Summary: It has long been known that smokers are four times more likely to develop age-related macular degeneration (AMD), but the biological “why” has remained elusive. A new study reveals that cigarette smoke does more than just release damaging free radicals; it causes profound epigenetic changes in the eye’s protective cells.
By analyzing retinal pigmented epithelial (RPE) cells, researchers found that smoke exposure physically alters chromatin structure, effectively “locking away” the genes needed for cellular repair. While younger eyes can temporarily activate protective “aging hallmark” genes to survive the stress, older eyes lose this ability, leading to rapid cell death and vision loss.
Key Facts
- Epigenetic Sabotage: Smoke exposure causes non-permanent shifts in gene expression by altering chromatin accessibility—the physical ability of a cell to turn repair genes on or off.
- Loss of the “Safety Net”: Young RPE cells can activate a specific subset of “hallmarks of aging” genes to survive smoke stress; aged cells fail to trigger this protection and die.
- RPE Dysfunction: Retinal pigmented epithelial (RPE) cells are the “guardians” of light-sensing photoreceptors. When smoke damages them, the eye loses its ability to maintain sight.
- Mitochondrial Collapse: Smoke-induced changes specifically target genes linked to mitochondrial function, cellular self-cleanup (autophagy), and protein stability (proteostasis).
- Human-Mouse Link: Researchers identified 1,698 shared gene expression changes between mice and human donors, confirming that these epigenetic shifts are central to human AMD development.
Source: JHM
Through a series of experiments supported by the National Institutes of Health, Johns Hopkins Medicine (JHM) researchers say they have advanced understanding of how smoking damages the eye and contributes to the development of age-related macular degeneration (AMD), the leading worldwide cause of visual impairment and blindness among people 50 and older.
It has long been known that people who smoke are four times more likely to develop age-related macular degeneration than non-smokers, but smoking’s role in eye disease development and progression has remained unclear.
In a report published in the Proceedings of the National Academy of Sciences (PNAS) on Jan. 16, 2026, JHM researchers describe how they compared how retinal pigmented epithelial (RPE) cells — which protect and maintain light-sensing photoreceptors necessary for sight — changed in 3-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,” says James T. Handa, M.D., principal investigator and chief of the retina division of the Wilmer Eye Institute. The new study, Handa says, shows smoking also causes epigenetic changes (non-permanent shifts in gene expression that are not caused by changes in a cell’s DNA sequence) to RPE cells that have widespread effects on the eye and its ability to respond to environmental stress.
The researchers identified these so-called “epigenetic” changes by using single nuclear ATAC sequencing (snATAC-seq) and single nuclear RNA-sequencing (snRNA-seq) to study RPE cells from young and aged mice three, six and 10 days post-cigarette smoke condensate (CSC) injection, and those exposed to cigarette smoke daily for four months.
Together, these genetic sequencing techniques helped the team identify dysfunctional RPE cells and understand how chromatin accessibility — the ability to physically access chromatin, a condensed structure of DNA, RNA, and proteins that control which genes are turned on or off — changed post-exposure. Such changes, if found, would indicate drastic shifts in a cell’s ability to adapt, function, and survive.
In both young and aged mice, acute exposure to injected cigarette smoke condensate (CSC) 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 – genes that prevent or regulate processes linked to aging. Such processes include genomic instability, shortened telomeres (shrinkage of the ends of chromosomes) and disruption of cells’ energy-producing mitochondria, among others.
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 age-related macular degeneration, the researchers say.
Notably, the researchers say, they found that a separate, distinct subset of hallmarks of aging genes were expressed only in the dysfunctional cells of young CSC-treated mice, but not their aged CSC-treated counterparts. Similar observations were made in young and aged mice that had been exposed to cigarette smoke daily for four months.
“We saw the expression of aging genes linked to mitochondrial function, proteostasis [protein stability], autophagy [cellular self-cleanup], inflammation and metabolism increased only in the young, dysfunctional CSC-treated RPE cells,” says Handa.
Using a molecular labeling method called TUNEL that lets researchers identify dead cells, the researchers reported aging gene activation protected young CSC-treated cells as their aged CSC-treated counterparts, which did not express those genes, died.
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.
“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,” says Handa.
Building on their findings, Handa’s team plans on characterizing how age and continuous cigarette smoke exposure contributes to eye damage and comorbidities seen in patients with late-stage AMD.
Funding: The study was supported by the National Institutes of Health (EY033765, EY031594, EY035805, EY031594, EY036173, EY031779, EY001765, EY034571), the Research to Prevent Blindness Stein Innovation Award, and a BrightFocus Foundation macular degeneration research grant (M2020166).
Alongside co-first authors Krishna Kumar Singth and Yang Jin, additional study authors include Imran Bhutto, Seth Blackshaw, Marisol Cano, James T. Handa, Thanh Hoang, Ming-Wen Hu, Isabella Palazzo, Jiang Qian, Debasish Sinha and Shusheng Wang.
James T. Handa is on the scientific advisory boards for Character Biosciences, Cirrus Pharmaceuticals and Seeing Medicines. Seth Blackshaw is a co-founder of CDI Labs and a member of their scientific advisory board. Debasish Sinha is the chief scientific officer for Ikshana Therapeutics, Inc.
Key Questions Answered:
A: The toxins in cigarette smoke enter the bloodstream and reach the delicate tissues in the back of your eye. The study found that these toxins don’t just “damage” cells; they actually rewrite the “instruction manual” for your DNA (epigenetics), making it impossible for your eye cells to heal themselves.
A: To an extent. The study showed that young eyes have a temporary “safety net” of protective genes that kick in during smoke exposure. However, as you age, that safety net disappears. By the time you reach middle age, your eyes can no longer fight off the epigenetic stress, leading to permanent cell death.
A: Quitting stops the ongoing epigenetic assault, but the study highlights that some of these changes to your chromatin arrangement may be long-lasting. The goal of this research is to identify which changes are permanent so scientists can develop “epigenetic therapies” to unlock those repair genes once again.
Editorial Notes:
- This article was edited by a Neuroscience News editor.
- Journal paper reviewed in full.
- Additional context added by our staff.
About this AMD and visual neuroscience research news
Author: Rebekah Mikeasky
Source: JHM
Contact: Rebekah Mikeasky – JHM
Image: The image is credited to Neuroscience News
Original Research: Closed access.
“Molecular underpinnings of induced degenerative heterogeneity in the retinal pigment epithelium” by Krishna Kumar Singh, Yang Jin, Ming-Wen Hu, Isabella Palazzo, Marisol Cano, Thanh Hoang, Imran Bhutto, Shusheng Wang, Debasish Sinha, Seth Blackshaw, Jiang Qian, and James T. Handa. PNAS
DOI:10.1073/pnas.2505412123
Abstract
Molecular underpinnings of induced degenerative heterogeneity in the retinal pigment epithelium
Cigarette smoking induces epigenetic changes that can cause degenerative heterogeneity with aging and disease. In disease such as age-related macular degeneration (AMD), the leading worldwide cause of blindness among the elderly, retinal pigment epithelial (RPE) cell heterogeneity is a key change.
Since smoking is a powerful risk factor for AMD, we hypothesized that smoke induces epigenetic-mediated degenerative RPE heterogeneity.
We administered cigarette smoke condensate (CSC) to young and aged mice. Using snRNA-seq and single nuclear ATAC sequencing, we identified distinct healthy and dedifferentiated RPE clusters in both aged vehicle- and young CSC-treated mice. Dedifferentiated RPE had globally decreased chromatin accessibility and expression of genes linked to “hallmarks of aging.”
Notably, young, dedifferentiated RPE also exhibited a compensatory upregulation of hallmarks of aging-related genes including mitochondrial function and proteostasis while aged dedifferentiated RPE did not, which decreased their survival following CSC treatment, as experimentally verified with TUNEL labeling.
Similar populations of dedifferentiated and healthy RPE were identified both in mice exposed to cigarette smoke for 4 mo and in macular RPE from a donor who smoked and another with early AMD, but not from a nonsmoker donor.
Degenerative cellular heterogeneity that includes an abnormal cluster can jeopardize cell survival and represents a hallmark of ocular aging.
