Researchers have restored vision in old mice and in mice with damaged retinal nerves by resetting some of the thousands of chemical marks that accumulate on DNA as cells age. The work, published on 2 December in Nature1, suggests a new approach to reversing age-related decline, by reprogramming some cells to a ‘younger’ state in which they are better able to repair or replace damaged tissue.
“It is a major landmark,” says Juan Carlos Izpisua Belmonte, a developmental biologist at the Salk Institute for Biological Studies in La Jolla, California, who was not involved in the study. “These results clearly show that tissue regeneration in mammals can be enhanced.”
But researchers also caution that the work has so far has been carried out only in mice, and it remains to be seen whether the approach will translate to people, or to other tissues and organs that are ravaged by time.
Ageing affects the body in myriad ways — among them, adding, removing or altering chemical groups such as methyls on DNA. These ‘epigenetic’ changes accumulate as a person ages, and some researchers have proposed tracking the changes as a way of calibrating a molecular clock to measure biological age, an assessment that takes into account biological wear-and-tear and can differ from chronological age.
That has raised the possibility that epigenetic changes contribute to the effects of ageing. “We set out with a question: if epigenetic changes are a driver of ageing, can you reset the epigenome?” says David Sinclair, a geneticist at Harvard Medical School in Boston, Massachusetts, and a co-author of the Nature study. “Can you reverse the clock?”
There were suggestions that the approach could work: in 2016, Belmonte and his colleagues reported2 the effects of expressing four genes in mice genetically engineered to age more rapidly than normal. It was already known that triggering these genes could cause cells to lose their developmental identity — the features that make, for example, a skin cell look and behave like a skin cell — and revert to a stem-cell like state. But rather than turn the genes on and leave them that way, Belmonte’s team turned them on for only a few days, then switched them off again, in the hope of reverting cells to a ‘younger’ state without erasing their identity.
The result was mice that aged more slowly, and had a pattern of epigenetic marks indicative of younger animals. But the technique had disadvantages: previous work had shown that if the genes are present in extra copies or expressed for too long, some mice will develop tumours.
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 that is associated with cancer — and crammed the remaining three genes into a virus that could shuttle them into cells. He also included a switch that would allow him to turn the genes on by giving mice water spiked with a drug. Withholding the drug would switch the genes back off again.
Because mammals lose the ability to regenerate components of the central nervous system early in development, Lu and his colleagues decided to test their approach there. They picked the eye’s retinal nerves. They first injected the virus into the eye to see if expression of the three genes would allow mice to regenerate injured nerves — something that no treatment had yet been shown to do.
Lu remembers the first time that he saw a nerve regenerating from injured eye cells. “It was like a jellyfish growing out through the injury site,” he says. “It was breathtaking.”
The team went on to show that its system improved visual acuity in mice with age-related vision loss, or with increased pressure inside the eye — a hallmark of the disease glaucoma. The approach also reset epigenetic patterns to a more youthful state in mice and in human cells grown in the laboratory.
It is still unclear how cells preserve a memory of a more youthful epigenetic state, says Sinclair, but he and his colleagues are trying to find out.
Leap to the clinic
In the meantime, Harvard has licensed the technology to Boston company Life Biosciences, which, Sinclair says, is carrying out preclinical safety assessments with a view to developing it for use in people. It would be an innovative approach to treating vision loss, says Botond Roska, director of the Institute of Molecular and Clinical Ophthalmology in Basel, Switzerland, but will probably need considerable refinement before it can be deployed safely in humans, he adds.
The history of ageing research is littered with unfulfilled promises of potential fountains of youth that failed to make the leap to humans. More than a decade ago, Sinclair caused a stir by suggesting that compounds — including one found in red wine — that activate proteins called sirtuins could boost longevity. Although he and others continue to study the links between sirtuins and ageing that were originally observed in yeast, the notion that such compounds can be used to lengthen human lifespan has not yet been borne out, and has become controversial.
Ultimately, the test will be when other labs try to reproduce the reprogramming work, and try the approach in other organs affected by ageing, such as the heart, lungs and kidneys, says Judith Campisi, a cell biologist at the Buck Institute for Research on Aging in Novato, California.
Those data should emerge swiftly, she predicts. “There are many labs now who are working on this whole concept of reprogramming,” says Campisi. “We should be hopeful but, like everything else, it needs to be repeated and it needs to be extended.”
Nature 588, 209 (2020)
Read the related News & Views, ‘Sight restored by turning back the epigenetic clock’.
Lu, Y. et al. Nature 588, 124–129 (2020).
Ocampo, A. et al. Cell 167, 1719–1733 (2016).