Beyond free radicals – how cigarette smoke accelerates eye aging

Researchers at Johns Hopkins Medicine say they have advanced understanding of how smoking damages the eye and contributes to the development of age-related macular degeneration (AMD).

While it is clear that people who smoke are more likely to develop AMD than non-smokers, smoking’s role in eye disease development remained unclear, they said.

In a report published in the Proceedings of the National Academy of Sciences, the researchers compared how retinal pigmented epithelial cells changed in three-month-old and 12-month-old mice after acute and chronic cigarette smoke exposure (these ages correspond to young adulthood and late middle age in humans).

"Smoking is often assumed to accelerate aging by releasing tissue-damaging molecules called free radicals," said Professor James Handa, principal investigator and head of the retina division at the Wilmer Eye Institute at Johns Hopkins. This study showed that smoking also causes epigenetic changes – non-permanent shifts in gene expression that are not caused by changes in a cell's DNA sequence – to retinal pigmented epithelial (RPE) cells that have widespread effects on the eye and its ability to respond to environmental stress, he said.

Using genetic sequencing techniques, the team studied RPE cells from mice three, six and 10 days after they were injected with cigarette smoke condensate, and those exposed to cigarette smoke daily for four months. Researchers were able to identify dysfunctional RPE cells and understand how chromatin accessibility changed post-exposure. Such changes, if found, would indicate drastic shifts in a cell's ability to adapt, function and survive, they said.

In both young and aged mice, acute exposure to injected condensate caused the formation of dysfunctional RPE clusters with decreased expression of core RPE cell function genes, decreased chromatin accessibility and decreased expression of "hallmarks of aging" genes, which prevent or regulate processes linked to aging. Such processes include genomic instability, shrinkage of the ends of chromosomes and disruption of cells' energy-producing mitochondria, among others, they explained.

Changes in chromatin arrangement caused by acute cigarette smoke stress limited the ability of young and aged mouse RPE cells to function, and replicated characteristics seen in humans with AMD, the researchers said.

Notably, they found that a separate, distinct subset of hallmarks of aging genes were expressed only in the dysfunctional cells of young mice treated with cigarette smoke condensate, but not their aged counterparts. Similar observations were made in young and aged mice that had been exposed to cigarette smoke daily for four months.

Conducting additional experiments with RPE cells donated by two people without AMD, who did not smoke, one person without AMD who smoked, and one person with early AMD, the researchers identified 1,698 genes that either increased or decreased in expression and were shared between dysfunctional human and mouse RPE cells.

Collectively, they suggested the shared hallmarks of aging genes may be relevant to AMD development and progression, said Prof Handa. "Knowing environmental stress can interfere with the eye's ability to produce the genes needed to stay healthy, we now want to narrow down which changes are temporary and which are permanent.”