Key Takeaways
- Smoke exposure speeds up aging and damage in a key group of cells that are the first casualties in early age-related macular degeneration.
- These damaged cells send out a unique set of messages that could enable specialists to detect the disease very early—long before it leads to vision loss.
- Young eyes can turn on a natural backup system to save these damaged cells, while older eyes cannot.
A new understanding of how smoking sharply raises the risk of age-related macular degeneration (AMD) is paving the way for new methods of preventing or halting the disease before it can cause vision loss.
Macular Degeneration Research grant recipient Krishna Singh, PhD, has made a series of key discoveries that could one day help detect the earliest signs of AMD, and then “turn off” the disease by reactivating a natural rescue system that stops working in later life.
Originally from India, Dr. Singh was drawn to a career in science by a powerful desire to prevent the kind of extended suffering his eldest brother endured before succumbing to cancer. Later, Dr. Singh switched his focus from infectious disease to vision research, driven by his father’s experience of slowly losing 90% of his eyesight to glaucoma.
After joining Johns Hopkins University’s Wilmer Eye Institute, Dr. Singh became interested in a part of the eye that is the first casualty in macular degeneration: the retinal pigment epithelium (RPE), where macular degeneration starts. A single layer of cells that sits underneath the retina, the RPE acts as the life support system for light-sensing cells that produce signals the brain translates into images.
Cigarette smoke and aging cause similar damage to RPE cells
In his previous work investigating how tuberculosis-causing bacteria can survive challenging conditions inside the body, Dr. Singh became an expert at decoding messages cells send out in response to stresses in their environment. These messaging pathways can either allow the cell to adapt and survive, or push it toward decline and death. Many factors, including aging and light, put stress on the RPE; however, “smoking is the strongest and best studied,” Dr. Singh said. So could studying how the RPE responds to cigarette smoke help us better how AMD first develops?
Findings by Dr. Singh’s team, published in 20261, strongly suggest the answer is yes.
“In our study, smoke made the retinal pigment epithelium (RPE) look a lot like the RPE of older mice,” Dr. Singh explained. “This suggests smoking and aging share some of the same paths to damage, so learning about one teaches us about the other.” What’s more, since smoke-induced changes mimic some of those that occur with age, “we could study in days or months what normally takes a lifetime,” Dr. Singh added.
In both cases, the pattern of damage was similarly patchy. “Abnormal-looking cells sit right next to cells that look healthy,” said Dr. Singh. This is called degenerative heterogeneity. The next phase of Dr. Singh’s research will look at whether the abnormal cells are simply more likely to wither and die, or whether they somehow trigger damage to their healthy neighbors.
Exploring the effects of smoking could potentially reveal the weak points in RPE cells’ defenses. “If we learn exactly how smoke pushes RPE cells over the edge, we learn which defenses fall first,” said Dr. Singh. “Those defenses are likely to matter for many people with AMD, not only for smokers.”
Survival of damaged RPE cells depends on age
And indeed, his team’s work revealed a key insight: RPE cells’ ability to save themselves following smoke exposure depended on age. “When young RPE cells were stressed by smoke, they turned on a back-up plan that helped them survive,” Dr. Singh explained. “Older cells had lost this backup plan.”
The research team also used cutting-edge techniques to look inside 100,000 individual cells, allowing them to see which genes each cell was using. It also revealed which parts of the DNA instruction book where the genes are stored were open and readable.
Smoke exposure changed the way DNA was ‘packaged,’ essentially glueing together pages containing crucial instructions for the operation of nearly 1,700 genes. (The same patterns showed up in eye tissue from human donors, too. “We found abnormal RPE cells in the [tissue] donor who smoked, and in the [tissue] donor with early AMD, but not in donors who did not smoke,” noted Dr. Singh. “We also found 1,698 genes that changed in both the abnormal mouse cells and the abnormal human cells.”)
Exposure to cigarette smoke “closed many of the pages in the damaged RPE cells so they could no longer read the instructions to do their own jobs,” Dr. Singh said. In the future, the unique signature of behavior displayed by ‘sick’ cells could be used to detect the earliest changes that lead to AMD.
But perhaps the most important aspect of the team’s discovery is that these changes don’t take place in the DNA itself, but rather in part of its ‘packaging’—a set of chemical tags or ‘bookmarks’ which decide which genes are switched on and off, collectively referred to as epigenetics.
Is it possible to reactivate RPE cells’ natural defense system?
“Unlike permanent changes in the DNA code, some epigenetic changes may be reversible,” said Dr. Singh. “This raises exciting possibilities. Could we restore damaged RPE cells’ normal gene activity and prevent them from degenerating? We also want to understand whether we can reactivate the natural protective mechanisms that young RPE cells use to survive oxidative stress.”
The next phase of Dr. Singh’s research will explore possible methods of doing just that. Other research has established that a protein called NRF2 is a sort of master switch for the cell’s defense system, and production of NRF2 is reduced in people with early AMD.
Dr. Singh’s new BrightFocus project takes this idea one step further. He and his team are investigating whether making small tweaks to NRF2 via a process called acetylation changes how effectively it protects RPE cells. “Acetylation involves adding small chemical groups to a protein, which can change how it functions,” he said. In preliminary experiments, the team has already shown that blocking an enzyme involved in acetylation strengthens NRF2’s protective response in RPE cells exposed to cigarette smoke.
“Ultimately, my research goal is to identify ways to preserve RPE cells’ normal functions,” Dr. Singh said. “If we can restore the natural defense mechanisms of aging retinal cells before they are permanently damaged, we may open a new path toward preventing and slowing vision loss in AMD.”
Both Dr. Singh’s upcoming project, and the work leading up to it, were made possible by support from BrightFocus Foundation’s Macular Degeneration Research program. A two-year 2024 Macular Degeneration Research Postdoctoral Fellowship was “instrumental in building my scientific independence and preparing me to establish my own research program,” said Dr. Singh. “I am deeply grateful to BrightFocus and its donors for believing in early-career scientists and supporting research that has the potential to make a meaningful difference in the lives of people affected by AMD.”
