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Researchers restore vision in old mice and mice with damaged retinal nerves by resetting some of the thousands of chemical markers that build up on DNA as cells age. Work, published on 2 December in Nature1, offers a new approach to reverse age-related decline. By reprogramming certain cells in a state «smaller» in which they are better able to repair or replace damaged tissue

“This is a key step”, says Juan Carlos Ispissoa Belmonte, evolutionary biologist at the Salk Institute for Biological Studies in La Jolla, in California, who did not participate in the study. “These results clearly show that it can promote tissue regeneration in mammals.”

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But the researchers also warn that the work has so far only been done on mice, and it remains to be seen whether this approach will result from humans or other tissues and organs that have been ruined by time.

Aging affects the body in many ways, among which the addition, removing or modifying chemical groups such as methyl on DNA. These changes «epigenetics» accumulate as a person ages, and some researchers have suggested tracking the changes as a way to calibrate a watch. Molecular to measure biological age, which is an assessment that takes into account biological erosion and may differ from chronological age

This increased the likelihood that epigenetic changes could contribute to the effects of aging. “We started with a question: if epigenetic changes are the engines of aging, can you reset the epigenome?” «Can you go back?», Says David Sinclair, geneticist at Harvard Medical School in Boston, Massachusetts, and co-author of the study of nature.

It has been suggested that this approach might work: in 2016, Belmonte and colleagues2 reported the effects of expressing four genes in mice genetically engineered to age faster than usual. Stimulation of these genes was previously known to lead to loss. Cells for their evolutionary identity – the traits that make, for example, a skin cell that looks and acts like a skin cell – and return to a state similar to a stem cell, but instead of activating genes and leaving them like that, the Belmonte team lit them for a few days, then turned them off again. I hope to bring the cells back to a state “smaller” without erasing their identity.

The result were mice that aged more slowly and had a pattern of epigenetic markers indicative of younger animals, but this technique has drawbacks: previous work has shown that if genes are present in extra copies or have been expressed for too long, Some mice will develop tumors.

In Sinclair's lab, geneticist Yuancheng Lu searched for a safer way to regenerate cells. He dropped one of the four genes used by Team Belmonte – one of the genes linked to cancer – and crammed the other three into a virus that could pass it into cells and also included a key that allows Must activate genes by giving mice water enriched with a drug that blocking the drug will turn off the genes again

Since mammals lose the ability to regenerate central nervous system components early in their evolution, Luo and his colleagues decided to test their approach there. They chose the retinal nerves. They first injected the virus into the eye to see if expressing the three genes would allow the mice to regenerate the affected nerves.. Something that hasn't yet been proven to work

Lu remembers the first time he saw a nerve regenerate from infected eye cells saying: «It was like a jellyfish growing from the wound site.» «It was amazing»

The team then showed that their system improved visual acuity in mice with age-related vision loss or increased intraocular pressure. – a feature of glaucoma. This approach also restores epigenetic patterns at a younger state in mice and in human cells that are cultured.. In the laboratory

It is still not clear how cells preserve the memory of a younger genetic disease, said Sinclair, but he and his colleagues try to figure it out.

Meanwhile, Harvard University has licensed Life Biosciences technology in Boston, who, said Sinclair, performs preclinical safety assessments with the aim of developing them for use in people, explains Boutund Ruska, Director of the Basel Institute of Molecular and Clinical Ophthalmology, in Swiss. It would be an innovative approach to treat vision loss, but it would likely require significant improvement before it could be safely deployed in humans, he adds.

The history of aging research is filled with broken promises of potential fountains of youth that failed to make the leap for humans for more than a decade, Sinclair caused a stir by suggesting that compounds – including that found in red wine – activate proteins called sirtuins. It may improve longevity Although he and others continue to study the links between sirtuin and aging that were initially seen in yeast, the idea that such compounds could be used to extend human life has not yet been proven and has become controversial

Ultimately, the test will take place when other laboratories attempt to reproduce the reprogramming work, by experimenting with the method in other organs affected by aging, such as the heart, lungs and kidneys, explains Judith Campisi, cell biologist at the Buck Institute for Aging Research in Novato, in California. p>

You expect this data to emerge quickly. “There are many labs now working on this whole reprogramming concept.”, said Campisi. “We should be optimistic but, like everything else, the command must be repeated and must be extended.”

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nature

ISSN 1476-4687 (online)

The cell, the research, aging, biology, the epigenetic clock

News – THAT – Reversing the body clock restores vision in elderly mice

Source: https://www.nature.com/articles/d41586-020-03403-0

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