Back in the days of big hair and masses of leather, Cher wanted to “turn back time” if she could find a way! Well, get your stockings and suspenders ready and head for the docks, as her eighties “vision” may be on the cusp of coming true with the help of epigenetic reprogramming!
Specifically, resear-Cher-s led by David A. Sinclair (Harvard Medical School, USA) asked whether reprogramming technology (commonly employed to transform somatic cells into pluripotent stem cells) could reverse the accumulation of aging-related epigenetic modifications that negatively impact tissue function and regenerative potential. They aimed to “turn back time” on the epigenetic clock and provide a more youthful outlook to the eyes of aging mice, given the significant negative impact of aging on the central nervous system.
So, let’s hear more from Lu and colleagues, who “Believe” that the power of epigenetic reprogramming via the ectopic expression of Oct4, Sox2, and Klf4 (OSK) is “Strong Enough” for their desired purposes:
- OSK expression in retinal ganglion cells within the eyes of young and adult mice results in axon regeneration after optic nerve crush-injury without altering cell fate, inducing pluripotency, or causing unwanted cell growth
- Improved regeneration occurs alongside the reversal of injury-induced DNA methylation (similar to progressive DNA methylation accumulation during aging) through TET1 and TET2 DNA demethylase activity, as measured by a ribosomal DNA methylation clock
- Analysis in human neurons also demonstrates that OSK expression counteracts axonal loss and DNA methylation induced by chemotherapeutic drug treatment
- Following the onset of experimental glaucoma, a leading cause of age-related blindness, OSK expression in mouse eyes rescues the characteristic loss of retinal ganglion cells, restores axonal density, and improves visual acuity
- Finally, OSK expression in naturally aged mouse eyes recovers youthful levels of visual acuity, which correlates to the restoration of youthful gene expression patterns in retinal ganglion cells via the TET1/2-mediated reversal of aging-induced DNA methylation
The next stage in this exciting research includes evaluating the impact of other relevant epigenetic modifications, such as H3K27me3, and devising an answer to a few vexing questions – how do cells encode this youthful epigenetic information, and how does reprogramming read this information and act upon it?
“Our study demonstrates that it’s possible to safely reverse the age of complex tissues such as the retina and restore its youthful biological function,” said senior author David A. Sinclair. “If affirmed through further studies, these findings could be transformative for the care of age-related vision diseases like glaucoma and to the fields of biology and medical therapeutics for disease at large.”
For more on how reprogramming technology can help to turn back time (and less about ’80s music), see Nature, December 2020.