br Crosstalk between epigenetics and metabolism with age
Crosstalk between epigenetics and metabolism with age Energy balance and tight metabolic control are key determinants of organism-wide functional maintenance and healthy aging. The ability of an animal to respond to stress, such as changes in temperature, oxygen levels, and nutrient availability, gradually declines with age. Variations in the epigenome allow for the adjustment of gene expression to match environmental changes and energy requirements by regulating accessibility of the transcriptional machinery to DNA. This interplay between metabolism and epigenetics depends on the fact that histone-modifying enzymes utilize substrates, including the metabolites NAD+, ATP, S-adenosylmethionine (SAM), acetyl-CoA, and α-ketoglutarate [, , ], which are dysregulated with extreme diets and age. In Drosophila, acute as well as maternal HFD and HSD are known to modify the expression of metabolic genes in adult offspring [211,212]. Paternal HSD can modify the offspring's chromatin state and gene transcription in a manner dependent upon tri-methylation of histone H3 at lysine 9 (H3K9me3) or lysine 27 (H3K27me3) . In addition, HSD was found to cause lifelong changes in gene expression via inhibition of dFOXO activity . Not surprisingly, null dfoxoΔ mutants and HSD-fed flies displayed overlapping changes in gene expression and specifically an enrichment in transcripts encoding epigenetic modifiers, such as Sirt-1 and -2, Histone deacetylase 1 (HDAC1), Su(z)12, and Enhancer of zeste (Ez) [177,214]. Ez is the primary catalytic subunit of the evolutionarily-conserved Polycomb repressive complex 2 (PRC2). PRC2 mediates gene silencing by promoting H3K27me3 . Upon aging, there are also profound tissue-specific changes in metabolism and energy balance analogous to those induced by HFD and HSD, as discussed earlier. In addition to an age-dependent decline in glycolysis in fly heads, and reduced ATP levels and NADH/NAD+ ratio in muscles, Ma et al. also identified a dramatic drift in the H3K27me3 repressive marks in Drosophila musculature  (note the brain, as opposed to the heart, preferentially uses glycolysis over fatty 2-NBDG oxidation for ATP production [216,217]). Interestingly, mutants heterozygous for PRC2 components, including Pcl, Su(z)12, Ez, and esc, showed an increase in lifespan that correlated with reduced levels of H3K27me3 and a reduction in the age-associated shift in H3K27me3 modifications in muscles [161,218]. The authors additionally found an increase in transcripts involved in glycolysis in muscle tissues from Pcl and Su(z)12 compound heterozygous mutant flies . Similarly, PRC2 heterozygous mutants had ATP levels and NADH/NAD+ ratios comparable to those of young wild-type flies, as mentioned above . These data suggest that aging leads to a genome-wide drift in H3K27me3 repressive modifications, which causes changes in transcription that result in reduced glycolysis and/or defective glucose metabolism. In aging fly hearts, an opposite shift from fatty acid oxidation to glycolysis is expected with age, but definitive studies have yet to be conducted. Since histone methyltransferases rely on the availability of the universal methyl donor SAM, it would be interesting to study the regulation of this metabolite in old flies and their hearts. Evidence currently suggests that SAM is important for heart function and healthy aging , possibly in part by regulating the levels of histone methylation. In fact, the Radical S-Adenosyl methionine Domain containing 1 (RSAD1) enzyme has been linked to heart development, and mutations lead to congenital heart disease . NAD+ is an important co-factor for the Sirtuin group of protein deacetylases. The age-associated reduction in NADH/NAD+ ratio reported by Ma, et al. in Drosophila muscles  contrasts with findings in mammals (various tissues) in which NAD+ levels have been shown to decline with age, and replenishment of the NAD+ pool by supplementation with dietary precursors could drive the observed increase in healthspan . However, we would like to emphasize again that tissue and species discrepancies would have to be more extensively scrutinized to determine potential fundamental differences. Indeed, overexpression of the NAD+ synthase CG9940 in flies resulted in a mild but significant extension of lifespan . Consistently, NAD+ dependent Sir2 (Sirt1 in mammals) has been implicated in lifespan extension not only in flies but also in yeast and mammals in a tissue- and dose-dependent manner [, , ]. For instance, in Drosophila, modest overexpression of dSir2 increased lifespan, while excessive levels of dSir2 resulted in decreased lifespan . Importantly, the extension of lifespan achieved by CR in flies has been shown to be dependent on dSir2 expression levels . A loss in age-related gene silencing of a position effect variegation reporter was also observed upon global mild overexpression of dSir2 . Finally, evidence suggests that replenishing the NAD+ pool by overexpressing NAD+ synthase decreases arrhythmia and fibrillations in old flies compared to age-matched controls . However, these studies are not entirely conclusive, and the specific roles of NAD+ and Sir2 in cardiac aging need to be characterized in greater detail.