A Rewired Metabolism Links the Aging Epigenome to Vision Loss

They say hindsight is 20/20, but for those of us looking over at a lifetime of memories, things might seem a little blurrier through our aging eyes. That’s because, unlike the fine wines, delectable whiskies, and smelly cheeses that we love to catabolize, the human epigenome tends not to age very well and a wide range of perceptive studies has provided evidence that alterations to the epigenome during normal aging contribute to the functional decline of tissues such as the retina. However, how changes at the epigenetic level prompt aging-associated tissue dysfunction, such as vision loss, remains poorly understood.

With many sets of keen eyes focused on this problem, researchers led by Anand Swaroop (National Eye Institute, National Institutes of Health, Bethesda, MD, USA) recently explored how age-induced alterations to the epigenome influence the function of rod photoreceptors within the retina via an eye-watering range of epigenomic and transcriptomic analyses. Rod photoreceptor dysfunction and associated vision loss is common in aging adults with metabolic stress highlighted as a primary driver of age-related remodeling in the retina – so can metabolic rewiring link epigenomic alterations to age-related losses in visual acuity?

To address this question, the talented team purified rod photoreceptors from young (three-month-old), middle-aged (12-month-old), and old (18- and 24-month-old) mice thanks to the expression of a fluorescent report under the control of a neural retina-specific leucine zipper gene promoter (Nrl). To explore the association of the epigenome and gene regulation during aging, they performed whole-genome bisulfite sequencing (WGBS) in rod photoreceptors and integrated this data with transcriptional- (RNA-sequencing), chromatin accessibility- (ATAC-sequencing), and histone modification- (H3K27ac/H3K27me3) profiles.

 So, let’s hear from Corso-Diaz and colleagues on how their eye-opening new study turned their perceptive questions into an eye-popping scientific reality:

  • Three-month-old mice possess DNA unmethylated regions that display an open chromatin conformation and an enrichment of consensus binding sites for rod transcription factors, thereby suggesting them to be regulatory regions critical for rod-specific transcriptional programs
  • By comparing the integrated epigenomic profiles of young and older mice,  the team found over 2,000 non-random differentially DNA methylated regions (DMRs) associated with aging, mostly representing gains of methylation at sites of no or low methylation
    • Fascinatingly, DMRs occur at regulatory regions for genes involved in longevity, metabolism, and rod photoreceptor pathways
  • With regards to metabolic alterations, many DMRs associated with genes for mitochondrial respiratory chain subunits and those essential for fatty acid beta-oxidation
    • Transcriptional analysis highlighted the downregulation of genes related to glucose metabolism, OXPHOS, and the tricarboxylic acid cycle as well as the upregulation of genes related to fatty acid metabolism, insulin signaling, and glycogen synthesis
    • Fascinatingly, ex vivo assays provided evidence that the age-related alterations to the epigenome induce lower basal mitochondrial oxygen consumption and higher fatty acid dependency in aged retinal tissues

Whatever your view, these farseeing findings look to forge a link between the epigenome and metabolism that explains the age-related decline in rod photoreceptor function. Can we now use this information to inhibit the loss of function in the aging retina?

“Our study elucidates the molecular changes and biological pathways linked with aging of rod photoreceptors, light-sensing cells of the retina. Future investigations can now move forward to study how we can prevent or delay vision loss in aging and hopefully reduce the risk of associated neurodegeneration” said the study’s lead investigator, Anand Swaroop.

“Future studies will assess whether DNA methylation contributes to alterations in the expression of metabolic genes and thus introduce epigenomic editing as a therapeutic possibility for age-related retinal disease,” said the study’s first author, Ximena Corso-Díaz.

For all the details on how a rewired metabolism may link epigenomic alterations to the loss of function in multiple tissues, cast an eye over all the details of this eye-catching new study at Cell Reports, April 2020.

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