Researchers restore lost sight in mice, offering clues to reverse aging | Science

By Kelly ServickDec 2, 2020 at 5:30 p.m.

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 neurons in mouse eyes to make them more resistant to damage and able to grow back after injury, like cells in younger mice. The study suggests that the hallmarks of aging, and possibly the keys to reversing it, lie in the epigenome, proteins and other compounds that decorate DNA and influence which genes 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 “argues that [idea], but in no way proves it, ”she adds. If researchers can replicate these findings in other animals and explain their mechanism, she says, the work could lead to treatments in humans for age-related eye diseases and beyond.

Epigenetic factors influence our metabolism, our susceptibility to various diseases and even the way emotional trauma is passed down from generation to generation. Harvard Medical School’s molecular biologist David Sinclair, who has long researched anti-aging strategies, also looked for signs of aging in the epigenome.

“The big question was, is there a reset button?” he says. “Would the cells know how to get younger and healthier?”

In the new study, Sinclair and colleagues aimed to rejuvenate cells by inserting genes encoding “reprogramming factors,” which regulate gene expression – the reading of DNA to make proteins. The team chose three of four factors scientists have used for more than 10 years to transform adult cells into induced pluripotent stem cells, which look like cells from an early embryo. (Exposure of 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 transmit information from light-sensitive photoreceptors to the brain using long, tendril-shaped structures called axons, which make up the optic nerve. There is a gap 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 test whether their treatment could bring back some of that resilience, Sinclair and his colleagues crushed the optic nerves of mice with forceps and injected a harmless virus into the eye carrying the genes for all three reprogramming factors. The injection prevented some damaged retinal ganglion cells from dying and even prompted some to grow new axons reaching the brain, the team reports today in Nature.

When researchers looked at methylation patterns – the location of DNA chemical labels called methyl groups that regulate gene expression – they found that the changes caused by the injury resembled those in aging cells. mouse. In parts of the genome, 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 necessary to remove methyl groups from DNA saw no benefit from treatment.

“This‘It’s really something special, ”says Leonard Levin, visual neuroscientist at McGill University. The experiments suggest how famous and well-studied reprogramming factors restore cells. But big questions remain, he says: How do these factors cause the addition or removal of methyl groups? How does this process help the retinal ganglion cells?

Sinclair’s team also tested the approach in mice with a disease designed to mimic glaucoma, a leading cause of age-related blindness in humans. In glaucoma, the optic nerve is damaged, often by a buildup of pressure in the eye. Sinclair and his colleagues injected tiny beads into the eyes of the animals that prevented normal drainage and increased pressure, which damaged the retinal ganglion cells.

Four weeks later, the animals’ visual acuity had decreased by approximately 25%, as measured by a vision test in which mice move their heads to follow the movement of vertical bars displayed on computer screens. But after the genetic treatment, the animals recovered about half of their lost acuity – the first demonstration of restored vision in mice after this glaucoma injury.

Still, the improvement in acuity was small, Levin notes. And, he says, the treated mice were at a relatively early stage of damage, and not in the near or total blindness that people experience when glaucoma goes untreated for years. It is therefore 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 latest set of experiments, Sinclair and his colleagues injected the reprogramming factor genes into the eyes of healthy one-year-old mice, roughly the equivalent of the middle-aged mouse. At this point, the animals had visual acuity scores about 15% lower than their 5-month-old counterparts. Four weeks after treatment, the older mice had similar acuity scores as the younger ones. In their cells, the researchers saw patterns of DNA methylation and gene expression resembling those of younger animals.

In all three sets of experiments, Sinclair says, cells appeared to respond to reprogramming factors by fine-tuning their gene expression to match a youthful state. He sees this behavior as a clue that cells keep a record of their epigenetic past, even though it is not known how that record is stored. A company co-founded by Sinclair, Life Biosciences, is developing treatments for diseases associated with aging, including glaucoma, and he says he now plans to test the safety of this gene therapy approach in larger animals.

Yun says that as a strategy to reverse aging or treat disease, reset the epigenome “is very difficult. Reprogramming cells to a previous state carries a risk of causing uncontrolled growth and cancer. Future studies should test how the three factors affect other types of cells and tissues and confirm that the reprogrammed cells maintain their youthful state over the long term, she says. “There are a lot of roads to go.”