Activin signaling targeted by insulin/dFOXO regulates aging and muscle proteostasis in Drosophila.
Reduced insulin/IGF signaling increases lifespan in many animals. To understand how insulin/IGF mediates lifespan in Drosophila, we performed chromatin immunoprecipitation-sequencing analysis with the insulin/IGF regulated transcription factor dFOXO in long-lived insulin/IGF signaling genotypes. Dawdle, an Activin ligand, is bound and repressed by dFOXO when reduced insulin/IGF extends lifespan. Reduced Activin signaling improves performance and protein homeostasis in muscles of aged flies. Activin signaling through the Smad binding element inhibits the transcription of Autophagy-specific gene 8a (Atg8a) within muscle, a factor controlling the rate of autophagy. Expression of Atg8a within muscle is sufficient to increase lifespan. These data reveal how insulin signaling can regulate aging through control of Activin signaling that in turn controls autophagy, representing a potentially conserved molecular basis for longevity assurance. While reduced Activin within muscle autonomously retards functional aging of this tissue, these effects in muscle also reduce secretion of insulin-like peptides at a distance from the brain. Reduced insulin secretion from the brain may subsequently reinforce longevity assurance through decreased systemic insulin/IGF signaling.
Department of Ecology and Evolutionary Biology, Brown University, Providence, Rhode Island, United States of America.
Hua
H
Bai
Ping
P
Kang
Ana Maria
AM
Hernandez
Marc
M
Tatar
D028341:Activins / Q000235:genetics* / Q000378:metabolism; D000375:Aging / Q000235:genetics / Q000502:physiology; D000818:Animals; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism; D029721:Drosophila Proteins / Q000235:genetics* / Q000378:metabolism; D004331:Drosophila melanogaster / Q000235:genetics / Q000502:physiology; D051858:Forkhead Transcription Factors / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D007328:Insulin / Q000235:genetics* / Q000378:metabolism; D000078790:Insulin Secretion; D008136:Longevity / Q000235:genetics* / Q000502:physiology; D015398:Signal Transduction
C527373:Atg8a protein, Drosophila; D002352:Carrier Proteins; C517156:Daw protein, Drosophila; D029721:Drosophila Proteins; C477334:FOXO protein, Drosophila; D051858:Forkhead Transcription Factors; D007328:Insulin; D028341:Activins