated processes in the context of the whole organism. C. elegans seems to use multiple isoforms from a single gene to fine-tune IIS-mediated processes, in contrast to the situation in mammals, where four different FOXO genes perform overlapping and distinct functions. The insulin/IGF-1 signalling (IIS) pathway is involved in various biological processes, including regulation of longevity. In the worm Caenorhabditis elegans, the transcription factor DAF-16a, one of two isoforms, has a major role in this pathway, regulating longevity, stress response and dauer diapause. These authors describe a new isoform, DAF-16d/f, which is also important in the regulation of lifespan. The DAF-16 isoforms functionally cooperate to fine-tune IIS-mediated processes in the context of a whole organism. The insulin/IGF-1 signalling (IIS) pathway has diverse roles from metabolism to longevity1,2,3,4,5. In Caenorhabditis elegans, the single forkhead box O (FOXO) homologue, DAF-16, functions as the major target of the IIS pathway2,3,6,7. One of two isoforms4,5,8, DAF-16a, is known to regulate longevity, stress response and dauer diapause8,9,10,11. However, it remains unclear how DAF-16 achieves its specificity in regulating these various biological processes. Here we identify a new isoform, DAF-16d/f, as an important isoform regulating longevity. We show that DAF-16 isoforms functionally cooperate to modulate IIS-mediated processes through differential tissue enrichment, preferential modulation by upstream kinases, and regulating distinct and overlapping target genes. Promoter-swapping experiments show both the promoter and the coding region of DAF-16 are important for its function. Importantly, in mammals, four FOXO genes have overlapping and different functions6,12, and in C. elegans, a single FOXO/DAF-16 uses distinct isoforms to fine-tune the IIS-mediated processes in the context of a whole organism.