Neurons in the eyes of mice can be reprogrammed to a more youthful state in which they re-acquire the ability to regenerate and restore vision, a study in Nature reports. The study sheds light on the mechanisms of ageing, and identifies new potential therapeutic targets for age-related neuronal diseases such as glaucoma.
Retinal ganglion cells are a type of neuron found in the eye; they extend projections, called axons, from the eye into the brain. These axons can survive and regenerate if they are damaged early in development, but not in later adult life. David Sinclair and colleagues demonstrate that expressing three Yamanaka transcription factors (proteins that can turn genes on and off) — OCT4, SOX2 and KLF4 — in the retinal ganglion cells of mature mice with damage to the optic nerve reprograms these neurons to a more youthful state. The mice were able to grow new axons, some of which extended all the way to the base of the brain. The same treatment also reversed neuron loss and restored vision, both in old mice and in a mouse model of glaucoma.
At the molecular level, damage and recovery appear to involve epigenetic change — molecular changes, such as methylation, that alter patterns of gene expression. When the retinal ganglion cells were damaged, molecules called methyl groups accumulated on the cells’ DNA. As the neurons recovered, demethylation occurred, leading to a more youthful methylation pattern. The findings support the idea that ageing is underpinned by an accumulation of epigenetic changes and that it may be possible to reverse the age of a complex tissue and restore its biological function. Furthermore, the study also indicates that mammalian tissues retain a record of youthful information, encoded in part by DNA methylation, which can be accessed to improve tissue function.
In an accompanying News & Views, Andrew Huberman asks whether the findings are relevant to humans. He indicates that although the effects of the transcription factors described here remain to be tested in humans, the results suggest that they may be able to reprogram brain neurons across species.
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