Epigenetic drift of H3K27me3 in aging links glycolysis to healthy longevity in Drosophila

Abstract

Epigenetic alteration has been implicated in aging. However, the mechanism by which epigenetic change impacts aging remains to be understood. H3K27me3, a highly conserved histone modification signifying transcriptional repression, is marked and maintained by Polycomb Repressive Complexes (PRCs). Here, we explore the mechanism by which age-modulated increase of H3K27me3 impacts adult lifespan. Using Drosophila, we reveal that aging leads to loss of fidelity in epigenetic marking and drift of H3K27me3 and consequential reduction in the expression of glycolytic genes with negative effects on energy production and redox state. We show that a reduction of H3K27me3 by PRCs-deficiency promotes glycolysis and healthy lifespan. While perturbing glycolysis diminishes the pro-lifespan benefits mediated by PRCs-deficiency, transgenic increase of glycolytic genes in wild-type animals extends longevity. Together, we propose that epigenetic drift of H3K27me3 is one of the molecular mechanisms that contribute to aging and that stimulation of glycolysis promotes metabolic health and longevity.

As time flies by: Investigating cardiac aging in the short-lived Drosophila model

“…These results are in line with a reduction in oxygen utilization and ATP synthesis in aging rat ventricles [160]. In flies, a decrease in ATP levels and in NADH/NAD + and GSH/ (GSH+GSSG) ratios was also found in muscle tissues, supporting a bioenergetic decline with age [161]. However, it is well documented that transcription of genes related to glycolysis declines with age in Drosophila heart and muscle tissues [15,24,161].…”

“…In flies, a decrease in ATP levels and in NADH/NAD + and GSH/ (GSH+GSSG) ratios was also found in muscle tissues, supporting a bioenergetic decline with age [161]. However, it is well documented that transcription of genes related to glycolysis declines with age in Drosophila heart and muscle tissues [15,24,161]. Furthermore, Ma et al provided metabolomic data from fly heads supporting a reduction in glycolysis [161].…”

“…However, it is well documented that transcription of genes related to glycolysis declines with age in Drosophila heart and muscle tissues [15,24,161]. Furthermore, Ma et al provided metabolomic data from fly heads supporting a reduction in glycolysis [161]. While the mechanistic underpinnings of energetic decline between certain animal models and discrete tissues might differ, it is possible that they converge and impact analogous downstream effectors.…”

“…While the mechanistic underpinnings of energetic decline between certain animal models and discrete tissues might differ, it is possible that they converge and impact analogous downstream effectors. For instance, flies heterozygous for different subunits of the Polycomb Repressive Complex 2 (Pcl c421/+ ; Su(z)12 c253/+ ), which are long-lived, have elevated ATP and cellular redox levels [161]. Therefore, metabolomic studies on young vs. old fly hearts would be crucial to determine the conservation of mechanisms underlying the cardiac energetic imbalance that occurs with age.…”

DNA Break-Induced Epigenetic Drift as a Cause of Mammalian Aging

“…In worms, for example, deletion of genes for the H3K4 trimethylation complex that catalyzes the formation of euchromatin extends lifespan (Greer et al, 2010;Greer et al, 2011). In flies, levels of repressive heterochromatin marks, such as H3K9me2, H3K9me3 and H3K27me3 are altered during aging (Larson et al, 2012;Ma et al, 2018;Wood et al, 2010), the suppression of which by calorie restriction or overexpression of fly dSir2 maintains a youthful epigenome, suppresses the agedependent expression of potentially deleterious transposable elements, and extends lifespan (Jiang et al, 2013;Rogina and Helfand, 2004;Wood et al, 2016). The long-lived naked mole rat has a relatively stable epigenome, with increased levels of repressive marks compared to mice (Tan et al, 2017) and in mice and humans, a loss of histones is seen in senescent cells (Ivanov et al, 2013;O'Sullivan et al, 2010) and in quiescent muscle stem cells (satellite cells) during aging (Liu et al, 2013).…”