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  • Drosophila melanogaster has proven to be

    2019-07-06

    Drosophila melanogaster has proven to be a valuable animal model for studying the aging heart. Flies age in a matter of weeks (five to seven for a typical cardiac aging study) [[10], [11], [12], [13], [14], [15]] and are amenable to extensive genetic manipulation [16,17]. Genes that are differentially expressed over time can be readily tweaked temporally and spatially in large, isogenous populations of offspring [[17], [18], [19]]. The adult fruit fly heart comprises approximately 80 mature cardiomyocytes that are aligned along two opposing bilateral rows to form a linear cardiac tube (Fig. 1) [20]. Coordination of contractility is governed by two pacemakers believed to exist at posterior and anterior regions of the heart. Depending on which pacemaker is dominant, the circulation can flow toward the head or posterior of the fly [21,22]. The cardiomyocytes consist of conserved, minimally-redundant components including those involved in the cytoskeleton, calcium handling, protein homeostasis (i.e. proteostasis), metabolism, and Ezatiostat structure [10,12,13,15,[23], [24], [25]]. Overall, the relative simplicity of the fruit fly heart renders it an attractive model for rapid cardiac senescence investigations. With the emergence and advancement of techniques for assessing whole genomes, transcriptomes, and proteomes under differing conditions and with age, considerable data have been collected on cardiomyocytes from invertebrate and vertebrate models. Here, we discuss how the fly has been utilized to investigate the physiological, genetic, and epigenetic bases of cardiac aging. Drosophila and mammalian hearts and cardiomyocytes share many of the same traits of cardiac senescence, including systolic and diastolic dysfunction, increased arrhythmia, a decline in proteostasis, and decreased metabolic fitness [11,12,24,[26], [27], [28]]. Additionally, the fruit fly has been successfully used as a model of obesity and its exacerbation of normal cardiac aging as well as to investigate the effects of exercise on heart health over time [[29], [30], [31]].
    Cardiac aging is characterized by several histological, physiological, and biochemical changes. Aged myocardium from rodents and humans demonstrates structural remodeling, which includes left ventricular (LV) hypertrophy due to increased cardiomyocyte size [7,[32], [33], [34], [35], [36], [37], [38], [39]]. Concomitant with hypertrophy are alterations in LV shape and dimensions [8,[40], [41], [42]]. For example, using cardiac magnetic resonance imaging, age-associated changes in LV structure and function were assessed in a multi-ethnic cohort of ~5000 individuals free of cardiovascular disease [42]. The authors reported a marked age-related increase in LV mass/volume ratio. This was ~25% higher in the old vs. young age group and was driven by a proportionately greater magnitude of age-associated decline in LV end diastolic volume compared to that of LV mass. Moreover, the significant age-dependent decrease in LV end diastolic volume exceeded the decrease in LV end systolic volume, which resulted in reduced stroke volume. While the cardiac tube of Drosophila has been reported to hypertrophy in response to genetic manipulation [43], altered wall thickness or mass with age has not been reported. However, several studies have demonstrated changes in shape and dimensions of fruit fly hearts over time [15,23,44], akin to those in humans described above [42]. Wild-type Drosophila heart tubes display a progressive decrease in both diastolic and systolic diameters with age [15,23,24]. The decline in diastolic dimensions is greater than that for systolic dimensions, which highlights deterioration in contractile performance, as manifest by significantly reduced fractional shortening [15,23,24]. Healthy aging is accompanied by additional variations in cardiac contraction. The mean shortening velocity during systole has been reported to decrease in mammals [8,[45], [46], [47]]. The slowing of myocardial contraction with advanced age, including that observed during lightly loaded isotonic contractions using heart muscle from senescent vs. younger adults rats, may be in part due to the switching from α- to β-myosin heavy chain gene expression [8,45,46,48,49]. The cardiac tubes of wild-type Drosophila lines likewise exhibit depressed shortening velocities in five- relative to one-week-old flies under basal and/or loaded conditions [13]. While there is currently no evidence of a switch in myosin heavy chain isoforms that have distinct hydrolytic and mechanical activities, aging fly hearts do show changes in the expression of several myofilamentous genes, including tropomyosin, actins, α-actinin, troponin-C, and tropomodulin [15,24], which may contribute to reduced contractile speeds.