Summary: Long established epidemiological data show smokers are about four times more likely to develop age-related macular degeneration (AMD). New research from Johns Hopkins Medicine reveals why: cigarette smoke triggers widespread epigenetic changes in the retinal pigment epithelium (RPE), altering chromatin accessibility and preventing activation of the genes required for cellular repair. These changes undermine RPE function, hasten cell death in older eyes, and help explain how smoking accelerates AMD risk.
By profiling RPE cells at high resolution, the investigators demonstrate that smoke exposure does more than produce oxidative damage. It physically reorganizes chromatin — the DNA-protein complex that determines which genes can be turned on — effectively locking away protective gene programs. Young RPE cells can temporarily engage a set of “hallmarks of aging” genes to survive acute smoke stress, but aged RPE cells lose that adaptive response and die more readily, a pattern that mirrors features of human AMD.
Key Findings
- Epigenetic interference: Cigarette smoke provokes non-permanent changes in gene expression by reducing chromatin accessibility in RPE cells, limiting the cell’s ability to activate repair and maintenance genes.
- Age-dependent protection: A distinct protective subset of aging-related genes is induced in young, stressed RPE cells but not in aged cells; loss of this protective response in older cells leads to increased cell death.
- RPE vulnerability: The RPE supports photoreceptors and maintains retinal health. Smoke-induced RPE dysfunction undermines the eye’s capacity to preserve vision.
- Targeted cellular pathways: Affected genes include those governing mitochondrial health, proteostasis (protein stability), and autophagy (cellular cleanup), processes essential for RPE survival and function.
- Cross-species relevance: The team identified 1,698 shared gene expression changes between mouse models and human donor RPE cells, supporting the translational relevance of these epigenetic alterations to human AMD.
Source: JHM
Overview: Supported by the National Institutes of Health, Johns Hopkins Medicine researchers used single-nucleus genomic technologies to trace how cigarette smoke exposure reshapes the molecular landscape of the RPE and contributes to age-related macular degeneration, a leading cause of vision loss in people over 50 worldwide.
Published in the Proceedings of the National Academy of Sciences (PNAS) on Jan. 16, 2026, the study compared RPE responses in 3-month-old and 12-month-old mice — ages approximating young adulthood and late middle age in humans — after both acute and prolonged cigarette smoke exposure. The experiments used cigarette smoke condensate (CSC) injections for acute injury and daily smoke exposure over four months for chronic exposure.
“People often assume smoking accelerates aging primarily through oxidative damage,” says James T. Handa, M.D., principal investigator and chief of the retina division at the Wilmer Eye Institute. “Our data show a complementary mechanism: smoke provokes epigenetic changes in RPE cells that broadly impair the eye’s ability to respond to stress.”
The team combined single-nucleus ATAC sequencing (snATAC-seq), which maps chromatin accessibility, with single-nucleus RNA sequencing (snRNA-seq) to examine how gene expression and chromatin state shifted in RPE cells at three, six and 10 days after CSC injection and after chronic smoke exposure. These methods revealed the emergence of dysfunctional, dedifferentiated RPE clusters characterized by reduced expression of key RPE function genes and globally decreased chromatin accessibility.
Both young and aged mice developed these dysfunctional RPE clusters after acute CSC exposure, recapitulating molecular features observed in human AMD tissue. Importantly, a separate subset of aging-related genes — those involved in mitochondrial maintenance, proteostasis, autophagy, inflammation and metabolism — were upregulated only in the dysfunctional RPE cells from young mice. Aged dysfunctional RPE failed to mount this compensatory response, and these cells were more likely to undergo cell death, as verified by TUNEL labeling.
To assess relevance to human disease, the researchers analyzed donated human RPE cells from two non-smoking donors without AMD, one smoker without AMD and one donor with early AMD. They identified 1,698 genes whose expression changed in common between dysfunctional mouse and human RPE cells, strengthening the link between smoke-induced epigenetic shifts and human AMD development.
“Recognizing that environmental stressors can suppress the gene programs needed for tissue maintenance opens a path to new questions,” Handa says. “Our next steps are to distinguish which epigenetic changes are reversible and which are persistent, and to explore therapeutic approaches that could restore access to blocked repair genes.”
The investigators plan further studies to detail how age and chronic cigarette smoke exposure drive the cellular and molecular changes that underlie advanced AMD and related vision-threatening comorbidities.
Funding: This research was funded by the National Institutes of Health (grants EY033765, EY031594, EY035805, EY036173, EY031779, EY001765, EY034571), the Research to Prevent Blindness Stein Innovation Award, and a BrightFocus Foundation macular degeneration research grant (M2020166).
Co-first authors Krishna Kumar Singh and Yang Jin led the study. Additional contributors include Imran Bhutto, Seth Blackshaw, Marisol Cano, Thanh Hoang, Ming-Wen Hu, Isabella Palazzo, Jiang Qian, Debasish Sinha and Shusheng Wang. Disclosures: James T. Handa serves on scientific advisory boards for Character Biosciences, Cirrus Pharmaceuticals and Seeing Medicines. Seth Blackshaw is a co-founder and scientific advisor of CDI Labs. Debasish Sinha is chief scientific officer for Ikshana Therapeutics, Inc.
Key Questions Answered:
A: Toxins from cigarette smoke enter the bloodstream and reach retinal tissues. This study shows they do more than cause oxidative injury: they trigger epigenetic remodeling that alters chromatin accessibility in RPE cells, preventing expression of the genes needed for maintenance and repair.
A: Partially. Young RPE cells can transiently activate protective aging-related genes in response to smoke stress, providing some resilience. That protective response weakens with age, so older eyes are less able to recover and are more prone to permanent damage.
A: Quitting removes ongoing exposure and may prevent further epigenetic insult, but some chromatin changes could be long-lasting. The study’s goal is to identify which alterations are reversible and to develop targeted epigenetic therapies that could restore access to repair genes.
Editorial Notes:
- This article was edited by a Neuroscience News editor.
- The primary journal paper was reviewed in full.
- Additional context was added by the news staff.
About this AMD and visual neuroscience research news
Author: Rebekah Mikeasky
Source: JHM
Contact: Rebekah Mikeasky – JHM
Image credit: Neuroscience News
Original Research: Closed access.
Title: Molecular underpinnings of induced degenerative heterogeneity in the retinal pigment epithelium
Citation: Singh K. K., Jin Y., Hu M.-W., et al., Proceedings of the National Academy of Sciences (PNAS), DOI: 10.1073/pnas.2505412123
Abstract
Molecular underpinnings of induced degenerative heterogeneity in the retinal pigment epithelium
Cigarette smoking induces epigenetic remodeling that contributes to degenerative heterogeneity in the retinal pigment epithelium (RPE), a hallmark of aging and diseases such as age-related macular degeneration (AMD). Given smoking’s strong association with AMD, the authors hypothesized that smoke exposure drives epigenetically mediated RPE dysfunction.
Using cigarette smoke condensate in young and aged mice, and applying single-nucleus RNA sequencing (snRNA-seq) together with single-nucleus ATAC sequencing (snATAC-seq), the study identified distinct populations of healthy and dedifferentiated RPE cells. Dedifferentiated RPE displayed globally reduced chromatin accessibility and lower expression of genes linked to core “hallmarks of aging.”
Notably, dedifferentiated RPE from young mice upregulated a compensatory set of aging-related genes tied to mitochondrial function and proteostasis, whereas aged dedifferentiated RPE did not, leaving them more vulnerable to cell death as confirmed by TUNEL labeling. Similar dedifferentiated and healthy RPE populations were found in mice after four months of cigarette smoke exposure and in macular RPE from a donor with smoking history and another donor with early AMD, but not in a nonsmoker donor.
These findings indicate that smoke-induced degenerative heterogeneity, driven by altered chromatin accessibility and disrupted aging-related gene programs, undermines RPE survival and represents a key feature of ocular aging and AMD pathogenesis.