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


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.


  1. 1

    Clancy, D. J., Gems, D., Hafen, E., Leevers, S. J. & Partridge, L. Dietary restriction in long-lived dwarf flies. Science 296, 319 (2002)

    CAS  Article  Google Scholar 

  2. 2

    Clancy, D. J. et al. Extension of life-span by loss of CHICO, a Drosophila insulin receptor substrate protein. Science 292, 104–106 (2001)

    ADS  CAS  Article  Google Scholar 

  3. 3

    Holzenberger, M. et al. IGF-1 receptor regulates lifespan and resistance to oxidative stress in mice. Nature 421, 182–187 (2003)

    ADS  CAS  Article  Google Scholar 

  4. 4

    Kenyon, C., Chang, J., Gensch, E., Rudner, A. & Tabtiang, R. A. C. elegans mutant that lives twice as long as wild type. Nature 366, 461–464 (1993)

    ADS  CAS  Article  Google Scholar 

  5. 5

    Tatar, M. et al. A mutant Drosophila insulin receptor homolog that extends life-span and impairs neuroendocrine function. Science 292, 107–110 (2001)

    ADS  CAS  Article  Google Scholar 

  6. 6

    Tu, M. P., Epstein, D. & Tatar, M. The demography of slow aging in male and female Drosophila mutant for the insulin-receptor substrate homologue chico. Aging Cell 1, 75–80 (2002)

    CAS  Article  Google Scholar 

  7. 7

    Houthoofd, K., Braeckman, B. P., Johnson, T. E. & Vanfleteren, J. R. Life extension via dietary restriction is independent of the Ins/IGF-1 signalling pathway in Caenorhabditis elegans. Exp. Gerontol. 38, 947–954 (2003)

    CAS  Article  Google Scholar 

  8. 8

    Lakowski, B. & Hekimi, S. The genetics of caloric restriction in Caenorhabditis elegans. Proc. Natl Acad. Sci. USA 95, 13091–13096 (1998)

    ADS  CAS  Article  Google Scholar 

  9. 9

    Henderson, S. T. & Johnson, T. E. daf-16 integrates developmental and environmental inputs to mediate aging in the nematode Caenorhabditis elegans. Curr. Biol. 11, 1975–1980 (2001)

    CAS  Article  Google Scholar 

  10. 10

    Lin, K., Dorman, J. B., Rodan, A. & Kenyon, C. daf-16: An HNF-3/forkhead family member that can function to double the life-span of Caenorhabditis elegans. Science 278, 1319–1322 (1997)

    ADS  CAS  Article  Google Scholar 

  11. 11

    Lin, K., Hsin, H., Libina, N. & Kenyon, C. Regulation of the Caenorhabditis elegans longevity protein DAF-16 by insulin/IGF-1 and germline signaling. Nature Genet. 28, 139–145 (2001)

    CAS  Article  Google Scholar 

  12. 12

    Ogg, S. et al. The Fork head transcription factor DAF-16 transduces insulin-like metabolic and longevity signals in C. elegans. Nature 389, 994–999 (1997)

    ADS  CAS  Article  Google Scholar 

  13. 13

    Wolff, S. et al. SMK-1, an essential regulator of DAF-16-mediated longevity. Cell 124, 1039–1053 (2006)

    CAS  Article  Google Scholar 

  14. 14

    Avery, L. The genetics of feeding in Caenorhabditis elegans. Genetics 133, 897–917 (1993)

    CAS  PubMed  PubMed Central  Google Scholar 

  15. 15

    C. elegans sequencing consortium. Genome sequence of the nematode C. elegans: a platform for investigating biology. Science 282, 2012–2018 (1998)

  16. 16

    Horner, M. A. et al. pha-4, an HNF-3 homolog, specifies pharyngeal organ identity in Caenorhabditis elegans. Genes Dev. 12, 1947–1952 (1998)

    CAS  Article  Google Scholar 

  17. 17

    Shih, D. Q., Navas, M. A., Kuwajima, S., Duncan, S. A. & Stoffel, M. Impaired glucose homeostasis and neonatal mortality in hepatocyte nuclear factor 3α-deficient mice. Proc. Natl Acad. Sci. USA 96, 10152–10157 (1999)

    ADS  CAS  Article  Google Scholar 

  18. 18

    Kaestner, K. H., Katz, J., Liu, Y., Drucker, D. J. & Schutz, G. Inactivation of the winged helix transcription factor HNF3α affects glucose homeostasis and islet glucagon gene expression in vivo. Genes Dev. 13, 495–504 (1999)

    CAS  Article  Google Scholar 

  19. 19

    Zhang, L., Rubins, N. E., Ahima, R. S., Greenbaum, L. E. & Kaestner, K. H. Foxa2 integrates the transcriptional response of the hepatocyte to fasting. Cell Metab. 2, 141–148 (2005)

    Article  Google Scholar 

  20. 20

    Kaestner, K. H., Hiemisch, H. & Schutz, G. Targeted disruption of the gene encoding hepatocyte nuclear factor 3γ results in reduced transcription of hepatocyte-specific genes. Mol. Cell. Biol. 18, 4245–4251 (1998)

    CAS  Article  Google Scholar 

  21. 21

    Shen, W., Scearce, L. M., Brestelli, J. E., Sund, N. J. & Kaestner, K. H. Foxa3 (hepatocyte nuclear factor 3γ) is required for the regulation of hepatic GLUT2 expression and the maintenance of glucose homeostasis during a prolonged fast. J. Biol. Chem. 276, 42812–42817 (2001)

    CAS  Article  Google Scholar 

  22. 22

    Gaudet, J. & Mango, S. E. Regulation of organogenesis by the Caenorhabditis elegans FoxA protein PHA-4. Science 295, 821–825 (2002)

    ADS  CAS  Article  Google Scholar 

  23. 23

    Mango, S. E., Lambie, E. J. & Kimble, J. The pha-4 gene is required to generate the pharyngeal primordium of Caenorhabditis elegans. Development 120, 3019–3031 (1994)

    CAS  PubMed  Google Scholar 

  24. 24

    Klass, M. R. Aging in the nematode Caenorhabditis elegans: major biological and environmental factors influencing life span. Mech. Ageing Dev. 6, 413–429 (1977)

    CAS  Article  Google Scholar 

  25. 25

    Dillin, A. et al. Rates of behavior and aging specified by mitochondrial function during development. Science 298, 2398–2401 (2002)

    ADS  CAS  Article  Google Scholar 

  26. 26

    Lee, S. S. et al. A systematic RNAi screen identifies a critical role for mitochondria in C. elegans longevity. Nature Genet. 33, 40–48 (2003)

    CAS  Article  Google Scholar 

  27. 27

    Azzaria, M., Goszczynski, B., Chung, M. A., Kalb, J. M. & McGhee, J. D. A fork head/HNF-3 homolog expressed in the pharynx and intestine of the Caenorhabditis elegans embryo. Dev. Biol. 178, 289–303 (1996)

    CAS  Article  Google Scholar 

  28. 28

    Furuyama, T., Nakazawa, T., Nakano, I. & Mori, N. Identification of the differential distribution patterns of mRNAs and consensus binding sequences for mouse DAF-16 homologues. Biochem. J. 349, 629–634 (2000)

    CAS  Article  Google Scholar 

  29. 29

    Giglio, M. P., Hunter, T., Bannister, J. V., Bannister, W. H. & Hunter, G. J. The manganese superoxide dismutase gene of Caenorhabditis elegans. Biochem. Mol. Biol. Int. 33, 37–40 (1994)

    CAS  PubMed  Google Scholar 

  30. 30

    Hunter, T., Bannister, W. H. & Hunter, G. J. Cloning, expression, and characterization of two manganese superoxide dismutases from Caenorhabditis elegans. J. Biol. Chem. 272, 28652–28659 (1997)

    CAS  Article  Google Scholar 

  31. 31

    Suzuki, N., Inokuma, K., Yasuda, K. & Ishii, N. Cloning, sequencing and mapping of a manganese superoxide dismutase gene of the nematode Caenorhabditis elegans. DNA Res. 3, 171–174 (1996)

    CAS  Article  Google Scholar 

  32. 32

    Honda, Y. & Honda, S. The daf-2 gene network for longevity regulates oxidative stress resistance and Mn-superoxide dismutase gene expression in Caenorhabditis elegans. FASEB J. 13, 1385–1393 (1999)

    CAS  Article  Google Scholar 

  33. 33

    Carroll, J. S. et al. Chromosome-wide mapping of estrogen receptor binding reveals long-range regulation requiring the forkhead protein FoxA1. Cell 122, 33–43 (2005)

    CAS  Article  Google Scholar 

  34. 34

    Giglio, A. M., Hunter, T., Bannister, J. V., Bannister, W. H. & Hunter, G. J. The copper/zinc superoxide dismutase gene of Caenorhabditis elegans. Biochem. Mol. Biol. Int. 33, 41–44 (1994)

    CAS  PubMed  Google Scholar 

  35. 35

    Dillin, A., Crawford, D. K. & Kenyon, C. Timing requirements for insulin/IGF-1 signaling in C. elegans. Science 298, 830–834 (2002)

    ADS  CAS  Article  Google Scholar 

  36. 36

    Puig, O. & Tjian, R. Transcriptional feedback control of insulin receptor by dFOXO/FOXO1. Genes Dev. 19, 2435–2446 (2005)

    CAS  Article  Google Scholar 

  37. 37

    Pierce, S. B. et al. Regulation of DAF-2 receptor signaling by human insulin and ins-1, a member of the unusually large and diverse C. elegans insulin gene family. Genes Dev. 15, 672–686 (2001)

    CAS  Article  Google Scholar 

  38. 38

    Murphy, C. T. et al. Genes that act downstream of DAF-16 to influence the lifespan of Caenorhabditis elegans. Nature 424, 277–283 (2003)

    ADS  CAS  Article  Google Scholar 

  39. 39

    Li, W., Kennedy, S. G. & Ruvkun, G. daf-28 encodes a C. elegans insulin superfamily member that is regulated by environmental cues and acts in the DAF-2 signaling pathway. Genes Dev. 17, 844–858 (2003)

    CAS  Article  Google Scholar 

  40. 40

    Apfeld, J. & Kenyon, C. Regulation of lifespan by sensory perception in Caenorhabditis elegans. Nature 402, 804–809 (1999)

    ADS  CAS  Article  Google Scholar 

  41. 41

    Libina, N., Berman, J. R. & Kenyon, C. Tissue-specific activities of C. elegans DAF-16 in the regulation of lifespan. Cell 115, 489–502 (2003)

    CAS  Article  Google Scholar 

  42. 42

    Wolkow, C. A., Kimura, K. D., Lee, M. S. & Ruvkun, G. Regulation of C. elegans life-span by insulinlike signaling in the nervous system. Science 290, 147–150 (2000)

    ADS  CAS  Article  Google Scholar 

  43. 43

    McElwee, J., Bubb, K. & Thomas, J. H. Transcriptional outputs of the Caenorhabditis elegans forkhead protein DAF-16. Aging Cell 2, 111–121 (2003)

    CAS  Article  Google Scholar 

  44. 44

    Tsuchiya, T. et al. Additive regulation of hepatic gene expression by dwarfism and caloric restriction. Physiol. Genomics 17, 307–315 (2004)

    MathSciNet  CAS  Article  Google Scholar 

  45. 45

    Fujii, M., Ishii, N., Joguchi, A., Yasuda, K. & Ayusawa, D. A novel superoxide dismutase gene encoding membrane-bound and extracellular isoforms by alternative splicing in Caenorhabditis elegans. DNA Res. 5, 25–30 (1998)

    CAS  Article  Google Scholar 

  46. 46

    Larsen, P. L. Aging and resistance to oxidative damage in Caenorhabditis elegans. Proc. Natl Acad. Sci. USA 90, 8905–8909 (1993)

    ADS  CAS  Article  Google Scholar 

  47. 47

    Brenner, S. The genetics of Caenorhabditis elegans. Genetics 77, 71–94 (1974)

    CAS  PubMed  PubMed Central  Google Scholar 

  48. 48

    Mello, C. C., Kramer, J. M., Stinchcomb, D. & Ambros, V. Efficient gene transfer in C. elegans: extrachromosomal maintenance and integration of transforming sequences. EMBO J. 10, 3959–3970 (1991)

    CAS  Article  Google Scholar 

  49. 49

    Hope, I. A. C. elegans: A Practical Approach (ed. Hope, I. A.) 88–90 (Oxford University Press, Oxford, 1999)

    Google Scholar 

  50. 50

    Shaner, N. C. et al. Improved monomeric red, orange and yellow fluorescent proteins derived from Discosoma sp. red fluorescent protein. Nature Biotechnol. 22, 1567–1572 (2004)

    CAS  Article  Google Scholar 

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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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Correspondence to Andrew Dillin.

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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).

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