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  • 2-NBDG Hence a dynamic and drifting epigenome likely makes


    Hence, a dynamic and drifting epigenome likely makes it difficult for 2-NBDG and tissues to achieve phenotypic stability, healthy aging, and longevity. Minor alterations to the epigenome may have major impacts on gene expression. Indeed, a significant change in transcription with age has been consistently reported at the cellular and tissue levels in different species ranging from flies to mice to humans [15,24,[188], [189], [190]]. The meta-transcriptomic analysis by Cannon et al. revealed that the pathways whose components displayed age-associated expression changes, and thus are potentially involved in cardiac aging, are conserved between fly and rodent hearts [24]. Despite conservation of the pathways, however, there was considerable variability in age-associated expression changes of particular genes among species. Interestingly, even between individual Drosophila hearts there was substantial transcriptome variability with age [24], perhaps reflecting the same phenomenon as has been reported in single cardiomyocytes from mice [191]. Thus, the accumulation of changes in gene expression over time may ultimately lead to similar cardiac aging phenotypes across species [24]. In line with these results, a recent study performed in three different tissues on 168 pairs of genetically identical, human female, monozygous twins identified a total of 137 genes with similar age-related expression changes and 42 genes with unique age-related changes between co-twins [192]. These data support the idea that with age, gene expression differences depend not only on genetic factors but also on environmental cues as well as stochastic variations that may happen simply by chance. These alterations could result from a combined imbalance in the activity of transcription factors, splicing factors, or epigenetic modifiers and could contribute to the characteristic individual variability observed during age-associated functional decline. There is growing evidence that chromatin structure is altered in an age-dependent manner in different animal models and that modulation of epigenetic factors significantly impacts lifespan [193]. Indeed, deleterious age-associated epigenetic changes are well documented in many tissues. For example, an age-related gain of methylation at promoter CpG islands, which are CG-rich regions typically located 5′ to the transcriptional start site, is thought to increase the incidence of cancer, in part by silencing tumor suppressor genes [[194], [195], [196]]. Conversely, age-associated loss of DNA methylation at other regions of the genome may contribute to de-repression of retrotransposons, thereby causing genome instability [197]. Remarkably, the epigenetic clock, based on the methylation state of CpGs, is an accurate marker of chronological age. It is also believed to be a promising molecular biomarker of biological age, showing a strong correlation with age-associated phenotypes [187,198,199]. For instance, using the Horvath estimation for biological age based on DNA methylation, a 4% increase in the risk of developing CVD was observed per year of advanced biological age [200]. Epigenetic modifiers control chromatin packaging into at least two distinct states, heterochromatin or euchromatin, in part by modifying DNA methylation, by acetylation or methylation of histone tails, or by binding to the DNA or to nucleosome core particles. In flies, systemic mild overexpression of the Heterochromatin Protein 1 (HP1) led to an increase in heterochromatin levels and lifespan extension with improved muscle integrity and function [201]. HP1 helps in the maintenance of heterochromatin by interacting with nuclear lamins. Expression of nuclear lamins has been shown to decline with age in fly and human cells [[202], [203], [204]]. Loss of Lamin-B in the Drosophila fat body correlates with an increase in retrotransposon activation [205]. Indeed, there is a progressive de-repression of retrotransposons with age, shown by a 2-fold increase in RNA expression of previously annotated retrotransposon elements [205]. Retrotransposons are the most common type of transposable elements (TEs). Upon activation, some TEs can move to new locations in the genome, which can lead to mutations and DNA damage. Thus, the age-dependent reduction in heterochromatin documented in yeast, flies, and senescent mammalian cells could trigger activation of retrotransposons, leading to DNA instability and aging phenotypes [[205], [206], [207]]. Interestingly, using a position effect variegation reporter, a delay in age-related gene de-repression was found when flies underwent caloric restriction, which increases lifespan, as discussed earlier [206]. This exemplifies the plasticity of the epigenome and underscores a challenge that long-lived cardiomyocytes must overcome to maintain vital functionality over a lifetime, whether that be weeks or decades.