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  • While there is increasing evidence showing that manipulation

    2019-07-06

    While there is increasing evidence showing that manipulation of the 2NBDG state and epigenetic modifiers can alter/extend lifespan [184], little is known about the epigenetic mechanisms that may preserve healthy cardiac aging, specifically. To make headway, its low genetic redundancy makes the fly a well-poised model for epigenetic cardiac aging studies [20,178,227,228]. The histone deacetylases HDAC1 and HDAC2 regulate the expression of genes involved in cardiac morphogenesis and heart physiology in mammals [229]. The Drosophila protein reduced potassium dependency-3 (Rpd3) shows high homology with human HDAC1 and moderate homology with human HDAC2 [138]. Heterozygous fly [230] and yeast [231] rpd3 mutants (rpd3+/−) exhibited increased lifespan. Rpd3 works in a complex with SIN3 to repress expression of multiple glycolytic genes, genes involved in the oxidation of fatty acids into acyl-CoA in the mitochondrial matrix, and genes involved in ROS response [232]. It remains unclear if the rpd3+/− mutant fly lifespan extension is accompanied by improved cardiac aging. However, heart-restricted knockdown of rpd3 was found to extend lifespan and prevent the age-related reduction in heart rate of old flies [233]. While transcriptomic analysis of Drosophila heart samples suggested that rpd3 transcript levels are not modified with age [15], the beneficial effects of rpd3 knockdown on healthspan might result from a change in global acetylation levels. Heart-specific rpd3-knockdown flies experienced an increase in resistance against oxidative stress (20 mM methyl viologen hydrate), elevated ambient temperature (37 °C), and starvation compared to single transgenic controls. Whole-fly transcript levels of sod2, dfoxo, and sir2 were also found to be increased upon heart-specific reduction of rpd3 [233]. sod2 expression could potentially lead to a more efficient removal of superoxide radicals produced in the mitochondria upon induction of oxidative stress. These results are in agreement with the reported lifespan extension achieved upon ubiquitous moderate overexpression of sir2 [225] and improved cardiac aging, but not lifespan, upon modest heart-specific overexpression of dfoxo [15,135]. Altogether, these data suggest that mild reduction of rpd3 can alter gene expression, thus improving the aging heart by enhancing the responses to stress and de-repressing expression of genes involved in energy balance such as dfoxo. Therefore, during normal aging, other epigenetic modifiers, including those potentially controlled by dFOXO [177], may have profound effects on gene programs, possibly leading to energy imbalance and cardiomyocyte malfunction. Epigenetic modifications have been shown to be at the intersection of metabolic equilibrium and gene expression. The exact mechanisms underlying the energy imbalance and loss of chromosome homeostasis upon aging remain unknown. However, there is increasing evidence indicating that epigenetic modifications can have a significant impact on the quality of aging [234]. Because epigenetic changes are reversible, reestablishing a healthy epigenome might reduce the functional decline observed in cardiomyocytes over time. A potential mechanism by which epigenetic cardioprotection can be promoted is through pro-longevity metabolic interventions such as CR, rapamycin, and exercise [235,236].
    Reduction of age-related heart deterioration as result of aerobic exercise Accumulating evidence suggests that switching to a healthier lifestyle (e.g. reduced sugar and fat consumption, increased physical activity, etc.) can reduce the risk of heart failure [237]. Many animal models and cohort analyses have shown that aerobic exercise reduces the risk of death from CVD [238,239]. Indeed, the strongest inverse correlation between exercise and heart failure was observed in the elderly [240]. A two-year clinical trial showed that high-intensity exercise increased maximal oxygen uptake (VO2max) and reduced LV stiffness in previously sedentary, but otherwise healthy, middle-aged male participants [241]. These studies suggest that aerobic exercise not only improves cardiac function but also reverses the effects of sedentary aging on the heart to some extent. While there is compelling evidence supporting the benefits of exercise on heart function and healthy aging, the mechanisms underlying these phenomena are poorly understood.