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  • The TOR pathway can be activated directly

    2019-07-06

    The TOR pathway can be activated directly by Ezatiostat ic50 and indirectly by dietary sugar or fat (see above) through insulin-IGF signaling [171]. Reduced insulin-IGF signaling is known to prolong lifespan in different animal models by regulating growth, metabolism, and stress response [172,173]. In the fly, heart-specific reduction of signal transduction by InR, the single Drosophila insulin-like receptor, evidently improves cardiac physiology at advanced age [10,135]. In addition, overexpression of dfoxo, a negative effector of insulin signaling, in the adipose tissue (fat body in flies) protects flies from fat accumulation and HFD-induced heart dysfunction [31]. As discussed above, modest heart-specific overexpression of dfoxo ameliorated the functional decline of the aging heart [15]. Moreover, it prevented the deleterious effects of HFD on cardiac function, though systemic fat accumulation was not avoided [31]. High-sugar diet (HSD) in flies, as in mammals, results in augmented fat content and hyperglycemia, in turn inducing insulin resistance and cardiomyopathy [146,[174], [175], [176]]. Interestingly, findings in Drosophila suggest that consumption of diets high in sugar early in life leads to shortened lifespan due to maladaptive nutritional reprogramming [177]. HSD inactivates dFOXO, which seems to execute long-term transcriptional changes that affect the fitness of flies later in life [177]. Likewise, in the heart specifically, RNAi-mediated dFOXO suppression engenders a cardiac phenotype reminiscent of accelerated aging [15]. Taken together, aging and obesity seemingly share a low energy demand state, leading to pathological inhibition of FoxO and persistent TOR hyperactivation. Consequently, cells accumulate lipids, misfolded proteins, reactive oxygen species (ROS), and dysfunctional mitochondria, all of which lead to seemingly premature aging and heart function decline. The fly model, with simpler but largely conserved biochemical pathways, can aid in understanding the molecular and genetic changes induced by the metabolic imbalance that apparently stimulates accelerated cardiac aging. Thus, Drosophila can help in developing new targeted therapeutics.
    Epigenetic modifications of the aging heart An additional, primary hallmark of aging is the progressive accumulation of alterations to the epigenome [1]. While all cells of an organism contain the same DNA (with some exceptions, e.g. immune cells), their specific gene expression programs differ in response to internal and external cues. Such cues can trigger complex biological events including differentiation and environmental adaptation. Cellular differentiation is a highly regulated process. It is achieved in large part by altering the chromatin state, which enables proper gene expression to drive the process and thus control cellular phenotypes. Additionally, the chromatin state changes to match gene expression with fluctuating energetic demands. Thus, aging cells must face the challenge of staying healthy and remaining functionally competent by maintaining their epigenetic program and simultaneously retaining their capacity to respond to environmental fluctuations (e.g. diet or stress). This is of particular importance for long-lived cells, such as cardiomyocytes, which are terminally differentiated very early in life [178,179]. Chromatin structures are dynamically controlled by epigenetic modifications. These include heritable changes in DNA methylation, histone modifications, and non-coding RNAs, all of which can regulate gene expression without changing the genetic code. While the epigenome is maintained in a state of dynamic equilibrium [[180], [181], [182], [183]], evidence suggests that it is prone to “drift” over the lifespan of an organism [184]. Age-associated changes to the epigenome have been correlated with an abnormal transcriptome, which contributes to age-related pathologies including cancer, Alzheimer's disease, dementia, and CVD [[185], [186], [187]]. Additionally, experimental manipulation of epigenetic factors in various animal models suggests that they can modulate healthy lifespan [184].