d4eBP acts downstream of both dTOR and dFoxo to modulate cardiac functional aging in Drosophila

Abstract

Summary 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 insulinproducing 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.

Dietary composition regulatesDrosophilamobility and cardiac physiology

“…Across a range of different dietary concentrations, we found no significant difference in effect between most diets and our typical lab diet (10S/10Y). Furthermore, both genotypes exhibited failure rates similar to published wild-type results from this age (Wessells et al, 2004;Wessells et al, 2009). However, the 20S/10Y diet produced a significantly increased cardiac failure rate in response to pacing in both genotypes (Fig.4B, Fig.5B).…”

“…One proposed mechanism by which the interventions collectively known as dietary restriction improve healthspan and longevity is by increasing levels of autophagy (Bjedov et al, 2010;Partridge et al, 2011). Genetic interventions in regulators of autophagy, such as target of rapamycin (TOR) and eukaryotic initiation factor 4e binding protein (4eBP), have previously been shown to preserve aging cardiac function (Luong et al, 2006;Wessells et al, 2009) and negative geotaxis during aging (Demontis and Perrimon, 2010). In rodent models, exercise-induced autophagy is a key component necessary for the benefits of exercise (He et al, 2012).…”

“…Full relative caloric intake calculations for each genotype/diet are presented in supplementary material TableS2. reduction in TOR signaling both reduces triglyceride storage and protects aging cardiac performance in Drosophila (Luong et al, 2006;Wessells et al, 2009). Conversely, flies fed a high-fat diet (Birse et al, 2010) or flies with genetic mutations that increase lipid storage in the myocardium have decreased cardiac performance (Lim et al, 2011;Sujkowski et al, 2012).…”

Phospholipid homeostasis regulates lipid metabolism and cardiac function through SREBP signaling in Drosophila

“…To measure adult heart response to external electrical pacing, intact fly hearts were analyzed according to previously described protocols (Wessells et al , 2009KA Ocorr et al 2007). Briefly, eight to 10 female flies were placed between two electrodes touching conductive jelly spread over the electrodes.…”

TOR and ageing: a complex pathway for a complex process

“…Epistasis analysis in flies suggests that activation of d4E-BP/Thor may be tightly linked to the longevity benefits of dietary restriction [65]. Enhanced 4EBP1 activity in Drosophila is protective in cardiovascular and neurodegenerative disease models [66,67]. Therefore, altered activity of two key TOR substrates, S6K1 and 4E-BP, can lead to enhanced longevity and protection against age-related disease, raising the question of whether they act by the same mechanism and, if not, which of these events are more tightly coupled to lifespan extension by rapamycin.…”