Do old and damaged cells remember what it was like to be young? That’s the suggestion of new study, in which scientists reprogrammed neurons in mouse eyes to make them more resistant to damage and able to regrow after injury—like the cells of younger mice. The study suggests that hallmarks of aging, and possibly the keys to reversing it, lie in the epigenome, the proteins and other compounds that decorate DNA and influence what genes are turned on or off.
The idea that aging cells hold 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 that [idea], but by no means proves it,” she adds. If researchers can replicate these results in other animals and explain their mechanism, she says, the work could lead to treatments in humans for age-related disease in the eye and beyond.
Epigenetic factors influence our metabolism, our susceptibility to various diseases, and even the way emotional trauma is passed through generations. Molecular biologist David Sinclair of Harvard Medical School, who has long been on the hunt for antiaging strategies, has 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 scientists have used for more than 10 years to turn adult cells into induced pluripotent stem cells, which resemble the cells of an early embryo. (Exposing animals to all four factors can cause tumors.)
The team focused specifically on neurons at the back of the eye called retinal ganglion cells. These cells relay information from light-sensitive photoreceptors to the brain using long tendrillike structures called axons, which make up the optic nerve. There’s a stark divide between youth and age in these cells: An embryonic or newborn mouse can regenerate the optic nerve if it gets severed, but that ability vanishes with time.
To test whether their treatment could bring back some of that resilience, Sinclair and colleagues crushed the optic nerves of mice using forceps and injected a harmless virus into the eye carrying the genes for the three reprogramming factors. The injection prevented some damaged retinal ganglion cells from dying and even prompted some to grow new axons reaching back to the brain, the team reports today in Nature.
When the researchers looked at methylation patterns—the DNA location of chemical tags called methyl groups that regulate gene expression—they found that changes caused by the injury resembled those in aging mouse cells. In certain parts of the genome, the treatment reversed those changes. The researchers also found that the benefits of the introduced genes depended on cells’ ability to alter their methylation patterns: Mice lacking certain enzymes necessary to remove methyl groups from DNA saw no benefit to the treatment.
“That’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 methyl groups to be added or removed? How does that process help 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 gets damaged, often by a buildup of pressure in the eye. Sinclair and his colleagues injected tiny beads into the animals’ eyes that prevented normal drainage and increased pressure, which damaged retinal ganglion cells.
Four weeks later, the animals’ visual acuity had declined by about 25%, as measured by a vision test in which mice move their heads to track the movement of vertical bars displayed on computer monitors. But after the genetic treatment, the animals gained back roughly half of their lost acuity—the first demonstration of restored vision in mice after this glaucomalike injury.
Still, the improvement in acuity was small, Levin notes. And, he says, the treated mice were in a relatively early stage of damage, not the state of near or total blindness that people experience when glaucoma goes untreated 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 there are already “very good treatments” 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 1-year-old healthy mice, roughly the mouse equivalent of middle-age. By this stage, the animals had visual acuity scores about 15% lower 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 resembling those of younger animals.
In the three sets of experiments, Sinclair says, the cells seemed to respond to the reprogramming factors by fine-tuning their gene expression to match a youthful state. He sees that behavior as a hint that cells keep a record of their epigenetic past, even though it’s not clear how that record is stored. A company Sinclair cofounded, Life Biosciences, is developing treatments for diseases associated with aging, including glaucoma, and he says he’s now planning to test the safety of this gene therapy approach in larger animals.
Yun says that as a strategy for reversing aging or treating disease, resetting the epigenome “is a very difficult one.” Reprogramming cells to an earlier state carries a risk of prompting uncontrolled growth and cancer. Future studies should test how the three factors affect other types of cells and tissues and confirm that reprogrammed cells maintain their youthful state long-term, she says. “There are a lot of roads to be traveled.”