Three Blind Mice: Could reversal of cellular degeneration promise a cure for ageing?

By Lyle Horne

American scientists have cured mice suffering from blindness in a landmark study that could someday promise a cure for ageing. The work, published in Nature, suggests that by reprogramming some cells to a ‘younger’ state, it is possible to repair or replace damaged tissue, effectively overhauling the ageing process. Juan Belmonte, a developmental biologist at the Salk Institute for Biological Studies, described the study as “a major landmark“. “These results clearly show that tissue regeneration in mammals can be enhanced.” But researchers have been quick to warn that the work is still in the early stages and has been carried out only in mice. It remains to be seen whether the approach will translate to people or other tissues and organs damaged by time.

Ageing affects the body in myriad ways, adding, removing or altering chemicals known as methyl groups that attach to DNA. These ‘epigenetic‘ changes accumulate, and researchers can determine a cell’s ‘biological age’ by monitoring them, which can sometimes differ from its actual chronological age. This has raised evidence towards the possibility that epigenetic changes contribute to the effects of ageing. One of the study authors David Sinclair, a geneticist at Harvard Medical School in Boston, claimed that it might be possible to “reverse the clock” by leveraging this knowledge.

There were already suggestions that the approach could work. In 2016, a different study reported the effects of expressing four specific genes in mice that were already genetically engineered to age more rapidly than normal. We already suspected that activating these genes could cause cells to lose their developing identity. This was corroborated by the study when the features that made a skin cell behave like a skin cell were activated and were in fact reverted to a stem-cell-like state. But rather than activating the genes and leaving them that way, the team turned activated them for only a few days and then stopped, hoping to revert 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 weaknesses: previous work had shown that if the genes are expressed for too long, some mice will develop tumours.

In the more recent study, geneticists looked for a safer way to rejuvenate cells. They dropped one of the four genes used by the 2016 team — one associated with cancer — and packed the remaining three genes into a virus that could vector them into cells. They also included a genetic switch that would allow them to activate the genes 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 the central nervous system’s components early in development, they decided to test their approach there. They picked the eye’s retinal nerves. First, injecting the virus into the eye to see if the expression of the three genes would allow mice to regenerate injured nerves — something that no treatment had yet been shown to do.

One team member 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 breath-taking.” 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.

David Sinclair has licensed the technology to Boston company Life Biosciences, which are carrying out preclinical safety assessments 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. But will probably need considerable refinement before being deployed safely in humans.

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, the notion that such compounds can lengthen the human lifespan was not borne out by further research. The claim attracted significant controversy and has somewhat overshadowed Sinclair’s latest work.

Ultimately, the test will be when other labs try to reproduce the reprogramming work and push the approach in other organs affected by ageing, such as the heart, lungs and kidneys. If these studies show the same promise, we could be onto something. Although it might seem like science fiction, the possibility of life extension is not incredibly far-fetched. As demonstrated above, the mechanisms of ageing and death are well understood. And according to many scientists, it is only a matter of time.     

The views expressed in this article are the author’s own, and may not reflect the opinions of the St Andrews Economist.

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