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The researchers inserted genes into mouse eye cells to protect and restore the optic nerve (red fibers in the microscope image of a healthy mouse retina, above).
NIGMS / Bryan William Jones / Robert E. Marc / University of Utah / Science Source
By Kelly Servick
Do old and damaged cells remember what it was like to be young? That’s the suggestion of a new study, in which scientists reprogrammed the neurons in the mice’s eyes to make them more resistant to damage and able to grow back after injury, like cells from younger mice. The study suggests that the hallmarks of aging, and perhaps the keys to reversing it, reside in the epigenome, proteins and other compounds that decorate DNA and affect genes that are turned on or off.
The idea that aging cells retain a memory of their young epigenome “is very provocative,” says Maximina Yun, a regenerative biologist at the Dresden University of Technology who was not involved in the work. The new study “supports it [idea]But it doesn’t prove it at all, ”he adds. If researchers can replicate these findings in other animals and explain their mechanism, he says, the work could lead to treatments in humans for age-related diseases in the eye and beyond.
Epigenetic factors affect our metabolism, our susceptibility to various diseases and even the way emotional trauma is passed on through the generations. Molecular biologist David Sinclair of Harvard Medical School, who has long been on the hunt for anti-aging strategies, also looked for signs of aging in the epigenome.
“The big question was: is there a reset button?” he says. “Would cells know how to become younger and healthier?”
In the new study, Sinclair and his collaborators aimed to rejuvenate cells by inserting genes that encode “reprogramming factors,” which regulate gene expression – the reading of DNA to make proteins. The team chose three of the four factors that scientists have used for more than 10 years to turn adult cells into induced pluripotent stem cells, which resemble cells from an early embryo. (Exposure of animals to all four factors can cause cancer.)
The team specifically focused on neurons in the back of the eye called retinal ganglion cells. These cells transmit information from photosensitive photoreceptors to the brain using long tendril-like structures called axons, which make up the optic nerve. There is a clear division between youth and age in these cells: an embryonic or newborn mouse can regenerate the optic nerve if it is severed, but this ability wears off over time.
To see if their treatment could restore some of that resilience, Sinclair and colleagues squeezed the optic nerves of the mice using forceps and injected a harmless virus into the eye that carried genes for the three reprogramming factors. The injection prevented some damaged retinal ganglion cells from dying and even prompted some to grow new axons to reach the brain, the team today reports. Nature.
When the researchers looked at the patterns of methylation, the DNA location of chemical labels called methyl groups that regulate gene expression, they found that the changes caused by the lesion resembled those in aged mouse cells. In some parts of the genome, the treatment reversed these changes. The researchers also found that the benefits of the introduced genes depended on the cells’ ability to alter their methylation patterns: mice lacking certain enzymes needed to remove methyl groups from DNA saw no benefit for the treatment.
“That‘It’s really something special, “says Leonard Levin, a visual neuroscientist at McGill University. The experiments suggest how the famous and well-studied reprogramming factors restore cells. But big questions remain, he says: how do these factors cause the addition or the removal of methyl groups? How does this process help the retinal ganglion cells?
Sinclair’s team also tested the approach in mice with a condition meant to mimic glaucoma, a leading cause of age-related blindness in humans. In glaucoma, the optic nerve is damaged, often from a buildup of pressure in the eye. Sinclair and his colleagues injected small beads into the animals’ eyes which prevented normal drainage and an increase in pressure, which damaged the retinal ganglion cells.
Four weeks later, the animals’ visual acuity had decreased by about 25 percent, as measured by a vision test in which mice move their heads to follow the movement of vertical bars displayed on computer monitors. But after the genetic treatment, the animals recovered about half of their lost acuity, the first demonstration of restored vision in mice after this glaucous-like injury.
However, the improvement in acuity was minimal, Levin notes. And, he says, the treated mice were in a relatively early stage of damage, not the near or complete blindness that people experience when glaucoma isn’t treated for years. So it’s too early to say whether this approach could benefit people who have lost much of their vision. Levin adds that “excellent treatments” already exist for early stage glaucoma to prevent vision loss with medicated eye drops or surgery to lower eye pressure.
In a final set of experiments, Sinclair and colleagues injected the reprogramming factor genes into the eyes of healthy 1-year-old mice, roughly the equivalent of the middle-aged mouse. At this point, the animals had approximately 15% lower visual acuity scores than their 5-month-old counterparts. Four weeks after treatment, older mice had similar acuity scores to younger ones. In their cells, the researchers saw patterns of DNA methylation and gene expression similar to those of younger animals.
In the three series of experiments, Sinclair says, cells appeared to respond to reprogramming factors by fine-tuning their gene expression to match a juvenile state. He sees that behavior as a clue that cells retain a record of their epigenetic past, although it is not clear how that record is stored. A company co-founded by Sinclair, Life Biosciences, is developing treatments for diseases associated with aging, including glaucoma, and says it now plans to test the safety of this gene therapy approach in larger animals.
Yun says that as a strategy to reverse aging or cure disease, reset the epigenome “it is very difficult. “Reprogramming cells to an earlier state carries the risk of causing uncontrolled growth and cancer. Future studies should test how the three factors affect other cell types and tissues and confirm that reprogrammed cells retain their long-term youthful state. he says. “There are many ways to go.”
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