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PHA-4/Foxa mediates diet-restriction-induced longevity of C. elegans

Abstract

Reduced food intake as a result of dietary restriction increases the lifespan of a wide variety of metazoans and delays the onset of multiple age-related pathologies. Dietary restriction elicits a genetically programmed response to nutrient availability that cannot be explained by a simple reduction in metabolism or slower growth of the organism. In the nematode worm Caenorhabditis elegans, the transcription factor PHA-4 has an essential role in the embryonic development of the foregut and is orthologous to genes encoding the mammalian family of Foxa transcription factors, Foxa1, Foxa2 and Foxa3. Foxa family members have important roles during development, but also act later in life to regulate glucagon production and glucose homeostasis, particularly in response to fasting. Here we describe a newly discovered, adult-specific function for PHA-4 in the regulation of diet-restriction-mediated longevity in C. elegans. The role of PHA-4 in lifespan determination is specific for dietary restriction, because it is not required for the increased longevity caused by other genetic pathways that regulate ageing.

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Figure 1: smk-1 and pha-4 are required for diet-restriction-mediated longevity.
Figure 2: pha-4 is required during adulthood to regulate longevity in response to dietary restriction.
Figure 3: Regulation and localization of pha-4 in response to dietary restriction.
Figure 4: Increased dosage of pha-4 extends lifespan.
Figure 5: Differential transcriptional regulation of sod s by pha-4 and daf-16 in response to dietary restriction and IIS.

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Acknowledgements

We thank the Dillin laboratory for critical comments on this work; M. Montminy and R. Shaw for comments on the manuscript; and S. Mango for reagents and discussion during the course of this work. We thank R. Tsien for use of dTOMATO. This work was supported by grants from the NIH/NIA, The Ellison Medical Foundation and the American Diabetes Association. H.A. thanks the Jane Coffin Childs Foundation for support. A.D. is founder of Proteoguard Pharmaceuticals.

Author Contributions A.D., S.W., H.A. and S.P. conceived the framework of the manuscript. A.D., S.W. and S.P. wrote the paper. A.D. oversaw the entire project. S.W. and H.A. screened all forkhead-related genes for their role in dietary restriction. J.D. performed the isp-1(qm150) experiments. S.P. created all transgenic lines, performed overexpression, localization, BDR and Q-PCR experiments.

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Panowski, S., Wolff, S., Aguilaniu, H. et al. PHA-4/Foxa mediates diet-restriction-induced longevity of C. elegans. Nature 447, 550–555 (2007). https://doi.org/10.1038/nature05837

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