Through a series of experiments supported by the National Institutes of Health, researchers at Johns Hopkins Medicine have advanced understanding of how smoking damages the eye and contributes to the development of age-related macular degeneration (AMD), the leading global cause of vision loss and blindness among people aged 50 and older. While it has long been recognised that smokers are about four times more likely to develop AMD than non-smokers, the biological pathways underlying this increased risk have remained unclear, limiting efforts to understand how smoking influences disease onset and progression fully.
In findings published on 16 January 2026 in the Proceedings of the National Academy of Sciences (PNAS), the research team investigated how retinal pigmented epithelial (RPE) cells respond to cigarette smoke exposure. These cells play a critical role in protecting and maintaining photoreceptors necessary for vision. The scientists compared changes in RPE cells from young (3-month-old) and older (12-month-old) mice—roughly corresponding to early adulthood and late middle age in humans—following both acute exposure to cigarette smoke condensate and prolonged daily exposure over four months.
According to James T. Handa, senior investigator and chief of the retina division at the Wilmer Eye Institute, smoking has traditionally been linked to ageing through the release of tissue-damaging free radicals. However, this study demonstrates that smoking also induces epigenetic alterations—changes in gene expression that do not involve modifications to the DNA sequence itself. These epigenetic shifts affect how RPE cells function and respond to environmental stress, potentially undermining the eye’s ability to maintain normal physiological processes over time.
To uncover these mechanisms, the researchers used advanced genomic tools, including single-nucleus ATAC sequencing and RNA sequencing, to analyse RPE cells at multiple time points after smoke exposure. These methods allowed the team to identify dysfunctional cell populations and examine changes in chromatin accessibility—the degree to which genetic material is available for activation. Reduced chromatin accessibility was associated with diminished cellular adaptability, indicating that affected cells may struggle to function properly or survive under stress conditions.
Across both young and older mice, acute smoke exposure led to the formation of dysfunctional RPE cell clusters characterised by reduced expression of genes essential for normal cell function, decreased chromatin accessibility, and lower activity of genes associated with key “hallmarks of ageing,” such as genomic stability, telomere maintenance, and mitochondrial health. These changes closely resembled patterns observed in human AMD, suggesting that cigarette smoke can rapidly induce disease-like cellular dysfunction. Notably, the researchers observed that in young mice, certain ageing-related genes—linked to mitochondrial function, protein stability, cellular recycling, inflammation, and metabolism—were activated in response to smoke exposure. In contrast, this protective response was absent in older mice.
Further experiments showed that activation of these genes helped protect younger cells from death, while older cells without this response were more vulnerable. Additional analyses of human donor RPE cells identified nearly 1,700 genes with altered expression shared between mouse and human dysfunctional cells, highlighting common pathways that may drive AMD development. The findings suggest that environmental stressors such as smoking can disrupt the eye’s genetic regulatory systems, impairing its ability to remain healthy. Looking ahead, the researchers aim to determine which of these changes are reversible and how ageing and prolonged smoke exposure together contribute to more severe eye damage and complications associated with advanced AMD.
More information: Krishna Kumar Singh et al, Molecular underpinnings of induced degenerative heterogeneity in the retinal pigment epithelium, Proceedings of the National Academy of Sciences. DOI: 10.1073/pnas.2505412123
Journal information: Proceedings of the National Academy of Sciences Provided by Johns Hopkins Medicine
