Reverse vision loss by restoring epigenetic information from youth

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Aging is a fact of life that cannot be avoided. From the moment we are born, every part of us begins to age, and slowly over time the cells and tissues in our body gradually decline in their ability to repair and restore themselves. Our eyes are even more affected by this event, especially nowadays, as our daily routines include more screen time and less sleep.

But what if the aging process could be stopped or, better yet, reversed? In a new study from Harvard Medical School (HMS), researchers are doing just that. Using a mouse model, they were able to reverse age-related vision loss, in addition to ocular nerve damage caused by widespread eye disease. Their revolutionary results were obtained by reprogramming cells to their youthful epigenetic state.

The study, published in Nature, is a first-of-its-kind achievement in restoring glaucoma-induced vision loss in mice, a disease for which there has been no cure in humans. The prospect is that if this work can be replicated in other studies, it will undoubtedly change the way eye disease and other age-related disorders and nerve damage are treated in the future.

The research team included renowned aging expert David Sinclair, professor of genetics at the Blavatnik Institute and co-director of the Paul F. Glenn Center for Aging Research at HMS, and Yuancheng Lu, genetics researcher at HMS and former Ph . D. student at the Sinclair lab. Zhigang He, HMS Professor of Neurology and Ophthalmology at Boston Children’s Hospital, as well as Bruce Ksander, Associate Professor of Ophthalmology at HMS, and Meredith Gregory-Ksander, Assistant Professor of Ophthalmology at HMS, both from Schepens Eye Research Institute from Massachusetts. Eye and ear.

Glaucoma, one of the leading causes of blindness worldwide, is a neurodegenerative disease of the eye that becomes more common with age. His damage was considered permanent. However, more recent studies have shown that epigenetic factors may play a role in the onset and progression of glaucoma and other eye diseases. In previous articles we have discussed the role of DNA methylation in age-related macular degeneration and how DNA hydroxymethylation affects retinal development.

This latest study now confirms what scientists have been arguing from the start, that aging is directly correlated with epigenetic changes that disrupt the activity of certain genes. Throughout our life, our cells accumulate certain regulators that attach themselves to our DNA and modify gene expression levels. These changes can be caused by a number of environmental influences such as smoking, air pollution, diet, etc. As they accumulate, our bodies weaken and we become more vulnerable to injury and disease.

Epigenetic changes occur above the DNA sequence and do not alter the underlying genetic code; therefore, they are reversible, unlike genetic modifications. Since the effects of aging are epigenetic in origin, the Harvard team set out to determine whether they could reset the epigenome to its former, healthier state.

Although changes in DNA methylation patterns are used to determine the basis of aging clocks, it is not known whether older people retain the information needed to restore these patterns or whether or not it might improve tissue function. The central nervous system, for its part, fails in its capacity for regeneration and loses its function over time.

The team used a method based on the work of Nobelist, Shinya yamanaka who discovered how to create induced pluripotent stem cells by activating four transcription factors, Oct4, Sox2, Klf4 and c-Myc, (known as Yamanaka factors) to clear epigenetic markers on cells. This process causes cells to return to their embryonic state – a point where they can develop into any type of cell. However, previous animal studies have shown that they can also induce tumor growth and completely erase a cell’s identity. To prevent this from happening, lead author Lu modified the method to not include the c-Myc gene, as it associates with many types of cancer at high expression levels.

To determine if the altered gene combination was found to be regenerative, the researchers targeted the central nervous system because it ages faster than any other part of the body. They delivered the restored Oct4, Sox2 and Klf4 genes, normally active in embryos, to the retinas of adult mice with optic nerve damage via an adeno-associated virus (AAV) or a gene therapy vector that does not integrate to the genome.

The treatment was successful on several levels. Not only did it promote nerve regeneration after injury, it also reversed vision loss in mice with glaucoma and reverse vision loss in aging mice without eye disease.

David Sinclair said, “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.

Ksander added: “Recovery of visual function after injury has rarely been demonstrated by scientists. This new approach, which successfully reverses several causes of vision loss in mice without the need for a retinal transplant, represents a new treatment modality in regenerative medicine.

It’s important to note that the research team advises that their results be replicated in other studies first, including different animal models, before beginning any human testing. Nevertheless, the results are promising, confirming their hypothesis of epigenetic involvement in aging and to identify a pathway that could lead to advanced treatment methods for glaucoma as well as various other age-related human diseases.

“What this tells us is that the clock doesn’t just represent time, it’s time,” Sinclair said. “If you wind up the hands of the clock, time also goes back. “

According to these scientists, once their results are confirmed in other studies, the team could launch clinical trials within two years. The results so far have been encouraging. Even 12 months after treatment with the combination of three genes, there were no unwanted side effects in the mice.

Source: Yuancheng Lu et al. Reprogramming to recover youthful epigenetic information and restore vision. Nature 588, 124-129 (2020).

Reference: R Jaslow. Vision review: Scientists reverse age-related vision loss and glaucoma damage in mice. Harvard Medical School. December 2, 2020.

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