Reversing the biological clock restores vision in older mice

Researchers restored vision in old mice and mice with damaged retinal nerves by restoring some of the thousands of chemical markings that build up 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 where they are better able to repair or replace damaged tissue.

“It’s an important 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 improved.”

But the researchers also caution that the work so far has only been done on mice, and whether the approach will result in people or other time-ravaged tissues and organs remains to be seen.

Visionary approach

Aging affects the body in a myriad of ways, including the addition, removal or alteration of 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 to calibrate a molecular clock to measure biological age, an assessment that takes into account biological wear and can differ from the chronological age.

This raised the possibility that epigenetic changes contribute to the effects of aging. “We started with a question: If epigenetic changes are an aging factor, can you reset the epigenome?” says David Sinclair, a geneticist at Harvard Medical School in Boston, Massachusetts, and co-author of Nature she studies. “Can you reverse the clock?”

There have been suggestions that the approach might work: In 2016, Belmonte and his colleagues reported² the effects of the expression of four genes in genetically modified mice to age faster than normal. It was already known that activating these genes could cause cells to lose their developmental identity – the characteristics that, for example, make a skin cell look and behave like a skin cell – and return to a similar state to a stem cell. But instead of turning the genes on and leaving them like that, Belmonte’s team only turned them on for a few days, then turned them off again, hoping to restore the cells to a “younger” state without erasing their identity.

The result was mice that age more slowly and have a pattern of epigenetic markings indicative of younger animals. But the technique had drawbacks: Previous work had shown that if genes are present in extra copies or expressed for too long, some mice will develop tumors.

Genetic switch

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 associated with cancer – and crammed the remaining three genes into a virus that could transfer them into cells. He also included a switch that would allow him to activate genes by giving the mice water supplemented with a drug. Stopping the drug would turn off the genes again.

As mammals lose the ability to regenerate central nervous system components early in development, Lu and his colleagues decided to test their approach there. They selected the retinal nerves 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, which no treatment had yet been shown to do.

Lu remembers the first time he saw a nerve regenerate from damaged eye cells. “It was like a jellyfish growing through the wound 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 increased pressure within the eye, a hallmark of glaucoma disease. The approach also restored epigenetic patterns to a younger state in mice and human cells grown in the laboratory.

It’s still unclear how cells retain a memory of a more youthful epigenetic state, Sinclair says, but he and his colleagues are trying to find out.

Jump to the clinic

Meanwhile, Harvard has licensed the technology to Boston-based Life Biosciences, which Sinclair says is conducting preclinical safety assessments in order to develop 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 it will likely need considerable refinement before it can be safely deployed in humans, he adds. .

The history of aging research is littered with unfulfilled promises of potential fountains of youth that have 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 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 can be used to extend human lifespan has not yet been confirmed and has become controversial.

Ultimately, the test will be when other labs try to reproduce the reprogramming work and attempt the approach in other organs affected by aging, such as the heart, lungs and kidneys, says Judith Campisi, a cell biologist at the Buck Institute for Research on Aging. in Novato, California.

That data should emerge quickly, he predicts. “There are a lot of labs now that are working on this whole reprogramming concept,” Campisi says. “We should be confident but, like everything else, it needs to be repeated and it needs to be extended.”