d4eBP acts downstream of both dTOR and dFoxo to modulate cardiac functional aging in Drosophila.
dTOR (target of rapamycin) and dFoxo respond to changes in the nutritional environment to induce a broad range of responses in multiple tissue types. Both dTOR and dFoxo have been demonstrated to control the rate of age-related decline in cardiac function. Here, we show that the Eif4e-binding protein (d4eBP) is sufficient to protect long-term cardiac function against age-related decline and that up-regulation of dEif4e is sufficient to recapitulate the effects of high dTOR or insulin signaling. We also provide evidence that d4eBP acts tissue-autonomously and downstream of dTOR and dFoxo in the myocardium, where it enhances cardiac stress resistance and maintains normal heart rate and myogenic rhythm. Another effector of dTOR and insulin signaling, dS6K, may influence cardiac aging nonautonomously through its activity in the insulin-producing cells, possibly by regulating dilp2 expression. Thus, elevating d4eBP activity in cardiac tissue represents an effective organ-specific means for slowing or reversing cardiac functional changes brought about by normal aging.
Wessells
Robert
R
Department of Internal Medicine/Institute of Gerontology, University of Michigan Medical School, Ann Arbor, MI 48109, USA. wessells@med.umich.edu
Fitzgerald
Erin
E
Piazza
Nicole
N
Ocorr
Karen
K
Morley
Samantha
S
Davies
Claire
C
Lim
Hui-Ying
HY
Elmén
Lisa
L
Hayes
Michael
M
Oldham
Sean
S
Bodmer
Rolf
R
D000375:Aging / Q000502:physiology; D000818:Animals; D004330:Drosophila / Q000254:growth & development*; D029721:Drosophila Proteins / Q000235:genetics / Q000502:physiology*; D039561:Eukaryotic Initiation Factor-4E / Q000502:physiology; D051858:Forkhead Transcription Factors / Q000235:genetics / Q000502:physiology*; D018507:Gene Expression Regulation, Developmental; D006321:Heart / Q000254:growth & development / Q000502:physiology; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics / Q000502:physiology*; D008017:Life Expectancy; D009154:Mutation; D010448:Peptide Initiation Factors / Q000235:genetics / Q000502:physiology*; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics / Q000502:physiology*; D011494:Protein Kinases; D034622:RNA Interference / Q000502:physiology; D019893:Ribosomal Protein S6 Kinases / Q000235:genetics / Q000378:metabolism; D058570:TOR Serine-Threonine Kinases; D014714:Vertebrates / Q000254:growth & development / Q000502:physiology
D029721:Drosophila Proteins; D039561:Eukaryotic Initiation Factor-4E; D051858:Forkhead Transcription Factors; D047908:Intracellular Signaling Peptides and Proteins; D010448:Peptide Initiation Factors; D019869:Phosphatidylinositol 3-Kinases; D011494:Protein Kinases; D019893:Ribosomal Protein S6 Kinases; D058570:TOR Serine-Threonine Kinases; C477334:FOXO protein, Drosophila; C410006:Thor protein, Drosophila; C416303:target of rapamycin protein, Drosophila