Aging has implications for a wide range of diseases. Researchers have searched for ways to stop the aging process for millennia, but those methods remain elusive. Scientists at Harvard Medical School have now offered a glimmer of hope that the eye’s aging clock may be reversed, at least in animals.
By reprogramming the expression of three genes, the Harvard team succeeded in triggering mature nerve cells in the eyes of mice to assume a youthful state. The method reversed glaucoma in mice and reversed age-related vision loss in aged mice, according to results published in Nature.
If further studies prove the concept, they could pave the way for therapies that use the same approach to repair damage in other organs and possibly treat age-related diseases in humans, the Institute said. team.
The researchers focused on the “Yamanaka factors”, which are four transcription factors: Oct4, Sox2, Klf4 and c-Myc. In a Nobel Prize-winning discovery, Shinya Yamanaka found that factors can alter the epigenome – the way genes are turned on or off – and thus can transform mature cells into a stem cell-like state. It has been hypothesized that changes in the epigenome lead to cellular aging, in particular a process called DNA methylation, by which methyl groups are labeled on DNA.
Previous research has attempted to use the four Yamanaka factors to turn the clock back on aging in living animals, but this caused cells to take on unwanted new identities and induced tumor growth.
In their study, the Harvard researchers dropped the c-Myc gene in hopes of circumventing safety concerns while promoting a youthful profile in mouse cells.
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To test whether the approach works in live animals, the scientists used an adeno-associated virus to deliver the three genes into the retinas of mice with optic nerve damage. The treatment led to a two-fold increase in the number of retinal ganglion cells, which are neurons responsible for receiving and transmitting visual information. Further analysis showed that the injury accelerated DNA methylation age, while the gene cocktail counteracted this effect.
Next, the scientists tested whether gene therapy could also work in pathological contexts. In a mouse model of induced glaucoma, which is a leading cause of age-related blindness in humans, treatment increased the animals’ electrical activity of nerve cells and visual acuity.
But can therapy also restore vision loss caused by natural aging? In 12-month-old mice, gene therapy also restored ganglion cell electrical activity as well as visual acuity, the team reported.
By comparing cells from treated mice with retinal ganglion cells from young, 5-month-old mice, the researchers found that the mRNA levels of 464 genes were changed during aging and that gene therapy reversed 90% of these. changes. Scientists have also noticed reverse patterns of DNA methylation, suggesting that DNA methylation is not just the marker but rather the driver of aging.
“What this tells us is that the clock doesn’t just represent time, it is time. If you turn the hands of the clock up, time also goes backwards,” lead study author David Sinclair said in a statement.
The study marks the first time that glaucoma-induced vision loss has been reversed – not just slowed – in live animals, the team said.
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Other researchers are also investigating regenerative approaches to treating eye disease. A research group from the Center for Genomic Regulation in Barcelona has just shown that by modifying mesenchymal stem cells to express the chemokine receptors Ccr5 and Cxcr6, the retinal tissue could be saved from degeneration.
The idea of reversing age-related decline in humans through epigenetic reprogramming with gene therapy is exciting, Sinclair said. The Harvard researchers plan to do more animal work that could allow them to begin clinical trials in people with glaucoma in about two years.
“Our study demonstrates that it is possible to safely reverse the age of complex tissues such as the retina and restore its youthful biological function,” Sinclair said. “If confirmed by further studies, these findings could be transformative for the care of age-related vision diseases like glaucoma and for the fields of biology and medical therapeutics for disease in general. “
