Researchers have restored vision in old mice and in mice with damaged retinal nerves by resetting some of the thousands of chemical traits that build up on DNA as cells age. The work, published on December 2 in Nature1
“This is a major landmark,” said Juan Carlos Ispisua Belmonte, a development biologist at the Salk Institute for Biological Research in La Jolla, California, who was not involved in the study. “These results clearly show that tissue regeneration in mammals can be improved.”
But researchers also warn that so far the work has only been done on mice, and it remains to be seen whether the approach will turn into humans or other tissues and organs that have been devastated by time.
Aging affects the body in countless ways – including adding, removing or changing chemical groups such as flukes on DNA. These “epigenetic” changes accumulate with age, and some researchers suggest tracking changes as a way to calibrate a molecular clock to measure biological age, an estimate that takes into account biological wear and tear and may differ from chronological age.
This raised the possibility that epigenetic changes may contribute to the effects of aging. “We asked the question: If epigenetic changes are the engine of aging, can you reset the epigenome?” Said David Sinclair, a geneticist at Harvard Medical School in Boston, Massachusetts and co-author of Nature study. “Can you turn the clock?”
There were suggestions that the approach might work: in 2016, Belmonte and colleagues reported2 the effects of four gene expression in mice genetically engineered to age faster than normal. It was already known that the activation of these genes could cause cells to lose their identity in development – characteristics that make, for example, a skin cell look and behave like a skin cell – and return to a stem cell-like state. But instead of turning on the genes and leaving them that way, Belmonte’s team turned them on for just a few days, then turned them off again, hoping to return the cells to a “younger” state without erasing their identities.
The result is mice that age more slowly and have a pattern of epigenetic traits indicating younger animals. But the technique had drawbacks: previous work showed that if genes were present in additional copies or expressed for too long, some mice would develop tumors.
In Sinclair’s lab, geneticist Yuancheng Lu looked for a safer way to rejuvenate cells. He dropped one of the four genes used by Belmonte’s team – one linked to cancer – and crammed the other three genes into a virus that could transfer them to cells. It also includes a switch that will allow it to turn on genes by giving mice water added with a drug. Stopping the drug would turn off the genes again.
As mammals lose the ability to regenerate components of the central nervous system at the beginning of their development, Lou and his colleagues decided to try their approach there. They took the nerves of the retina of the eye. They first injected the virus into the eye to see if the expression of the three genes would allow the mice to regenerate damaged nerves – something that has not yet been proven to be a cure.
Lou remembers the first time he saw a nerve regenerating from injured eye cells. “It was like a jellyfish growing through the site of an injury,” he said. It was breathtaking.
The team continued to show that its system improves visual acuity in mice with age-related vision loss or increased pressure in the eye, a hallmark of glaucoma. The approach also restores epigenetic patterns to a younger state in mice and human cells grown in the laboratory.
It is not yet clear how the cells retain memory of a younger epigenetic condition, Sinclair said, but he and his colleagues are trying to understand.
Jump to the clinic
Harvard, meanwhile, licensed the technology to Boston-based Life Biosciences, which Sinclair said was conducting preclinical safety assessments to develop it for human use. This would be an innovative approach to treating vision loss, says Botond Rosca, director of the Institute of Molecular and Clinical Ophthalmology in Basel, Switzerland, but it will likely need significant improvement before it can be used safely in humans, he added. .
The history of aging research is full of unfulfilled promises of potential sources of youth that have failed to make a leap to people. More than a decade ago, Sinclair sparked a stir, suggesting that compounds, including those found in red wine, that activate proteins called sirtuins could increase longevity. Although he and others continue to study the links between sirtuins and aging that were originally observed in yeast, the idea of using such compounds to prolong human life has not yet been confirmed and has become controversial.
Ultimately, the test will be when other laboratories try to replicate the reprogramming work and test the approach in other organs affected by aging, such as the heart, lungs and kidneys, said Judith Campisi, a cell biologist at the Buck Aging Research Institute in New, California.
These data should appear quickly, she predicted. “There are a lot of labs right now working on this whole reprogramming concept,” says Campisi. “We have to hope, but like everything else, it has to be repeated and extended.”