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  • A profound well characterized and frequently cited hallmark


    A profound, well-characterized, and frequently-cited hallmark of cardiac aging is impaired diastolic function. In addition to decreased LV end diastolic volumes in humans and reduced cardiac tube diastolic diameters in flies, several indices of age-related diastolic dysfunction are shared among the species. Older vertebrate hearts fill more slowly than younger hearts and exhibit increased relaxation times [8,67]. The velocity at which the Drosophila Ezatiostat inhibitor reestablishes diastolic volumes is significantly lower for five- vs. one-week-old flies, at baseline and/or against elevated afterloads, consistent with impaired relaxation kinetics [13]. These changes are plausibly associated with the disruption of calcium homeostasis and cycling observed in aged myocardium and, potentially, with altered passive recoil of elastic elements compressed during systole [68]. Mammalian hearts normally experience changes in their material properties, including myocardial stiffening, with age [8,[69], [70], [71], [72], [73]]. Similarly, fly hearts display changes in passive mechanical properties over time [13,15,26,74]. Using an atomic force microscopy-based approach, five-week-old wild-type hearts were found to be significantly stiffer than one-week-old hearts [12,13,15,74]. The molecular basis of altered heart wall and cardiomyocyte compliance likely involves several factors. These include aberrant diastolic calcium handling, myofilament dysfunction, and extracellular matrix modifications and remodeling [26,68,[75], [76], [77], [78]].
    Extracellular matrix and matricellular proteins in cardiac aging Extracellular matrix and matricellular proteins (for brevity in this review, collectively termed ECM) are a large family of evolutionarily conserved proteins contributing to the structure and function of multicellular organisms [79]. The matrix proteins help form a structural “scaffold” that supports cell-cell and cell-matrix interactions, whereas the matricellular proteins contribute to the formation of the scaffold but do not integrate into it. ECM regulation in the heart is linked to cardiac output, with disruption or experimental modulation of ECM deposition causing cardiomyopathy in both mammalian and Drosophila models [80]. Abnormal or pathological accumulation of ECM proteins (fibrosis), particularly of collagens, occurs in the aging human heart and is associated with increased mortality [81,82]. Additionally, markers of fibrosis can be predictive of mortality in aged populations [83] and are generally associated with cardiac dysfunction [84]. Importantly, the mechanistic underpinnings of ECM turnover are of intense interest due to the clinical significance of fibrosis and intractability of its treatment. Most experimental research requires whole organisms to establish the pathophysiology of aging on organs and systems. Although mammalian models recapitulate the fibrosis-like features of aging human hearts [85,86], such models are costly, and long-term studies of aging are not widely reported. Thus, simpler systems to study ECM deposition in age-dependent cardiac dysfunction are beneficial. Although Drosophila may not provide the complexity of ECM components seen in humans and mammalian models, the fly provides enormous advantages in terms of genetic tractability, brevity of lifespan, and resource usage. With reference to collagens, Drosophila development is dependent on expression of the type-IV collagen α2 and α1 chains encoded by viking and Cg25C [87]. Alternatively, cardiac development is reliant on Multiplexin (COL18A1 in humans [88]) and Pericardin, a type-IV-like collagen that tethers the Drosophila heart to the underlying cuticle and to supportive alary muscles (Fig. 1, Fig. 2), which run perpendicular to the cardiac tube [89,90]. Although Pericardin was initially described as a matrix-forming type-IV-like collagen, it adopts prominent fiber-like structures, acting as a “tendinous bridge” between the heart and alary muscles [90,91].