Age-related cardiac disease model of Drosophila

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Abstract

We have begun to study the genetic basis of deterioration of cardiac function in the fruit fly Drosophila melanogaster as an age-related cardiac disease model. For this purpose we have developed heart function assays in Drosophila and found that the fly's cardiac performance, as that of the human heart, deteriorates with age: aging fruit flies exhibit a progressive increase in electrical pacing-induced heart failure as well as in arrhythmias. The insulin receptor and associated pathways have a dramatic and heart-autonomous influence on age-related cardiac performance in flies, suggestive of potentially similar mechanisms in regulating cardiac aging in vertebrates. Compromised KCNQ and KATP ion channel functions also seem to contribute to the decline in heart performance in aging flies, suggesting that the corresponding vertebrate gene functions may similarly decline with age, in addition to their conserved role in protecting against arrhythmias and hypoxia/ischemia, respectively. The fly heart is thus emerging as a promising genetic model for studying the age-dependent decline in organ function.

Introduction

Age-related diseases are becoming increasingly more prevalent in industrialized societies that have increasingly longer average life expectancies. These diseases are difficult to treat, in part because we do not sufficiently understand the distinction between ‘normal’ and disease-associated aging. By studying genetically tractable model systems it has become clear in recent years that both aging-related processes and disease progression may be influenced and regulated by specific genes. However, the mechanisms underlying the aging process in a normal or mutant organism and how the functional and morphological decline of organ systems is initiated, coordinated and executed is almost completely unknown. Since cardiac dysfunction is the most common cause of death in the elderly, an understanding of the progression and control of age-related changes in heart function becomes increasingly important as our societies become increasingly older. To date virtually nothing is known about the genetic mechanisms that control the age-dependent deterioration of the heart in health and disease. We have recently implemented assays for monitoring the cardiac stress response, arrhythmias and other dysfunctions in the simple Drosophila system, the only invertebrate genetic model with a heart. Given the high degree of parallel genetic functions between flies and vertebrates in cardiogenesis (Bodmer, 1995, Cripps and Olson, 2002, Zaffran and Frasch, 2002, Bodmer et al., 2005), and given the strikingly common mechanisms that determine lifespan and rate of overall aging (Guarente and Kenyon, 2000, Helfand and Rogina, 2003, Finch and Ruvkun, 2001, Partridge and Gems, 2002, Barbieri et al., 2003, Tatar et al., 2003), it is likely that the genetic basis of age-related changes in cardiac performance is also conserved. Thus, Drosophila is an ideal system to study the genetic basis of cardiac performance decline with age and disease. Below, we summarize the approaches we have taken and some of the insights that we have recently obtained.

Section snippets

Age-dependent increase in heart failure in flies

Chronic heart disease often accelerates the decline of cardiac function in older people (Ribera-Casado, 1999, McLaughlin, 2001, Busby et al., 1989, Maurer et al., 1995). The human heart has been demonstrated to undergo changes in function with advancing age, including increased prevalence of rhythmic abnormalities. These changes cause an age-related increase in the risk for congestive heart failure and contribute additional risk factors to other cardiac pathologies (Lakatta and Levy, 2003). As

Age-dependent increase in arrhythmias in flies

Although pacing-induced cardiac arrest or fibrillation is indicative of cardiac dysfunction it does not provide information as to the specific underlying causes or mechanisms. In order to further characterize the heart's contractile properties we used a high speed video camera to capture heart wall movements in a semi-intact fly preparation in which the heart is surgically exposed and most neuronal inputs to the heart are disrupted. We created M-mode records from these recordings and found that

KATP channel function and aging

The incidence of ischemic heart disease is strikingly on the rise in the modern world (Giordano, 2005). It is thus important to elucidate the molecular basis of the heart's response to hypoxia/ischemia and determine how this response changes with age, in order to devise preventive and therapeutic strategies. KATP channels are thought to sense the intracellular metabolic state; they are regulated by intracellular ATP/ADP ratio, which in turn is affected by metabolic stresses including hypoxia (

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