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  • Substantiating the role of proteostasis in the

    2019-07-06

    Substantiating the role of proteostasis in the aging heart remains a challenging task between species and even among individuals of the same species with similar genetic backgrounds [24]. As described above, microarray analysis of roughly 30 pooled adult Drosophila hearts highlighted an important role of the UPS in cardiac aging and dFOXO-mediated functional improvement [15]. However, a nanofluidic RNAseq evaluation of single Drosophila cardiac tubes indicated Ezatiostat price variation with age and no definitive role of UPS-associated genes in every fly [24,66]. Additional Ezatiostat price investigation into transcriptomes and proteomes of aged murine and simian LVs revealed that a number of components of the proteasome were actually upregulated rather than downregulated [13,24], a seemingly paradoxical result. While initially surprising, as there is a consensus that cellular aging is generally accompanied by decreased proteostasis [97], in many cases, decreased proteasome activity is not necessarily met by a decrease in proteasome components [118,120]. The presence of inactive or defective proteasomal proteins may contribute to or result from the age-associated loss of proteostasis. Alternatively, it is possible that the UPS is upregulated to counteract failing and/or downregulation of other branches of the proteostasis network [97,124]. Evidence suggests that autophagy and UPS each compensates for the other in cardiac pathologies [137], an interplay that may likewise accompany cardiac aging. Genes encoding proteins involved in chaperone-mediated refolding were also observed to exhibit disparate aging expression patterns among species [13,15,24]. Despite this, the mammalian heat shock protein HSPB8 (Hsp27 in Drosophila) exhibited conserved downregulation in cardiomyocytes over time among several species tested [13,15,114,138]. Further examination of molecular cardiac aging data across the animal kingdom is needed to confirm these findings and to test the potential universally cardioprotective properties of conserved targets.
    The decline of metabolic cardiac fitness with age It is well established that obesity and its associated metabolic disturbances are major risk factors for CVD [139]. Furthermore, the risk of obesity as well as CVD increases with age [7,140,141]. In addition to changes in PQC, an important hallmark of the aging process is the progressive dysfunction of white adipose tissue and the related metabolic alterations that lead to multi-organ damage [142]. In humans as well as in flies, fat progressively accumulates in non-adipose tissues [143,144]. This is a key factor in a vicious cycle that accelerates aging and the onset of age-related diseases, such as type 2 diabetes, cancer, and CVD [145]. The heart has a continuously high energetic demand. Therefore, cardiomyocytes are extremely mitochondria-rich in order to generate the ATP required for contraction, calcium handling, and cellular homeostasis in general. Heart tissue is thought to be especially sensitive to dietary changes, such as increased consumption of sugar and fat, since it is heavily dependent upon fatty acids for ATP production [146]. Excessive body fat accumulation causes maladaptive changes in the heart. Over time, in humans and vertebrate animal models, obesity may result in cardiomyocyte growth, interstitial fat infiltration, and triglyceride accumulation in the cells and contractile elements [30,[147], [148], [149], [150]]. These changes contribute to LV mass accrual, hypertrophy, altered chamber dimensions, and eventually dysfunction reminiscent of the age-associated myocardial disturbances described above [[151], [152], [153]]. Similarly, flies fed a high fat diet (HFD, 30% coconut oil) accumulate high levels of triglycerides, become hyperglycemic, and exhibit functional and structural changes in their cardiac tubes [30,31]. These alterations include elevated heart rate, reduced fractional shortening, and increased incidence of arrhythmia and non-contractile heart regions, resembling age-related changes in function [30,31]. Even a small, 2% increase in fat consumption during midlife, over the course of three weeks, has a significantly detrimental impact on Drosophila cardiac function and overall healthspan [154]. Restricting food consumption to only 12 daylight hours per day, compared to ad libitum-fed flies, partially protected against diet- and age-induced decline in cardiac function as evidenced by preserved fractional shortening and heart rate parameters and reduced arrhythmicity [154]. Time restricted feeding also prevented the body weight gain observed in ad libitum-fed flies over time [154]. Transcriptomic analysis of heart samples suggested that mitochondrial electron-transport chain complexes and circadian clock pathways mediate these benefits, at least to some degree [154]. These data provide evidence supporting the general idea that healthy heart aging depends on efficient metabolism and cardiac senescence can be improved by modifying diet.