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Comment by Dorota Skowronska-Krawczyk on:

86863 Reprogramming to recover youthful epigenetic information and restore vision, Lu Y; Brommer B; Tian X et al., Nature, 2020; 588: 124-129

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Age is one of the most relevant clinical traits in predicting disease risk, mental and physical performance, mortality, and other important health issues. Given the increased lifespan and decreased fertility, the average population age is anticipated to significantly increase in the next few decades, bringing the wealth of interest in studying aging and improving quality of life in advanced age individuals. On a molecular level, aging is associated with a gradual decline in the efficiency and accuracy of molecular processes, including changes in gene expression and epigenetics, leading to a deterioration of cell functions and regenerative capacity. Epigenetic aging of tissues and organs has been tightly correlated with global genome hypomethylation accompanied by specific regions, called CpG islands, hypermethylation. The rates of methylation changes at subsets of affected sites were calculated and used to determine the cellular 'epigenetic' age, which generally well correlates with chronological age and therefore allows to assess biological aging in a quantitative manner,^1,2 feature beautifully used in the reviewed work of Lu et al. In this work, David Sinclair's team seeks to restore the youthful epigenetic landscape of retinal ganglion cells (RGCs) to increase their regenerative capability. In a series of elegant experiments, the group has shown that concomitant overexpression of Oct4, Sox2, and Klf4 (OSK) pluripotency factors in RGCs allows restoring vision in several mouse models:

1. After the optic nerve crush injury, overexpression of OSK factors in the retina was able to induce robust axon regrowth in the optic nerve without inducing the cell division. This ability was dependent on the presence of DNA demethylation enzymes, Tet proteins, which expression is upregulated upon OSK expression.

2. In the microbeads-induced mouse model of glaucoma, OSK overexpression four weeks after the beads injection, is able to restore vision by increasing the number of healthy axons, again without inducing the RGC proliferation.

3. In 12 months old animals, overexpression of OSK factors improved optomotor response, visual acuity, and partially restored transcriptional program as seen in younger animals.

Several points were not fully described and will require further studies. As shown in several figures, there is a set (or sets?) of CpGs that are demethylated in the given model but are re-methylated after the OSK factors overexpression (e.g., Fig. 2e, Extended Data Fig. 5j). What are the genes that have this specific dynamic of methylation? Is it a particular group of genes? Are they close to repeats or non-coding RNAs? What is the mechanism of the re-methylation after OSK overexpression? The team has several interesting avenues to pursue in the future.

Finally, the authors ask: 'how cells encode and store youthful epigenetic information', suggesting that there is a particular program that can be stored by the cell. Although intriguing, this is not the only way to explain the results observed by the group. Similar to what happens in age-related methylation patterns, where sets of the same sites are methylated in aging in different tissues and organisms (which allowed the generation of 'methylation clocks'), the same sites are demethylated in the experiments presented in the discussed paper. These two sets of observations might, in fact, suggest that there are sites more susceptible to epigenetic changes and that undirected approaches are preferentially modifying the same sites. Interestingly, this might explain why the overexpression of other chromatin modifying enzymes also have a specific effect on the cell.³

The presented approach to treat age-related neurodegenerative diseases still requires adjustments before being brought to the clinic

The work of Lu and colleagues brings a fresh perspective on a current dogma of the inability of neurons to regenerate. The direct, quantitative measurement of aging through the methylation clock allows one to work on improvements and describing further the mechanism of the regenerative process. Pointing to the specific enzymes that could be involved in the process of rejuvenation of neurons further expands potential future applications. The presented approach to treat age-related neurodegenerative diseases still requires adjustments before being brought to the clinic, for example the design and use of safe overexpression system in human eye. Still, this work provides solid data increasing confidence in potential rejuvenating treatments for age-related eye conditions.

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