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Insulin regulation of heart function in aging fruit flies


Insulin-IGF receptor (InR) signaling has a conserved role in regulating lifespan, but little is known about the genetic control of declining organ function. Here, we describe progressive changes of heart function in aging fruit flies: from one to seven weeks of a fly's age, the resting heart rate decreases and the rate of stress-induced heart failure increases. These age-related changes are minimized or absent in long-lived flies when systemic levels of insulin-like peptides are reduced and by mutations of the only receptor, InR, or its substrate, chico. Moreover, interfering with InR signaling exclusively in the heart, by overexpressing the phosphatase dPTEN or the forkhead transcription factor dFOXO, prevents the decline in cardiac performance with age. Thus, insulin-IGF signaling influences age-dependent organ physiology and senescence directly and autonomously, in addition to its systemic effect on lifespan. The aging fly heart is a model for studying the genetics of age-sensitive organ-specific pathology.

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Figure 1: D. melanogaster heart rate changes with age.
Figure 2: D. melanogaster heart contractions under normal and stimulated conditions.
Figure 3: Heart failure as a function of age after external electrical pacing from outbred wild-type offspring (WT; yw × Canton S).
Figure 4: Reduction in insulin receptor signaling improves heart performance at advanced ages.
Figure 5: Reduction in insulin-IGF signaling improves heart performance at advanced ages.
Figure 6: Heart-specific manipulation of insulin-receptor signaling affects age-related changes in cardiac physiology.
Figure 7: Heart-specific manipulation of insulin-IGF signaling alters heart performance autonomously with age.
Figure 8: Survival curves of male (M) and female (F) progeny from the cross of the heart-specific driver GMH5-Gal4 with UAS-InR or UAS-dPTEN.


  1. 1

    Guarente, L. & Kenyon, C. Genetic pathways that regulate ageing in model organisms. Nature 408, 255–262 (2000).

    CAS  Article  Google Scholar 

  2. 2

    Helfland, S.L. & Rogina, B. Molecular genetics of aging in the fly: is this the end of the beginning? Bioessays 25, 134–141 (2003).

    Article  Google Scholar 

  3. 3

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

    CAS  Article  Google Scholar 

  4. 4

    Herndon, L.A. et al. Stochastic and genetic factors influence tissue-specific decline in ageing C. elegans. Nature 419, 808–814 (2002).

    CAS  Article  Google Scholar 

  5. 5

    Garigan, D. et al. Genetic analysis of tissue aging in Caenorhabditis elegans: a role for heat-shock factor and bacterial proliferation. Genetics 161, 1101–1112 (2002).

    CAS  PubMed  PubMed Central  Google Scholar 

  6. 6

    Morley, J.F., Brignull, H.R., Weyers, J.J. & Morimoto, R.I. The threshold for polyglutamine-expansion protein aggregation and cellular toxicity is dynamic and influenced by aging in Caenorhabditis elegans. Proc. Natl. Acad. Sci. USA 99, 10417–10422 (2002).

    Article  Google Scholar 

  7. 7

    Hwangbo, D.S., Gersham, B., Tu, M.P., Palmer, M. & Tatar, M. Drosophila dFOXO controls lifespan and regulates insulin signalling in brain and fat body. Nature 429, 562–566 (2004).

    CAS  Article  Google Scholar 

  8. 8

    Lakatta, E.G. & Levy, D. Arterial and cardiac aging: major shareholders in cardiovascular disease enterprises: Part II: the aging heart in health: links to heart disease. Circulation 107, 346–354 (2003).

    Article  Google Scholar 

  9. 9

    Paternostro, G. et al. Age-associated cardiac dysfunction in Drosophila melanogaster. Circ. Res. 88, 1053 (2001).

    CAS  Article  Google Scholar 

  10. 10

    Wessells, R.J. & Bodmer, R. Screening assays for heart function mutants in Drosophila. Biotechniques 37, 58–60 (2004).

    CAS  Article  Google Scholar 

  11. 11

    Bodmer, R. Heart development in Drosophila and its relationship to vertebrate systems. Trends Cardiovasc. Med. 5, 21–27 (1995).

    CAS  Article  Google Scholar 

  12. 12

    Dowse, H. et al. A congenital heart defect in Drosophila caused by an action-potential mutation. J. Neurogenetics 10, 153–168 (1995).

    CAS  Article  Google Scholar 

  13. 13

    Khan, A.S., Sane, D.C., Wannenburg, T. & Sonntag, W.E. Growth hormone, insulin-like growth factor-1 and the aging cardiovascular system. Cardiovasc. Res. 54, 25–35 (2002).

    CAS  Article  Google Scholar 

  14. 14

    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).

    CAS  Article  Google Scholar 

  15. 15

    Promislow, D.E., Tatar, M., Khazaeli, A.A. & Curtzinger, J.W. Age-specific patterns of genetic variance in Drosophila melanogaster. I. Mortality. Genetics 143, 839–848 (1996).

    CAS  PubMed  PubMed Central  Google Scholar 

  16. 16

    Leevers, S. Growth control: invertebrate insulin surprises! Curr. Biol. 11, R209–R212 (2001).

    CAS  Article  Google Scholar 

  17. 17

    Stocker, H. & Hafen, E. Genetic control of cell size. Curr. Opin. Genet. Dev. 10, 529–535 (2000).

    CAS  Article  Google Scholar 

  18. 18

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

    CAS  Article  Google Scholar 

  19. 19

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

    CAS  Article  Google Scholar 

  20. 20

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

    CAS  Article  Google Scholar 

  21. 21

    Bohni, R. et al. Autonomous control of cell and organ size by CHICO, a Drosophila homolog of vertebrate IRS1-4. Cell 97, 865–875 (1999).

    CAS  Article  Google Scholar 

  22. 22

    Siegmund, T. & Korge, G. Innervation of the ring gland of Drosophila melanogaster. J. Comp. Neurol. 431, 481–491 (2001).

    CAS  Article  Google Scholar 

  23. 23

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

    CAS  Article  Google Scholar 

  24. 24

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

    CAS  Article  Google Scholar 

  25. 25

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

    CAS  Article  Google Scholar 

  26. 26

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

    CAS  Article  Google Scholar 

  27. 27

    Tu, M.-P., Yin, C.-M. & Tatar, M. Impaired ovarian ecdysone synthesis of Drosophila melanogaster insulin receptor mutants. Aging Cell 1, 158–160 (2002).

    CAS  Article  Google Scholar 

  28. 28

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

    Article  Google Scholar 

  29. 29

    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 

  30. 30

    Stambolic, V. et al. Negative regulation of PKB/Akt-dependent cell survival by the tumor suppressor PTEN. Cell 95, 29–39 (1998).

    CAS  Article  Google Scholar 

  31. 31

    Oldham, S. et al. The Drosophila insulin/IGF receptor controls growth and size by modulating PtdInsP(3) levels. Development 129, 4103–4109 (2002).

    CAS  PubMed  Google Scholar 

  32. 32

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

    CAS  Article  Google Scholar 

  33. 33

    Junger, M.A. et al. The Drosophila Forkhead transcription factor FOXO mediates the reduction in cell number associated with reduced insulin signaling. J. Biol. 2, 20 (2003).

    Article  Google Scholar 

  34. 34

    Gao, X., Neufeld, T.P. & Pan, D. Drosophila PTEN regulates cell growth and proliferation through PI3K-dependent and –independent pathways. Dev. Biol. 221, 404–418 (2000).

    CAS  Article  Google Scholar 

  35. 35

    Fernandez, R., Tabarini, D., Azpiazu, N. Frasch, M. & Schlessinger, J. The Drosophila insulin receptor homolog: a gene essential for embryonic development encodes two receptor isoforms with different signaling potential. EMBO J. 17, 3373–3384 (1995).

    Article  Google Scholar 

  36. 36

    Chen, C., Jack, J. & Garofalo, R.S. The Drosophila insulin receptor is required for normal growth. Endocrinology 137, 846–856 (1996).

    CAS  Article  Google Scholar 

  37. 37

    Venkatesh, T.V. et al. Cardiac enhancer activity of the homeobox gene tinman depends on CREB consensus binding sites in Drosophila. Genesis 26, 55–66 (2000).

    CAS  Article  Google Scholar 

  38. 38

    Bodmer, R. The gene tinman is required for specification of the heart and visceral muscles in Drosophila. Development 118, 719–729 (1993).

    CAS  PubMed  Google Scholar 

  39. 39

    Molina, M.R. & Cripps, R.M. Ostia, the inflow tracts of the Drosophila heart, develop from a genetically distinct subset of cardial cells. Mech. Dev. 109, 51–59 (2001).

    CAS  Article  Google Scholar 

  40. 40

    Hassan, B.A. et al. atonal regulates neurite arborization but does not act as a proneural gene in the Drosophila brain. Neuron 25, 549–561 (2000).

    CAS  Article  Google Scholar 

  41. 41

    Tatar, M., Priest, N. & Chien, S. Negligible Senescence during Reproductive Dormancy in Drosophila melanogaster. Am. Nat. 158, 248–258 (2001).

    CAS  Article  Google Scholar 

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We thank B. Edgar, E. Hafen, E. Rulifson, B. Hassan, H. Bellen and the Bloomington stock center for sending flies and K. Fitzgerald, A. Strobe and M. Montero for technical assistance with part of the heart performance assays. R.J.W. has been supported by a fellowship from the American Heart Association. This work received support from grants from National Institutes of Health (National Institute on Aging) and The Ellison Medical Foundation to M.T. and by National Institutes of Health (National Heart, Lung and Blood Institute and National Institute on Aging) to R.B.

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Corresponding author

Correspondence to Rolf Bodmer.

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The authors declare no competing financial interests.

Supplementary information

Supplementary Fig. 1

Arrest rates. (PDF 117 kb)

Supplementary Table 1

Summary of failure, arrest and recovery data for selected genotypes. (PDF 8 kb)

Supplementary Table 2

Adult heart rate data from relevant genotypes is displayed. (PDF 6 kb)

Supplementary Table 3

Comparison of male and female failure rate data. (PDF 6 kb)

Supplementary Table 4

Failure rates at 1 week and 5 weeks for outcrossed flies carrying UAS expression constructs. (PDF 6 kb)

Supplementary Table 5

Pupal heart rates from several wild-type genetic backgrounds are compared to heart rates of pupae expressing InR, dPTEN or dFOXO in the heart, as well as flies carrying each construct outcrossed in to wild-type genetic backgrounds. (PDF 6 kb)

Supplementary Video 1

GMH5-driven GFP expression in the adult myocardium of the heart in abdominal segments A2-A4. Spiral myofibril structure in the GFP-labeled contractile myocardial cells is evident34, and thus demonstrating the myocardial specificity of GFP expression by the GMH5 driver. (AVI 28715 kb)

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Wessells, R., Fitzgerald, E., Cypser, J. et al. Insulin regulation of heart function in aging fruit flies. Nat Genet 36, 1275–1281 (2004).

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