Study Reveals: Smoking Rewrites the Eye's Genetic Playbook

Research from Johns Hopkins has unravelled why smokers are four times more likely to develop age-related macular degeneration and the findings point toward a new class of targeted therapies.

Researchers at the Wilmer Eye Institute, Johns Hopkins Medicine, have for the first time mapped the molecular mechanisms by which cigarette smoke accelerates ageing in the eye's protective cells, opening a significant new chapter in the understanding of age-related macular degeneration (AMD).

AMD remains the leading worldwide cause of visual impairment and blindness among people aged 50 and older, and it has long been established that smokers are four times more likely to develop the condition than non-smokers yet the precise biological pathway connecting the two has remained frustratingly unclear.

The study, published in the Proceedings of the National Academy of Sciences on 16 January 2026, provides that missing link, and its implications for how eyecare professionals counsel and screen at-risk patients are considerable.

Beyond Free Radicals: A New Mechanism of Damage

"Smoking is often assumed to accelerate aging by releasing tissue-damaging molecules called free radicals," said lead investigator Dr James T. Handa, chief of the retina division at the Wilmer Eye Institute. The new research demonstrates that this is only part of the story.

The study shows that smoking also causes epigenetic changes, non-permanent shifts in gene expression not caused by alterations in the cell's DNA sequence, to retinal pigmented epithelial (RPE) cells, with widespread effects on the eye and its capacity to respond to environmental stress.

RPE cells are the unsung workhorses of ocular health. They protect and maintain the light-sensing photoreceptors necessary for sight. When they are compromised, the photoreceptors they support are left exposed, setting the stage for the degeneration that characterises AMD.

How the Research Was Conducted

The researchers used single nuclear ATAC sequencing and single nuclear RNA-sequencing to study RPE cells from young and aged mice at three, six and ten days following cigarette smoke condensate injection, as well as from mice exposed to cigarette smoke daily over four months. These techniques allowed the team to identify dysfunctional RPE cells and assess how chromatin accessibility, the physical ability of a cell to switch repair genes on or off, changed after exposure.

In both young and aged mice, acute cigarette smoke condensate exposure caused the formation of dysfunctional RPE clusters featuring decreased expression of core RPE cell function genes, reduced chromatin accessibility, and decreased expression of "hallmarks of aging" genes, the genes responsible for preventing or regulating processes linked to ageing, including genomic instability, telomere shortening, and disruption of energy-producing mitochondria.

A Critical Age-Dependent Difference

Perhaps the most clinically significant finding concerns the divergent response between younger and older eyes. A distinct subset of hallmarks of aging genes was expressed only in the dysfunctional RPE cells of young smoke-exposed mice, but not in their aged counterparts, a pattern repeated in both acute and chronic exposure models.

"We saw the expression of aging genes linked to mitochondrial function, proteostasis, autophagy, inflammation and metabolism increased only in the young, dysfunctional RPE cells," said Dr Handa. Using cell-death labelling techniques, the team confirmed that this activation of ageing genes appeared to confer a protective effect: younger cells survived, while their aged counterparts, unable to mount the same genetic response, died.

In other words, older eyes appear to lose the very molecular toolkit they need to fight back against smoke-induced damage, which may help explain why AMD predominantly manifests later in life.

Crossover to Human Tissue

Critically, the findings were not confined to mouse models. Additional experiments using RPE cells donated by human subjects, including non-smokers without AMD, a smoker without AMD, and a patient with early AMD, identified 1,698 genes that either increased or decreased in expression and were shared between dysfunctional human and mouse RPE cells, collectively suggesting that the shared hallmarks of aging genes identified in the study are relevant to AMD development and progression in humans.

What It Means for Clinical Practice

For optometrists and ophthalmologists, the research reinforces the importance of smoking cessation counselling as a concrete, evidence-based component of AMD risk management, not merely a general health recommendation. The study provides a molecular rationale for why every additional year of smoking may be compounding risk in ways invisible to standard clinical assessment.

It also signals a forthcoming evolution in therapeutic options. Dr Handa's team is now working to characterise which epigenetic changes caused by cigarette smoke are temporary and which are permanent, with the aim of developing targeted "epigenetic therapies" capable of unlocking the repair genes that smoke exposure effectively locks away.

Future research will focus on understanding how age and continuous cigarette smoke exposure together contribute to the eye damage and comorbidities seen in patients with late-stage AMD.