Turning back the clock: reversing aging to restore sight

Tick, tock; tick …. tock. I’d like you to imagine a giant clock counting off seconds, tracking history’s passing and marking the future’s arrival. Our clocks and calendars monitor time, distinguishing new pieces of information, people, and things from older ones. But how do our cells record time? If there are little molecular clocks inside each cell, could we turn them back? Could we trick cells into thinking they’re young again and reverse the effects of aging?

These are the questions that researchers Lu et al. explored in a ground-breaking scientific paper published in December 2020. One important known record of cellular time is epigenetics, a family of chemical changes that alter the cell’s ability to read its DNA. If you think of DNA as the molecular book that cells read to know how and when to make the RNA and proteins necessary for their functioning, epigenetics is like deciding to highlight a passage or to cross it out with Sharpie. Epigenetics helps the cell read out the right proteins at the right times to perform the right functions necessary for life. As a cell ages, these Sharpie marks and highlights build up on its DNA book: becoming disorganized, making DNA harder to read, and interfering with how the cell works. Like a heavily annotated used book, aged DNA bears an epigenetic record of time that is like a molecular clock.

Lu et al. developed a new tool to reset the epigenetic clock in eye cells that are necessary for sight. These specific neurons, called retinal ganglion cells (RGCs), usually survive as long as the organism does, building up epigenetic changes. This means they get progressively worse at helping you see and lose abilities they had bTick, tock; tick …. tock. I’d like you to imagine a giant clock counting off seconds, tracking history’s passing and marking the future’s arrival. Our clocks and calendars monitor time, distinguishing new pieces of information, people, and things from older ones. But how do our cells record time? If there are little molecular clocks inside each cell, could we turn them back? Could we trick cells into thinking they’re young again and reverse the effects of aging?

 These are the questions that researchers Lu et al. explored in a ground-breaking scientific paper published in December 2020. One important known record of cellular time is epigenetics, a family of chemical changes that alter the cell’s ability to read its DNA. If you think of DNA as the molecular book that cells read to know how and when to make the RNA and proteins necessary for their functioning, epigenetics is like deciding to highlight a passage or to cross it out with Sharpie. Epigenetics helps the cell read out the right proteins at the right times to perform the right functions necessary for life. As a cell ages, these Sharpie marks and highlights build up on its DNA book: becoming disorganized, making DNA harder to read, and interfering with how the cell works. Like a heavily annotated used book, aged DNA bears an epigenetic record of time that is like a molecular clock.

 Lu et al. developed a new tool to reset the epigenetic clock in eye cells that are necessary for sight. These specific neurons, called retinal ganglion cells (RGCs), usually survive as long as the organism does, building up epigenetic changes. This means they get progressively worse at helping you see and lose abilities they had before, like growing and recovering from injuries. The scientists’ approach was to force the cells to express three genes (Oct4, Sox2 and Klf4, abbreviated as OSK) using harmless viruses injected into mouse eyes. The proteins made by these genes change which genes the eye cells express, triggering them to revert to an immature cellular state.

Figure 1. OSK improves recovery from an RGC axon crush injury (crush site starred)

 The authors first tested how turning on OSK in RGCs would affect their ability to regenerate a crushed cell structure called an axon. Axons are an important part of neurons that transmit electric signals. In this experiment (left), Lu et al. stained re-growing RGC axons so that they glowed and could be observed with a microscope. Inducing OSK expression (bottom), compared to a control protein (top), caused more axons to regrow and those axons to grow further. Next, the authors examined how OSK expression affected the accuracy of a mouse’s vision. The authors tried this in aged mice and a mouse model of glaucoma, the most common cause of human blindness. They showed that OSK expression reversed glaucoma-related vision loss. Similarly, expressing OSK in aged mice’s eyes restored their vision to youthful levels. Finally, the authors explored the molecular effects of OSK expression in aged animals. OSK expression significantly reduced epigenetic signs of aging; specifically, OSK reduced DNA methylation, which is an epigenetic change that silences certain genes, like a Sharpie mark on our DNA “books.”

Ultimately, this paper suggests that expression of OSK proteins ca powerfully counteract disease, damage, and aging by directly and indirectly changing gene expression. Since OSK expression reverses epigenetic signs of aging, it could represent a revolutionary tool for regenerative medicine in many different cell types and organs. Future research should explore whether OSK expression can reverse aging in the heart and brain and precisely how epigenetic changes cause aging.efore, like growing and recovering from injuries. The scientists’ approach was to force the cells to express three genes (Oct4, Sox2 and Klf4, abbreviated as OSK) using harmless viruses injected into mouse eyes. The proteins made by these genes change which genes the eye cells express, triggering them to revert to an immature cellular state.

The authors first tested how turning on OSK in RGCs would affect their ability to regenerate a crushed cell structure called an axon. Axons are an important part of neurons that transmit electric signals. In this experiment (left), Lu et al. stained re-growing RGC axons so that they glowed and could be observed with a microscope. Inducing OSK expression (bottom), compared to a control protein (top), caused more axons to regrow and those axons to grow further. Next, the authors examined how OSK expression affected the accuracy of a mouse’s vision. The authors tried this in aged mice and a mouse model of glaucoma, the most common cause of human blindness. They showed that OSK expression reversed glaucoma-related vision loss. Similarly, expressing OSK in aged mice’s eyes restored their vision to youthful levels. Finally, the authors explored the molecular effects of OSK expression in aged animals. OSK expression significantly reduced epigenetic signs of aging; specifically, OSK reduced DNA methylation, which is an epigenetic change that silences certain genes, like a Sharpie mark on our DNA “books.”

Ultimately, this paper suggests that expression of OSK proteins ca powerfully counteract disease, damage, and aging by directly and indirectly changing gene expression. Since OSK expression reverses epigenetic signs of aging, it could represent a revolutionary tool for regenerative medicine in many different cell types and organs. Future research should explore whether OSK expression can reverse aging in the heart and brain and precisely how epigenetic changes cause aging.

Edited by Jessie Verhein

References

Lu, Y., Brommer, B., Tian, X. et al. Reprogramming to recover youthful epigenetic information and restore vision. Nature 588, 124–129 (2020). https://doi.org/10.1038/s41586-020-2975-4