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.

Click here to subscribe to Aging publication updates.

For media inquiries, please contact [email protected].

Dry Eyes? It May be Immune Infiltration in Aging Lacrimal Glands

In a new editorial, researchers from Baylor College of Medicine artfully discuss the immune system’s role in dry eye disease. 

The lacrimal gland, found in the upper outer part of the eye’s hollow area, is an important gland that makes tears to protect the eye from infections. It’s split into two parts: one near the inside of the eyelid that can be seen when the eyelid is flipped, and another part with ducts lower in the eye that connects to its counterpart. In their fully functioning status, these ducts release fluid onto the surface of the eye. As humans age (especially women), the lacrimal gland gradually becomes infiltrated by aberrant immune cells and can ultimately lead to an uncomfortable condition known as dry eye disease.

“Burning and redness in the eyes, grittiness and blurry vision make life miserable and currently, eye drops with a variety of lubricant components and in the most severe cases, immunosuppressors, are the only therapies approved for this disease.”

In a well-written new editorial paper, researchers Claudia M. Trujillo-Vargas and Cintia S. de Paiva from the Department of Ophthalmology at Baylor College of Medicine artfully discuss their recent studies which shed light on the immune system’s role in dry eye disease. On August 11, 2023, their editorial was published in Aging’s Volume 15, Issue 15, entitled, “Our search of immune invaders in the aged lacrimal gland.”

Editorial Summary

The authors write that their research group has been dedicated to investigating the changes that occur in the lacrimal gland due to aging and focus on immunopathological alterations. Due to limited human samples, their studies have centered on understanding the infiltration of lymphocytes, specifically B and T cells, in aged mice’s lacrimal glands. This infiltration has been linked to increased dysfunction of the ocular surface. 

“In the search of mechanisms that can counteract the effects of the overwhelming immune infiltration, we started characterizing one of the main players of immune tolerance, the thymic-derived T regulatory cells (Tregs).”

The researchers and their team have a particular interest in thymic-derived T regulatory cells (Tregs), which play a key role in immune tolerance. Paradoxically, in the aged glands, these Tregs, while exhibiting markers for their suppressive function, display heightened differentiation, infiltrate the tissue, produce inflammatory cytokines, and demonstrate impaired suppressive capabilities. When transferred to immunodeficient recipients, these dysfunctional Tregs replicate lacrimal gland pathology. 

Aged lacrimal glands contain highly differentiated CD4+ T cells of the Th1 and Th17 phenotypes, which exhibit exhaustion and immunopathological features. This environment hampers Tregs’ ability to suppress immune responses. There’s also an increase in naïve CD4+ T cells and IgD+ B cells, suggesting a unique environment for the recruitment of inexperienced immune cells in the gland.

Ectopic lymphoid structures, resembling those found in aged tissues, are observed in the lacrimal gland, potentially contributing to immune dysregulation. Despite the concept of immune cells being unwelcome invaders, the lacrimal gland relies on immune cell influx for surveillance purposes, as it is highly vascularized. Nonetheless, with age, immune cell infiltration intensifies, accompanied by fibrosis, duct issues and gland atrophy. Interestingly, antigen-presenting cells diminish, adding to the peculiar immune environment.

In their running analogy to the movie “Men in Black,” the researchers explain that they are seeking effective therapies, akin to the “noisy crickets,” to combat this pathological immune infiltration. They’re investigating differentially expressed genes in the aged gland, focusing on Tregs expressing Il1r2, CD81 and Tbx21, and B cells showing increased CD79a/b expression. The researchers are also exploring the gut microbiota’s role in ocular barrier disruption and dry eye disease in mice. This could lead to more cost-effective microbial treatments for dry eye disease in humans. However, the effectiveness of these therapies in impeding lymphocyte infiltration in aged lacrimal glands remains uncertain.

Conclusions & Future Directions

In conclusion, their editorial provides valuable insights into the role of the lacrimal gland in the immune system and how it could be used to develop new treatments for dry eyes and other age-related eye diseases. The authors’ research has shown that aged lacrimal glands are infiltrated not only by highly differentiated B but also T cells. This landscape is associated with increased ocular surface dysfunction. The authors suggest that this information could be used to develop new therapies for age-related eye diseases.

Considering the rising pollution and screen dependence in the past decade, the researchers predict an increase in severely damaged lacrimal glands in the elderly. This environment could foster the development of ectopic lymphoid structures, potentially leading to a higher prevalence of dry eye disease. As such, interventions will be required to mitigate the immune damage to the lacrimal gland. Ultimately, protecting the lacrimal glands from the consequences of immune dysregulation is a critical goal.

“Unquestionably, more than ‘fancy sunglasses’ would be needed to hinder the ‘carbonizing’ immune damage in the gland. Thus, Yes! We certainly need to protect our lacrimal glands from the scum of our own immune universe!”

Click here to read the full editorial published in Aging.

Aging is an open-access, traditional, peer-reviewed journal that has published high-impact papers in all fields of aging research since 2009. All papers are available to readers (at no cost and free of subscription barriers) in bi-monthly issues at Aging-US.com.

Click here to subscribe to Aging publication updates.

For media inquiries, please contact [email protected].

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