Drosophila as a model to study cardiac aging

Abstract

With age, cardiac performance declines progressively and the risk of heart disease, a primary cause of mortality, rises dramatically. As the elderly population continues to increase, it is critical to gain a better understanding of the genetic influences and modulatory factors that impact cardiac aging. In an attempt to determine the relevance and utility of the Drosophila heart in unraveling the genetic mechanisms underlying cardiac aging, a variety of heart performance assays have recently been developed to quantify Drosophila heart performance that permit the use of the fruit fly to investigate the heart's decline with age. As for the human heart, Drosophila heart function also deteriorates with age. Notably, with progressive age the incidence of cardiac arrhythmias, myofibrillar disorganization and susceptibility to heart dysfunction and failure all increase significantly. We review here the evidence for an involvement of the insulin-TOR pathway, the K(ATP) channel subunit dSur, the KCNQ potassium channel, as well as Dystrophin and Myosin in fly cardiac aging, and discuss the utility of the Drosophila heart model for cardiac aging studies.

Figure 1

Model of the effects of insulin/TOR signaling on cardiac aging. The insulin/TOR signaling is necessary for normal cardiac senescence to occur. A critical target of that pathway is d4eBP whose negative regulation in cardiac tissue is required for normal cardiac senescence to occur (red heart). In our model cardiac aging can be delayed when d4eBP function is maintained, either by increasing dFOXO expression or by reducing insulin-TOR pathway activation (green heart).

Figure 2

Rescue of functional decline during cardiac aging by KCNQ expression (A) KCNQ, dSUR expression decreases with age. RNA levels in isolated hearts were measured using qRT-PCR. KCNQ and dSUR RNA levels in hearts from 5-week old flies are decreased to 33% and 23%, respectively, of the levels in 1 week old flies (mean +/− independent experiments, a control gene SH3β was only reduced to 72% of 1-week levels. (B) Representative 10 sec M-modes made from wildtype flies and a fly in which a wildtype KCNQ cDNA is driven by the mesodermal/heart Gal4 driver 24B. Overexpression of KCNQ channels partially rescued the arrhythmic phenotype normally seen in 5 week old flies (bottom trace). (C) Heart-specific over-expression of KCNQ cDNA using the GMH5 driver¹³ rescues the age-related increases in arrhythmia. Hearts from 1 and 7 week old flies were filmed and the distribution of the heart beat lengths (heart periods) for each group of flies was plotted. Note that heart-specific over-expression of KCNQ reduces the variability of the heart period in (7week) old flies, to be similar to young flies. From ref..