Skip to main content

Thank you for visiting You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

Drosophila dFOXO controls lifespan and regulates insulin signalling in brain and fat body

A Corrigendum to this article was published on 03 March 2005


In Drosophila melanogaster, ageing is slowed when insulin-like signalling is reduced: life expectancy is extended by more than 50% when the insulin-like receptor (InR) or its receptor substrate (chico) are mutated, or when insulin-producing cells are ablated1,2,3. But we have yet to resolve when insulin affects ageing, or whether insulin signals regulate ageing directly or indirectly through secondary hormones. Caenorhabditis elegans lifespan is also extended when insulin signalling is inhibited in certain tissues, or when repressed in adult worms4,5, and this requires the forkhead transcription factor (FOXO) encoded by daf-16 (ref. 6). The D. melanogaster insulin-like receptor mediates phosphorylation of dFOXO, the equivalent of nematode daf-16 and mammalian FOXO3a7,8. We demonstrate here that dFOXO regulates D. melanogaster ageing when activated in the adult pericerebral fat body. We further show that this limited activation of dFOXO reduces expression of the Drosophila insulin-like peptide dilp-2 synthesized in neurons, and represses endogenous insulin-dependent signalling in peripheral fat body. These findings suggest that autonomous and non-autonomous roles of insulin signalling combine to control ageing.

This is a preview of subscription content, access via your institution

Relevant articles

Open Access articles citing this article.

Access options

Rent or buy this article

Prices vary by article type



Prices may be subject to local taxes which are calculated during checkout

Figure 1: Survivorship and stress resistance in adults with tissue-specific expression of dFOXO or dPTEN.
Figure 2: Tissue distribution of fat body drivers S132 and S1106.
Figure 3: Cellular localization of dFOXO in head and abdominal fat body.
Figure 4: The abundance and systemic impact of neuronal dilp mRNA in response to dFOXO expressed in head fat body.


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

    Article  ADS  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

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

    Article  ADS  CAS  Google Scholar 

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

    Article  ADS  CAS  Google Scholar 

  5. 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)

    Article  CAS  Google Scholar 

  6. 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)

    Article  ADS  CAS  Google Scholar 

  7. Puig, O., Marr, M. T., Ruhf, M. L. & Tjian, R. Control of cell number by Drosophila FOXO: downstream and feedback regulation of the insulin receptor pathway. Genes Dev. 17, 2006–2020 (2003)

    Article  CAS  Google Scholar 

  8. Junger, M. A. et al. The Drosophila Forkhead transcription factor FOXO mediates the reduction in cell number associated with reduced insulin signaling. J. Biol. [online] 2, Article 20; 〈〉 (2003).

  9. Roman, G., Endo, K., Zong, L. & Davis, R. L. P{Switch}, a system for spatial and temporal control of gene expression in Drosophila melanogaster. Proc. Natl Acad. Sci. USA 98, 12602–12607 (2001)

    Article  ADS  CAS  Google Scholar 

  10. Osterwalder, T., Yoon, K. S., White, B. H. & Keshishian, H. A conditional tissue-specific transgene expression system using inducible GAL4. Proc. Natl Acad. Sci. USA 98, 12596–12601 (2001)

    Article  ADS  CAS  Google Scholar 

  11. Dobens, L. L. et al. The Drosophila bunched gene is a homologue of the growth factor stimulated mammalian TSC-22 sequence and is required during oogenesis. Mech. Dev. 65, 197–208 (1997)

    Article  CAS  Google Scholar 

  12. Tatar, M., Bartke, A. & Antebi, A. The endocrine regulation of aging by insulin-like signals. Science 299, 1346–1351 (2003)

    Article  CAS  Google Scholar 

  13. Ashrafi, K. et al. Genome-wide RNAi analysis of Caenorhabditis elegans fat regulatory genes. Nature 421, 268–272 (2003)

    Article  ADS  CAS  Google Scholar 

  14. Garofalo, R. S. Genetic analysis of insulin signaling in Drosophila. Trends Endocrinol. Metab. 13, 156–162 (2002)

    Article  CAS  Google Scholar 

  15. Rulifson, E. J., Kim, S. K. & Nusse, R. Ablation of insulin-producing neurons in flies: growth and diabetic phenotypes. Science 296, 1118–1120 (2002)

    Article  ADS  CAS  Google Scholar 

  16. Cao, C. & Brown, M. R. Localization of an insulin-like peptide in brains of two flies. Cell Tissue Res. 304, 317–321 (2001)

    Article  CAS  Google Scholar 

  17. Brogiolo, W. et al. An evolutionarily conserved function of the Drosophila insulin receptor and insulin-like peptides in growth control. Curr. Biol. 11, 213–221 (2001)

    Article  CAS  Google Scholar 

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

    Article  ADS  CAS  Google Scholar 

  19. Blüher, M., Kahn, B. B. & Kahn, R. C. Extended longevity in mice lacking the insulin receptor in adipose tissue. Science 299, 572–574 (2003)

    Article  ADS  Google Scholar 

  20. Blüher, M. et al. Adipose tissue selective insulin receptor knockout protects against obesity and obesity-related glucose intolerance. Dev. Cell 3, 25–38 (2002)

    Article  Google Scholar 

  21. Simon, A. F., Shih, C., Mack, A. & Benzer, S. Steroid control of longevity in Drosophila melanogaster. Science 299, 1407–1410 (2003)

    Article  CAS  Google Scholar 

  22. Gerisch, B., Weitzel, C., Kober-Eisermann, C., Rottiers, V. & Antebi, A. A hormonal signaling pathway influencing C. elegans metabolism, reproductive development, and life span. Dev. Cell 1, 841–851 (2001)

    Article  CAS  Google Scholar 

  23. Jia, K., Albert, P. S. & Riddle, D. L. DAF-9, a cytochrome P450 regulating C. elegans larval development and adult longevity. Development 129, 221–231 (2002)

    CAS  PubMed  Google Scholar 

  24. Murphy, C. T. et al. Genes that act downstream of DAF-16 to influence the lifespan of Caenorhabditis elegans. Nature 424, 277–284 (2003)

    Article  ADS  CAS  Google Scholar 

  25. Saucedo, L. J. et al. Rheb promotes cell growth as a component of the insulin/TOR signaling network. Nature Cell Biol. 5, 566–571 (2003)

    Article  CAS  Google Scholar 

  26. Vellai, T. et al. Influence of TOR kinase on lifespan in C. elegans. Nature 426, 620 (2003)

    Article  ADS  CAS  Google Scholar 

Download references


We thank F. Lemieux, A. Bentle, M. Duon and M. Zerofsky for technical support, and A. Brunet, J. Wasserman, B. Edgar, G. Roman, O. Puig and T. Osterwalder for materials. This work was supported by the National Institute of Health (Institute of Aging), the American Federation of Aging Research, the Ellison Medical Foundation and a collaborative research grant from Pfizer.

Author information

Authors and Affiliations


Corresponding author

Correspondence to Marc Tatar.

Ethics declarations

Competing interests

The authors declare that they have no competing financial interests.

Supplementary information

Supplementary Figure S1

Expression of exogenous dFOXO in the eye disc reduces growth. We verify that our transformed strains produce eye growth phenotypes similar to those reported by previously published strains with UAS-FOXO. We test several independent inserts of both the wildtype dFOXO and the phosphorylation site mutant dFOXO-TM. We also demonstrate that our mifepristone feeding protocol induces the expected expression patterns with ELAV-{PSwitch}.

Supplementary Figure S2

These trials show that feeding mifepristone in yeast paste has no effect on survival or males or females. Data are presented to show that expression of dFOXO-TM in the head fat body, which increases longevity, does not alter gross fecundity.

Supplementary Figure S3 Legend

Supplementary Figure S3

This series of cryosection images show that induction of exogenous dFOXO-TM in the abdominal fat body is effective but does not cause a change in the endogenous dFOXO of the head fat body.

Supplementary Figure S4

Abundance of dilp mRNA from head measured by microarray. Insulin producing cells of adults are in the brain; dFOXO-TM was induced in the pericerebral fat body and produced a small but significant decrease in dilp2 from these neurons. These array data are refined and verified by real-time PCR analysis in the full text.

Supplementary Figure S5

The driver S32 is restricted to expression in the adult head. Using primers for sequence specific to the exogenous dFOXO-TM, message is detected in cDNA from head tissue and not from abdominal tissue.

Supplementary Table S1

When expressed through larval stages with broadly active drivers, dFOXO wildtype and phosphorylation mutant are lethal.

Supplementary Table S2

Summary of life table statistics for demographic trials with fat body and CNS-related mifepristone activated drivers directed at dFOXO, dFOXO-TM and PTEN. Data are given for male and females, and for the wildtype control trial plotted in Supplementary Figure 2.

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Hwangbo, D., Gersham, B., Tu, MP. et al. Drosophila dFOXO controls lifespan and regulates insulin signalling in brain and fat body. Nature 429, 562–566 (2004).

Download citation

  • Received:

  • Accepted:

  • Issue Date:

  • DOI:

This article is cited by


By submitting a comment you agree to abide by our Terms and Community Guidelines. If you find something abusive or that does not comply with our terms or guidelines please flag it as inappropriate.


Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing