UV-A Exposure, Cellular Senescence, and Vision Impairment

In this new study, researchers investigated the senescent phenotypes of human corneal endothelial cells upon UV-A exposure.

With an ever-increasing global population grappling with age-related ocular ailments like cataracts, dry eyes, glaucoma, and macular degeneration, the need for new research in this domain is more pressing than ever. 

In a new study, researchers Kohsaku Numa, Sandip Kumar Patel, Zhixin A. Zhang, Jordan B. Burton, Akifumi Matsumoto, Jun-Wei B. Hughes, Chie Sotozono, Birgit Schilling, Pierre-Yves Desprez, Judith Campisi (1948-2024), and Koji Kitazawa from the Buck Institute for Research on Aging, Kyoto Prefectural University of Medicine, University of Cambridge, and California Pacific Medical Center shed light on a pivotal aspect of corneal health – the impact of ultraviolet-A (UV-A) radiation on corneal endothelial cells. Their research paper was published on the cover of Aging’s Volume 16, Issue 8, entitled, “Senescent characteristics of human corneal endothelial cells upon ultraviolet-A exposure.”

“The objective of this study was to investigate the senescent phenotypes of human corneal endothelial cells (hCEnCs) upon treatment with ultraviolet (UV)-A.”

Corneal Health & Cellular Senescence

The cornea, a transparent tissue responsible for refracting incoming light onto the retina, plays a crucial role in our visual acuity. Its transparency is maintained by a single layer of cells called corneal endothelial cells (CEnCs), which cover the posterior surface. However, these cells possess a limited capacity for proliferation, rendering them susceptible to pathological cell loss, potentially leading to corneal endothelial dysfunction and, ultimately, visual impairment or blindness.

Current treatments for CEnC dysfunction include corneal endothelial transplantation using donor corneas and cell injection therapy utilizing cultured human CEnCs (hCEnCs). Nonetheless, pathological CEnC loss persists even after successful interventions, culminating in graft failure. To combat this, researchers have delved into the intricate mechanisms underlying hCEnCs loss, uncovering a potential link between corneal endothelial disease and cellular senescence.

While cellular senescence acts as a natural defense mechanism against uncontrolled cell proliferation, the accumulation of senescent cells can exacerbate pathological conditions and contribute to various age-related etiologies. Notably, senescent cells acquire an inflammatory phenotype known as the senescence-associated secretory phenotype (SASP), which can adversely alter the surrounding microenvironment over time.

The Study

In the current study, the researchers exposed hCEnCs to varying doses of UV-A radiation, ranging from 0 J/cm2 (mock) to 20 J/cm2. Cells treated with 10 Gy of ionizing radiation (IR) served as positive controls for senescence induction.

“UV-A accounts for about 90% of the UV radiation reaching the earth’s surface and is known to induce ROS causing oxidative stress [34]. Oxidative stress causes molecular alternation, leading to cellular senescence [35]. Observations of UV-A intensity suggest that exposure to 5 J/cm2 of UV-A is roughly equivalent to one hour of noonday sun exposure during the summer [34].”

Through a meticulous analysis of cell morphology, senescence-associated β-galactosidase (SA-β-gal) activity, cell proliferation, and expression of senescence markers (p16 and p21), the team identified that hCEnCs exposed to 5 J/cm2 of UV-A exhibited typical senescent phenotypes, including enlargement, increased SA-β-gal activity, decreased cell proliferation, and elevated expression of p16 and p21. The researchers employed RNA sequencing (RNA-Seq) and proteomics analysis to gain a comprehensive understanding of the senescence response in hCEnCs. 


RNA-Seq analysis revealed a significant overlap in the pathways modulated by UV-A and IR-induced senescence. Upregulated genes were enriched in pathways associated with extracellular matrix (ECM) organization, cellular component movement, response to cytokines, cell migration, and motility – processes intimately linked to corneal endothelial diseases.

Interestingly, while the number of significantly up- or down-regulated genes differed between UV-A and IR exposure, the proteomics analysis revealed a much smaller disparity in the number of altered proteins, suggesting that UV-A might be a more physiologically relevant method for inducing cellular senescence in hCEnCs. The proteomics analysis unveiled a wealth of information regarding the SASP of UV-A-induced senescent hCEnCs. Key SASP components, including STC1, GDF15, C7, C9, SERPINE2, and PDGFA, were identified among the top 40 secreted proteins.

The researchers also detected elevated levels of CXCL1, CXCL8, MMP2, COL6A2, COL8A1, COL12A1, and other proteins previously reported as SASP factors in various cell types. Notably, proteins associated with glycolysis, such as SLC2A1, GPI, ENO1, PKM, TPI1, and LDH, were also found to be significantly upregulated.

Conclusions & Future Directions

“Here, we showed that cellular senescence is induced in hCEnCs upon UV-A irradiation and conducted comprehensive analyses of RNA and protein expression.”

This study not only sheds light on the senescent characteristics of hCEnCs upon UV-A exposure but also highlights the potential role of cellular senescence in the pathogenesis of corneal endothelial diseases. By identifying the overlapping pathways and SASP factors modulated by both UV-A and IR-induced senescence, the researchers have paved the way for a deeper understanding of the molecular mechanisms underlying CEnC dysfunction.

Furthermore, the identification of specific proteins associated with corneal endothelial diseases, such as TGFBI, TGFB1, TGFB2, LOXL1, LOXL2, and complement factors, provides valuable insights into potential therapeutic targets and biomarkers for early detection and intervention.

As the research community continues to unravel the enigma of cellular senescence and its implications in ocular health, this study stands as a testament to the power of multidisciplinary approaches and cutting-edge techniques in advancing our understanding of age-related vision impairment.

Click here to read the full research paper published in Aging.

Aging is an open-access, traditional, peer-reviewed journal that publishes high-impact papers in all fields of aging research. All papers are available to readers (at no cost and free of subscription barriers) in bi-monthly issues at Aging-US.com.

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Common Age-Related Changes in Eye Lenses

In this 2019 study, researchers examined murine models to determine common age-related eye lens changes that contribute to eventual vision impairment and loss.

(Truncated) Figure 7. Whole lens staining for F-actin (phalloidin, green) and nuclei (DAPI, red) in 4-month-old and 18-month-old lenses.
Figure 7. Whole lens staining for F-actin (phalloidin, green) and nuclei (DAPI, red) in 4-month-old and 18-month-old lenses. (Truncated)
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A variety of eye disorders can occur as humans age, including age-related macular degeneration, cataracts, presbyopia, glaucomadry eyes, and temporal arteritis. These conditions can contribute to vision impairment and even vision loss. Unfortunately, the full gambit of common age-related eye lens changes which contribute to these disorders is not yet fully defined. However, while mice and primates are different species, their eye lenses share common characteristics. This means that studies in murine models regarding age-related eye lens changes may provide a baseline for aging studies on human eye lenses in the future. 

“Little is known about the morphological, mechanical, refractive and cellular changes that occur with advanced age in the lens. Mice offer an opportunity to investigate changes in lens morphometrics, stiffness, transparency and refractive properties with age in a relatively shortened period of time.”

To further define common age-related changes in eye lenses, researchers—from The Scripps Research InstituteUniversity of DelawareMorehouse School of MedicineNottingham Trent UniversityJapan Synchrotron Radiation Research Institute, and Boston University School of Medicine—conducted an extensive study of eye lenses among mice between one and 30 months of age. Their paper was published by Aging (Aging-US) in 2019, and entitled, “Age-related changes in eye lens biomechanics, morphology, refractive index and transparency.”

The Study

In this study, the researchers measured the size, refractive index (Gradient Refractive Index, GRIN) and stiffness of mouse lenses in young adult mice, starting at one and two months old, to very old mice of 24 to 30 months old. The team examined mechanisms of age-related cataracts, cell morphology in aged lenses, increased lens stiffness with age, and lens resilience. Methods used in this study include: lens biomechanical testing and morphometrics, live lens imaging, capsule thickness and fiber cell width measurements, phalloidin-staining of epithelial cells in whole lenses, scanning electron microscopy, transmission electron microscopy, and X-ray talbot interferometry. 

The researchers found that, with age, mouse eye lenses increased in size, nuclear fraction, stiffness, and resilience. After four months of age, lens capsule thickness and fiber cell width did not increase, but epithelial cell area increased slightly with age. In the lenses of mice older than 12 months, the researchers observed anterior cataracts, cortical haziness and ring cataracts. They found that the anterior cataracts were due to incomplete suture closure and detachment of anterior epithelial cells from the underlying fiber cells. The ring cataracts were linked to abnormal compaction of differentiating fiber cells. The hexagonal packing of fiber cells was shown to be disrupted with age. Lastly, the researchers observed that the gradient refractive index increased and then plateaued with age.

“Our comprehensive study of aging in wild-type mouse lenses in the B6 genetic background showed increased stiffness along with appearance of anterior, cortical and ring cataracts with age (Figure 14).”


Overall, the researchers demonstrate that age-related changes in mouse lenses mimic some aspects of aging in human lenses. Aside from the obvious study limitations (mouse-to-human translation), the data collected from this study provide a comprehensive overview of age-related changes in murine lenses, including lens size, stiffness, nuclear fraction, refractive index, transparency, capsule thickness, and cell structure.

“Whether there is a common molecular mechanism that drives changes in all the measured parameters remains unknown, but further biochemical and cell morphology studies will be needed to determine how subcellular aging affects the whole tissue.”

Click here to read the full research paper published by Aging (Aging-US).

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Aging (Aging-US) is an open-access journal that publishes research papers bi-monthly in all fields of aging research and other topics. These papers are available to read at no cost to readers on Aging-us.com. Open-access journals offer information that has the potential to benefit our societies from the inside out and may be shared with friends, neighbors, colleagues, and other researchers, far and wide.

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