“Sight Restored by Turning Back the Epigenetic Clock: Neurons Progressively Deteriorate With Age and Lose Resilience to Injury. It Emerges That Treatment With Three Transcription Factors Can Re-Endow Neurons in the Mature Eye With Youthful Characteristics and the Capacity to Regenerate.”, 2020-12-02 (; similar):
Ageing has negative consequences for all the cells and organs in our bodies. Our brains are no exception. Neurons in the developing brain form circuits that can adapt to change and regenerate in response to injury. These capacities have long been known to diminish over time, but the molecular shifts that underlie this deterioration have remained mysterious. et al 2020 show in a paper in Nature that neurons of the eye can be programmed to revert to a youthful state in which they reacquire their ability to resist injury and to regenerate. The authors’ findings shed light on mechanisms of ageing and point to a potent therapeutic target for age-related neuronal diseases.
…Lu et al asked whether it is possible to revert RGCs to a younger ‘age’, and whether doing so would allow the cells to regenerate. They infected RGCs in mice with adeno-associated viruses. These harmless viruses had been genetically engineered to induce expression of three of the ‘Yamanaka factors’—a group of four transcription factors (Oct4, Sox2, Klf4 and c-Myc) that can trigger mature cell types to adopt an immature state6. Such an approach normally comes with hazards in vivo: Yamanaka factors can cause cells to adopt unwanted new identities and characteristics, leading to tumours or death7. Fortunately, Lu and co-workers found that they could circumvent these hazards by expressing just Oct4, Sox2 and Klf4 (together called OSK).
The authors tested the infected RGCs’ ability to regenerate if the cells’ axons were crushed. They found that the OSK-expressing viruses triggered RGC regeneration and long-distance axon extension following damage to the optic nerve (Figure 1), with no apparent alterations to RGC identity, formation of retinal tumours or any other ill effects. OSK expression had beneficial effects on RGC axon regeneration in both young and aged mice. In some cases, the regenerated axons extended all the way from the eye to the optic chiasm (the location at the base of the brain at which the optic nerves from each eye cross to the opposite brain hemisphere). It is notable that the effects of OSK are seen in older animals, because studies of RGC regeneration are often conducted in relatively young animals, which have a residual natural regenerative ability. Thus, the evidence suggests that Lu and colleagues’ approach can fully restore long-distance regenerative capacity in mature RGCs—a milestone for the field.
…Why might reprogramming old RGCs to a younger state promote regeneration and restore vision? An emerging model in the field of ageing is that, over time, cells accumulate epigenetic noise—molecular changes that alter patterns of gene expression, including transcriptional changes and shifts in the patterns of methyl groups on DNA. Collectively, these changes cause cells to lose their identity and so to lose the DNA-expression, RNA-expression and protein-expression patterns that once promoted their youthful resilience. Given the growing excitement about DNA methylation as a marker of cell age, the authors asked whether OSK expression somehow counteracts the negative effects of ageing or axon injury on DNA methylation.
Ageing has negative consequences for all the cells and organs in our bodies. Our brains are no exception. Neurons in the developing brain form circuits that can adapt to change and regenerate in response to injury. These capacities have long been known to diminish over time, but the molecular shifts that underlie this deterioration have remained mysterious. et al 2020 show in a paper in Nature that neurons of the eye can be programmed to revert to a youthful state in which they reacquire their ability to resist injury and to regenerate. The authors’ findings shed light on mechanisms of ageing and point to a potent therapeutic target for age-related neuronal diseases.