Turning Back the Biological Clock on Aged and Injured Eye Cells

Reviewed by: Preeti Subramanian, PhD, BrightFocus Foundation

Age-related macular degeneration (AMD) causes deterioration of the sheet of cells behind the retina. These retinal pigment epithelial (RPE) cells change as they age, making them more prone to losing their ability to function. But what if we could turn back the clock and return these dysfunctional retinal cells to a youthful, healthy state? 

This is what BrightFocus Macular Degeneration Research grant recipient Dr. Shintaro Shirahama, MD, PhD, hopes to achieve. Dr. Shirahama is an ophthalmologist who specializes in retinal diseases and researcher at the Schepens Eye Research Institute of Massachusetts Eye and Ear, Harvard Medical School. His lab is working on a non-invasive method of restoring a supply of healthy retinal pigment epithelial cells in early AMD—a strategy that could stop the disease from progressing, and possibly even restore vision. 

What Happens to RPE Cells in AMD  

“Healthy retinal pigment epithelial cells play a critical role in maintaining vision," Dr. Shirahama explained. In particular, these cells keep light-sensing photoreceptor cells functioning smoothly. However, as AMD develops, they begin to malfunction or die. 

“In the early stage, waste products and lipids (fats) accumulate behind the eye, forming clumps called drusen,” Dr. Shirahama noted. The build-up of drusen impairs the retinal cell’s ability to carry out their normal functions, which include transporting nutrients, removing waste, and recycling photoreceptors. 

Drusen are a key feature of dry AMD, which is the most common form of the disease. Current treatments can only slow a type of damage that occurs in intermediate or an advanced stage of dry AMD. They don’t restore vision.   

Rewinding the Biological Clock in Eye Cells 

Dr. Shirahama and his colleagues are working on a way to give aged and damaged retinal pigment epithelial cells a new lease on life. 

In an earlier study, the team tested a method of reversing age in a different type of eye cell. The technique restored function to injured and aged cells, which play a central role in glaucoma. 

Dr. Shirahama now plans to apply the method to retinal pigment epithelial cells. Rewinding the biological age of these cells might stop the disease from progressing. This would prevent the worsening damage that leads to the loss of central vision. Central vision is what allows us to read and recognize faces. Currently, AMD is a leading cause of vision loss worldwide. 

In this new project, Dr. Shirahama’s lab will try to turn back the biological age of retinal pigment epithelial cells, he explained. To do so, they will introduce proteins called reprogramming factors into injured and damaged RPE cells. This de-aging cocktail is made up of three proteins known as OSK (Oct4, Sox2 and Klf4). 

The cocktail acts on the epigenome, a set of chemical tags or markers that sit on top of a cell’s DNA. These tags act like a cell's operating system, and their pattern changes as a person ages. 

One of these changes involves a family of markers called methyl groups. With age, specific regions of DNA collect extra methyl groups, which can corrupt the cells' epigenetic program. Segments of DNA called genes make proteins that cells need to function normally, and a garbled epigenetic program can interfere with this process. 

Building on an Earlier Success  

In their previous study, Dr. Shirahama's group found that the de-aging cocktail activated specific enzymes. These enzymes stripped away the age-related accumulation of methyl groups and restored the epigenome to a youthful pattern in another retinal cell. 

Called epigenetic reprogramming, this process leads to restoring cell function, Dr. Shirahama explained. Introducing the de-aging cocktail into aged/injured cells restored visual function as well. "Based on these results, we hypothesize that we can restore retinal pigment epithelial cell function in people with AMD," Dr. Shirahama said. 

This could have important advantages over current approaches to replacing damaged retinal cells. During cell transplantation, for example, new lab-grown cells are surgically placed behind the retina. “Retinal pigment epithelial cell transplantation mainly targets the advanced stages of AMD, when almost all of these cells have died," Dr. Shirahama said. By contrast, his team’s novel approach focuses on early to intermediate AMD—stages where the retinal cells are dysfunctional but not dead. In addition, the epigenetic reprogramming technique does not require surgery.  

Dr. Shirahama believes the research could lead to a new way of treating AMD. De-aging retinal cells could prevent early to intermediate AMD from progressing—and could even improve vision for people with AMD. 

That would offer new hope in a disease that can have life-altering consequences. Witnessing the devastating impact of AMD is what led Dr. Shirahama to pursue research. In his clinical practice, he cares for people with retinal diseases. “I have seen many patients who have no curative treatments,” he said.  

Without the BrightFocus research grant, Dr. Shirahama's upcoming study might not be possible. This funding "allows me to pursue an academic career where I can work on solving critical scientific questions,” Dr. Shirahama said. “I envision working on my current research as a foundation for developing new treatments for retinal diseases.” 

About BrightFocus Foundation

BrightFocus Foundation is a premier global nonprofit funder of research to defeat Alzheimer’s, macular degeneration, and glaucoma. Through its flagship research programs — Alzheimer’s Disease Research, Macular Degeneration Research, and National Glaucoma Research— the Foundation has awarded nearly $300 million in groundbreaking research funding over the past 51 years and shares the latest research findings, expert information, and resources to empower the millions impacted by these devastating diseases. Learn more at brightfocus.org.

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