Reversing Vision Loss by Restoring Youthful Epigenetic Information

Aging is a fact of life that cannot be avoided. From the moment we are born, every part of us starts to age, and slowly over time, the cells and tissues in our bodies progressively decline in their ability to repair and restore themselves. Our eyes get hit even harder by this occurrence, 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 out of Harvard Medical School (HMS), researchers are doing just that. Using a mouse model, they have successfully reversed age-related vision loss, in addition to ocular nerve damage caused by a prevalent eye disease. Their groundbreaking results were achieved by reprogramming cells back to their youthful epigenetic state.

The study, which was published in Nature, is a first of its kind achievement for the restoration of glaucoma-induced vision loss in mice, a condition which there has been no cure for in humans. The prospect is, if this work can be replicated in further studies, it would undoubtedly change the way eye disease and other age-related and nerve damage disorders will be 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 Biology of Aging Research at HMS, and Yuancheng Lu, a genetics research fellow at HMS and former Ph.D. student in the Sinclair lab. Also contributing were Zhigang He, HMS professor of neurology and ophthalmology at Boston Children’s Hospital, as well as Bruce Ksander, HMS associate professor of ophthalmology, and Meredith Gregory-Ksander, HMS assistant professor of ophthalmology, both of the Schepens Eye Research Institute of Massachusetts Eye and Ear.

Glaucoma, a leading cause of blindness worldwide, is a neurodegenerative disease of the eye that becomes more prevalent with age. Its damage has been considered permanent. However, newer studies have found 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 also how DNA hydroxymethylation affects retinal development.

This latest study now confirms what scientists have been arguing all along — that aging is directly correlated to epigenetic changes that upset the activity of certain genes. Throughout our lives, our cells accumulate certain regulators that attach to our DNA and modify gene expression levels. These changes can be caused by any number of environmental influences such as smoking, air pollution, diet, etc. As they accumulate, our bodies weaken, and we become more susceptible to injuries and illnesses.

Epigenetic modifications occur above the DNA sequence and do not alter the underlying genetic code; therefore, they are reversible, unlike genetic modifications. Because the effects of aging are epigenetically driven, the Harvard team set out to determine if they could reset the epigenome back to its former healthier state.

While changes to DNA methylation patterns are used to determine the basis for aging clocks, it is unknown if older people retain the information required to restore these patterns or whether or not it could improve tissue function. The central nervous system, for one, fails in its regenerative capability and loses function over time.

The team used a method built upon 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 the Yamanaka factors) to erase epigenetic markers on cells. This process causes cells to revert back to their embryonic state – a point where they can develop into any kind of cell. However, prior animal studies have found 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 not to include the c-Myc gene, as it associates with many types of cancers at high expression levels.

To determine if the modified gene combination proved to be regenerative, the researchers targeted the central nervous system because it ages more rapidly 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 gene therapy vector that does not integrate with the genome.

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

David Sinclair stated, “Our study demonstrates that it’s possible to safely reverse the age of complex tissues such as the retina and restore its youthful biological function.”

Ksander added, “Regaining visual function after the injury occurred has rarely been demonstrated by scientists. This new approach, which successfully reverses multiple 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 findings should be replicated in other studies first, including different animal models, before beginning any human testing. Even so, the results are promising, confirming their hypothesis for epigenetics involvement in aging and for identifying 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 the clock doesn’t just represent time—it is time,” Sinclair stated. “If you wind the hands of the clock back, time also goes backward.”

According to these scientists, once their findings are confirmed in other studies, the team could initiate clinical trials within two years. Thus far, the results have been encouraging. Even 12-months after treatment with the three gene combination, there have been no adverse 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 Revision: Scientists reverse age-related vision loss, glaucoma damage in mice. Harvard Medical School. December 2, 2020.

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