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.
Wessells
Robert J
RJ
The Burnham Institute, Center for Neuroscience and Aging, 10901 Torrey Pines Road, La Jolla, California 92037, USA.
Fitzgerald
Erin
E
Cypser
James R
JR
Tatar
Marc
M
Bodmer
Rolf
R
D000375:Aging / Q000502:physiology*; D000818:Animals; D003001:Cloning, Molecular; D003433:Crosses, Genetic; D029721:Drosophila Proteins / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D004331:Drosophila melanogaster / Q000502:physiology*; D005260:Female; D051858:Forkhead Transcription Factors; D006321:Heart / Q000502:physiology*; D006339:Heart Rate; D055504:Insulin Receptor Substrate Proteins; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics / Q000502:physiology; D008297:Male; D009154:Mutation / Q000235:genetics; D051059:PTEN Phosphohydrolase; D010744:Phosphoric Monoester Hydrolases / Q000378:metabolism; D020794:Receptor Protein-Tyrosine Kinases / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D011972:Receptor, Insulin / Q000502:physiology; D012737:Sex Factors; D015398:Signal Transduction / Q000502:physiology*; D014157:Transcription Factors / Q000378:metabolism
D029721:Drosophila Proteins; C477334:FOXO protein, Drosophila; D051858:Forkhead Transcription Factors; D055504:Insulin Receptor Substrate Proteins; D047908:Intracellular Signaling Peptides and Proteins; D014157:Transcription Factors; C120233:chico protein, Drosophila; C094982:InR protein, Drosophila; D020794:Receptor Protein-Tyrosine Kinases; D011972:Receptor, Insulin; D010744:Phosphoric Monoester Hydrolases; D051059:PTEN Phosphohydrolase; C487101:PTEN protein, Drosophila