2026-02-26 ジョンズ・ホプキンス大学
＜関連情報＞
- https://hub.jhu.edu/2026/02/26/cigarette-smoke-eye-aging/
- https://www.pnas.org/doi/10.1073/pnas.2505412123
網膜色素上皮における誘導変性異質性の分子基盤 Molecular underpinnings of induced degenerative heterogeneity in the retinal pigment epithelium
Krishna Kumar Singh, Yang Jin, Ming-Wen Hu, +8 , and James T. Handa
Proceedings of the National Academy of Sciences Published:January 16, 2026
DOI:https://doi.org/10.1073/pnas.2505412123
Significance
While smoking can accelerate aging through epigenetic alterations, it’s pathobiologic impact is unclear. Using single nuclear ATAC sequencing (snATAC-seq)/snRNA-seq, we report that acute smoke stress induced degenerative heterogeneity from decreased chromatin accessibility to retinal pigment epithelial (RPE) cells in young mice that was similar to age-related heterogeneity. “Hallmarks of aging” genes were decreased in the degenerative RPE cluster. Notably, young degenerative RPE exhibited induced hallmark aging genes involved in mitochondrial and proteostasis function, which unlike the aging cluster, enabled degenerative RPE to survive smoke stress. Mice exposed to chronic smoke also developed RPE heterogeneity. The relevance to human disease is suggested by similar RPE degenerative heterogeneity profiles in the macula of a smoker with and without age-related macular degeneration.
Abstract
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.
